Clinical trial NCT04017832
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2019-07-29; Completion date: 2021-10-27
Enrollment: 1441 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study compares 2 medicines for type 2 diabetes: oral semaglutide (a new medicine) and sitagliptin (a medicine doctors can already prescribe). Participants will either get oral semaglutide or sitagliptin - which treatment is decided by chance. Participants will get 2 tablets a day to take first thing in the morning on an empty stomach. Only 1 tablet has study medicine in it. The other tablet is a dummy medicine (placebo). After taking the semaglutide tablet, participants may not eat or drink anything for at least 30 minutes. After the 30 minutes, participants must take the sitagliptin tablet. Then participants can have their first meal of the day and take any other medicines they may need, including their metformin. The study will last for about 7 months (33 weeks). Participants will have 8 clinic visits and 1 phone call with the study doctor. At all 8 of the clinic visits, participants will have blood samples taken.

Detailed description:

Arms: arm 1: Oral semaglutide tablets 3 mg and sitagliptin placebo tablets for 26 weeks arm 2: Oral semaglutide tablets and sitagliptin placebo tablets. The dose of oral semaglutide will be escalated over 4 weeks, after which the target dose of 7 mg is taken for 22 weeks arm 3: Oral semaglutide tablets and sitagliptin placebo tablets. The dose of oral semaglutide will be escalated over 8 weeks, after which the target dose of 14 mg is taken for 18 weeks arm 4: Sitagliptin tablets and oral semaglutide placebo tablets for 26 weeks
Interventions: intervention 1: Oral semaglutide intervention 2: Sitagliptin intervention 3: Placebo (oral semaglutide) intervention 4: Placebo (sitagliptin)
Intervention descriptions: intervention 1: Oral semaglutide to be taken every morning in a fasting state, to be followed by sitagliptin placebo after 30 minutes. Only then participants can have their first meal of the day and their pre-study metformin tablets intervention 2: Sitagliptin to be taken every morning, 30 minutes after taking the oral semaglutide placebo tablet. Then participants can have their first meal of the day and their pre-study metformin tablets intervention 3: Placebo tablet to be taken first thing in the morning intervention 4: Placebo tablet to be taken 30 minutes after oral semaglutide

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04017832 
Sponsor trial ID: 
NN9924-4309 
Official title of study: 
PIONEER 12 China multi-regional clinical trial: Efficacy and 
safety of oral semaglutide versus sitagliptin in subjects with 
type 2 diabetes mellitus treated with metformin 
Document date*: 
28 January 2019 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content. 


Link
Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Appendix A .........................................................................................................................................
Appendix B..........................................................................................................................................
Appendix C .........................................................................................................................................
Attachment I and II............................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924 4309 (PIONEER 12)
Clinical Trial Report
Appendix 16.1.1
11 February 2022
1.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


 
Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38 
Page: 
1 of 120 
 
Protocol 
Updated protocol including: 
Protocol Final version 1.0, dated 31 January 2017 
Protocol Amendment  no. 1, Final version 1.0, dated 31 August 2018 
Protocol Amendment no. 2. Final version 3.0, dated 15 January 2019 
Trial ID: NN9924-4309 
PIONEER 12 China multi-regional clinical trial: Efficacy and safety 
of oral semaglutide versus sitagliptin in subjects with type 2 diabetes 
mellitus treated with metformin 
Trial phase: 3a 
Protocol originator 
 
Trial Operations, Semaglutide Diabetes & Diabetes Outcome 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
. 


 
Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38 
Page: 
2 of 120 
 
Table of contents 
Page 
Table of contents ............................................................................................................................................... 2 
Table of figures ................................................................................................................................................. 6 
Table of tables ................................................................................................................................................... 6 
List of abbreviations ......................................................................................................................................... 8 
1 
Summary .................................................................................................................................................. 10 
2 
Flow chart ................................................................................................................................................ 13 
3 
Background information and rationale for the trial ............................................................................ 17 
3.1 
Background information .............................................................................................................. 17 
3.1.1 
Type 2 diabetes mellitus ............................................................................................ 17 
3.1.2 
Glucagon-like peptide-1 ............................................................................................ 17 
3.1.3 
Oral semaglutide ........................................................................................................ 17 
3.1.4 
Non-clinical data ........................................................................................................ 18 
3.1.4.1 
Semaglutide ......................................................................................... 18 
3.1.4.2 
SNAC .................................................................................................. 19 
3.1.5 
Clinical data for oral semaglutide .............................................................................. 20 
3.1.5.1 
Pharmacokinetics ................................................................................ 20 
3.1.5.2 
Efficacy ............................................................................................... 21 
3.1.5.3 
Safety ................................................................................................... 21 
3.1.6 
Sitagliptin ................................................................................................................... 22 
3.2 
Rationale for the trial ................................................................................................................... 22 
4 
Objectives and endpoints ........................................................................................................................ 23 
4.1 
Objectives .................................................................................................................................... 23 
4.1.1 
Primary objective ....................................................................................................... 23 
4.1.2 
Secondary objectives ................................................................................................. 23 
4.2 
Endpoints ..................................................................................................................................... 23 
4.2.1 
Primary endpoint ........................................................................................................ 23 
4.2.2 
Secondary endpoints .................................................................................................. 23 
4.2.2.1 
Confirmatory secondary endpoints ..................................................... 23 
4.2.2.2 
Supportive secondary endpoints .......................................................... 23 
5 
Trial design .............................................................................................................................................. 25 
5.1 
Type of trial ................................................................................................................................. 25 
5.2 
Rationale for trial design .............................................................................................................. 25 
5.3 
Treatment of subjects ................................................................................................................... 26 
5.3.1 
Dosing instructions .................................................................................................... 27 
5.3.2 
Background medication ............................................................................................. 27 
5.4 
Treatment after discontinuation of trial product .......................................................................... 28 
5.5 
Rationale for treatment ................................................................................................................ 28 
6 
Trial population ....................................................................................................................................... 29 
6.1 
Number of subjects ...................................................................................................................... 29 
6.2 
Inclusion criteria .......................................................................................................................... 29 
6.3 
Exclusion criteria ......................................................................................................................... 29 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38 
Page: 
3 of 120 
 
6.4 
Rescue criteria .............................................................................................................................. 31 
6.5 
Criteria for premature discontinuation of trial product ................................................................ 31 
6.6 
Withdrawal from trial .................................................................................................................. 32 
6.7 
Subject replacement ..................................................................................................................... 32 
6.8 
Rationale for trial population ....................................................................................................... 32 
7 
Milestones................................................................................................................................................. 34 
8 
Methods and assessments ....................................................................................................................... 35 
8.1 
Visit procedures ........................................................................................................................... 35 
8.1.1 
Screening, visit 1 ........................................................................................................ 35 
8.1.2 
Fasting visits .............................................................................................................. 36 
8.1.3 
Randomisation and trial product administration ........................................................ 36 
8.1.4 
End-of-treatment (visit 8) and Follow-up (visit 9)..................................................... 37 
8.1.5 
Premature discontinuation of trial product and follow-up (visits 8A and 9A) .......... 37 
8.1.6 
Withdrawal................................................................................................................. 38 
8.1.6.1 
Lost to follow-up ................................................................................. 38 
8.1.7 
Investigator assessments ............................................................................................ 39 
8.2 
Subject related information/assessments ..................................................................................... 39 
8.2.1 
Demography............................................................................................................... 39 
8.2.2 
Diabetes history and diabetes complications ............................................................. 40 
8.2.3 
Concomitant illness and medical history ................................................................... 40 
8.2.4 
Concomitant medication ............................................................................................ 41 
8.2.5 
Childbearing potential ................................................................................................ 41 
8.2.6 
Tobacco use ............................................................................................................... 41 
8.3 
Efficacy assessments .................................................................................................................... 42 
8.3.1 
Laboratory assessments for efficacy .......................................................................... 42 
8.3.2 
Self-measured plasma glucose (SMPG) .................................................................... 42 
8.3.2.1 
7-point self-measured plasma glucose profile ..................................... 43 
8.3.3 
Body weight and height ............................................................................................. 43 
8.3.4 
Waist circumference .................................................................................................. 43 
8.3.5 
Patient-reported outcome questionnaire .................................................................... 44 
8.3.6 
Adverse events ........................................................................................................... 44 
8.3.6.1 
Adverse events requiring additional data collection ........................... 44 
8.3.7 
Physical examination ................................................................................................. 45 
8.3.8 
Vital signs .................................................................................................................. 46 
8.3.9 
Eye examination ........................................................................................................ 46 
8.3.10 
Electrocardiogram (12-lead) ...................................................................................... 47 
8.3.11 
Laboratory assessments for safety ............................................................................. 47 
8.3.12 
Pregnancy testing ....................................................................................................... 48 
8.3.13 
Hypoglycaemic episodes ........................................................................................... 48 
8.4 
Laboratory assessments ............................................................................................................... 51 
8.5 
Other assessments ........................................................................................................................ 51 
8.5.1 
Subject diary .............................................................................................................. 51 
8.6 
Subject compliance ...................................................................................................................... 52 
9 
Trial supplies ........................................................................................................................................... 53 
9.1 
Trial products ............................................................................................................................... 53 
9.2 
Labelling ...................................................................................................................................... 54 
9.3 
Storage ......................................................................................................................................... 54 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
4 of 120 
 
 
9.4 
Drug accountability and destruction ............................................................................................ 54 
9.5 
Auxiliary supplies ........................................................................................................................ 55 
10 Interactive voice/web response system .................................................................................................. 56 
11 Randomisation procedure and breaking of blinded codes .................................................................. 57 
11.1 
Breaking of blinded codes ........................................................................................................... 57 
12 Adverse events, technical complaints and pregnancies ....................................................................... 58 
12.1 
Definitions ................................................................................................................................... 58 
12.1.1 
Adverse event ............................................................................................................ 58 
12.1.2 
Serious adverse event ................................................................................................. 59 
12.1.3 
Non-serious adverse event ......................................................................................... 60 
12.1.4 
Medication errors ....................................................................................................... 60 
12.1.4.1 
Misuse or abuse of trial product .......................................................... 61 
12.1.5 
Adverse events requiring additional data collection .................................................. 61 
12.1.6 
Technical complaints ................................................................................................. 62 
12.2 
Reporting of adverse events ......................................................................................................... 63 
12.3 
Follow-up of adverse events ........................................................................................................ 66 
12.4 
Technical complaints and technical complaint samples .............................................................. 67 
12.4.1 
Reporting of technical complaints ............................................................................. 67 
12.4.2 
Collection, storage and shipment of technical complaint samples ............................ 68 
12.5 
Pregnancies in female subjects .................................................................................................... 68 
12.6 
Precautions and/or overdose ........................................................................................................ 69 
12.7 
Committees related to safety ........................................................................................................ 70 
12.7.1 
Novo Nordisk safety committee ................................................................................ 70 
12.7.2 
Event adjudication committee .................................................................................... 70 
13 Case report forms .................................................................................................................................... 75 
13.1 
Corrections to case report forms .................................................................................................. 75 
13.2 
Case report form flow .................................................................................................................. 76 
14 Monitoring procedures ........................................................................................................................... 77 
15 Data management .................................................................................................................................... 79 
16 Computerised systems............................................................................................................................. 80 
17 Statistical considerations ........................................................................................................................ 81 
17.1 
Sample size calculation ................................................................................................................ 83 
17.2 
Primary endpoint .......................................................................................................................... 89 
17.2.1 
Primary analysis for the primary estimand ................................................................ 89 
17.2.2 
Primary analysis for the secondary estimand ............................................................. 89 
17.2.3 
Sensitivity analyses .................................................................................................... 90 
17.2.3.1 
Other sensitivity analyses .................................................................... 91 
17.2.4 
Chinese subgroup analyses ........................................................................................ 91 
17.3 
Secondary endpoints .................................................................................................................... 91 
17.3.1 
Confirmatory secondary endpoints ............................................................................ 91 
17.3.2 
Supportive secondary endpoints ................................................................................ 92 
17.3.2.1 
Efficacy endpoints ............................................................................... 92 
17.3.2.2 
Safety endpoints .................................................................................. 95 
17.4 
Interim analysis ............................................................................................................................ 98 
17.5 
Patient-reported outcomes ........................................................................................................... 99 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
5 of 120 
 
 
17.5.1 
SF-36v2® (acute version) health survey ................................................................ 99 
17.5.2 
Responder analyses ................................................................................................ 101 
18 Ethics ...................................................................................................................................................... 102 
18.1 
Benefit-risk assessment of the trial ............................................................................................ 102 
18.1.1 
Risks and precautions .............................................................................................. 102 
18.1.1.1 
Oral semaglutide ............................................................................... 102 
18.1.1.2 
Sitagliptin .......................................................................................... 105 
18.1.2 
Benefits .................................................................................................................... 105 
18.1.3 
Risk and benefit conclusion ..................................................................................... 105 
18.2 
Informed consent ....................................................................................................................... 106 
18.3 
Data handling ............................................................................................................................. 106 
18.4 
Information to subjects during trial ............................................................................................ 107 
18.5 
Premature termination of the trial and/or trial site ..................................................................... 107 
19 Protocol compliance .............................................................................................................................. 108 
19.1 
Protocol deviations .................................................................................................................... 108 
19.2 
Prevention of missing data ......................................................................................................... 108 
20 Audits and inspections .......................................................................................................................... 109 
21 Critical documents ................................................................................................................................ 110 
22 Responsibilities ...................................................................................................................................... 111 
23 Reports and publications ...................................................................................................................... 112 
23.1 
Communication of results .......................................................................................................... 112 
23.1.1 
Authorship ............................................................................................................... 113 
23.1.2 
Site-specific publication(s) by investigator(s) ......................................................... 113 
23.2 
Investigator access to data and review of results ....................................................................... 113 
24 Retention of clinical trial documentation and human biosamples .................................................... 114 
24.1 
Retention of clinical trial documentation ................................................................................... 114 
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities ............ 115 
26 Indemnity statement ............................................................................................................................. 116 
27 References .............................................................................................................................................. 117 
 
Appendix A  
Calcitonin monitoring 
Appendix B 
 
Adverse events requiring additional data collection 
Appendix C 
 
Contraceptive guidance and collection of pregnancy information  
Attachment I   
Global list of key staff and relevant departments and suppliers 
Attachment II   
Country list of key staff and relevant departments 
 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
6 of 120 
 
 
Table of figures  
 
Page 
Figure 5–1 
Trial Design ............................................................................................................................ 25 
Figure 12–1 
Reporting of adverse events .................................................................................................... 65 
Figure 17–1 
Graphical illustration of the closed testing procedure ............................................................ 85 
Figure 17–2 
ADA classification of hypoglycaemia .................................................................................... 98 
 
Table of tables 
 
Page 
Table 5–1 
Overview – treatment of subjects ........................................................................................... 27 
Table 9–1 
Trial Products ......................................................................................................................... 53 
Table 12–1 
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................ 61 
Table 12–2 
Adverse events for adjudication ............................................................................................. 72 
Table 17–1 
Assumptions for sample size calculation ................................................................................ 84 
Table 17–2 
Calculated powers for individual hypotheses ......................................................................... 84 
Table 5–1 
Overview – treatment of subjects ........................................................................................... 27 
Table 9–1 
Trial Products ......................................................................................................................... 53 
Table 12–1 
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................ 61 
Table 12–2 
Adverse events for adjudication ............................................................................................. 72 
Table 17–1 
Assumptions for sample size calculation ................................................................................ 84 
Table 17–2 
Calculated powers for individual hypotheses ......................................................................... 84 
Table 5–1 
Overview – treatment of subjects ........................................................................................... 27 
Table 9–1 
Trial Products ......................................................................................................................... 53 
Table 12–1 
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................ 61 
Table 12–2 
Adverse events for adjudication ............................................................................................. 72 
Table 17–1 
Assumptions for sample size calculation ................................................................................ 84 
Table 17–2 
Calculated powers for individual hypotheses ......................................................................... 84 
Table 5–1 
Overview – treatment of subjects ........................................................................................... 27 
Table 9–1 
Trial Products ......................................................................................................................... 53 
Table 12–1 
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................ 61 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
7 of 120 
 
 
Table 12–2 
Adverse events for adjudication ............................................................................................. 72 
Table 17–1 
Assumptions for sample size calculation ................................................................................ 84 
Table 17–2 
Calculated powers for individual hypotheses ......................................................................... 84 
Table 5–1 
Overview – treatment of subjects ........................................................................................... 27 
Table 9–1 
Trial Products ......................................................................................................................... 53 
Table 12–1 
Adverse events requiring completion of specific event forms and/or are subject to event 
adjudication ............................................................................................................................ 61 
Table 12–2 
Adverse events for adjudication ............................................................................................. 72 
Table 17–1 
Assumptions for sample size calculation ................................................................................ 84 
Table 17–2 
Calculated powers for individual hypotheses ......................................................................... 84 
 
 
 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
8 of 120 
 
 
List of abbreviations 
AACE 
American Association of Clinical Endocrinologists 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BG 
blood glucose 
BMI 
body mass index 
CK 
creatine kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum concentration 
CRF 
case report form 
CTR 
clinical trial report 
DPP-4 
dipeptidyl peptidase-4 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EOT 
end-of-treatment 
FAS 
full analysis set 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 
GI 
gastrointestinal  
GLP-1 
glucagon-like peptide-1 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
HbA1c 
glycosylated haemoglobin 
HDL 
high-density lipoprotein 
IB 
Investigator’s brochure 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
9 of 120 
 
 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
independent ethics committee 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDL 
low-density lipoprotein 
MAR 
missing at random 
MI 
myocardial infarction 
MMRM 
mixed model for repeated measurements 
NYHA 
New York Heart Association 
OAD 
oral antidiabetic drug 
PG 
plasma glucose 
PIONEER 
Peptide InnOvatioN for Early diabEtes tReatment 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
SAS 
safety analysis set 
s.c. 
subcutaneous(ly) 
SIF 
safety information form 
SmPC 
summary of product characteristics 
SMPG 
self-measured plasma glucose 
SNAC 
sodium N-[8-(2-hydroxybenzoyl) amino]caprylate 
SUSAR 
suspected unexpected serious adverse reaction 
T2D 
type 2 diabetes mellitus 
TE 
treatment effects 
TEAE 
treatment-emergent adverse event 
tmax 
time to reach maximum observed concentration 
ULN 
upper limit of the normal 
UTN 
Universal Trial Number 
VLDL 
very-low-density lipoprotein 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
10 of 120 
 
 
1 
Summary 
Objectives and endpoints: 
Primary objective 
To compare the effect of three once-daily dose levels of oral semaglutide (3, 7 and 14 mg) versus 
sitagliptin 100 mg once-daily, both in combination with metformin, on glycaemic control in 
subjects with type 2 diabetes mellitus (T2D). 
Secondary objectives 
To compare the effect of three once-daily dose levels of oral semaglutide (3, 7 and 14 mg) versus 
sitagliptin 100 mg once-daily, both in combination with metformin, on body weight in subjects with 
T2D. 
To compare the safety and tolerability of three once-daily dose levels of oral semaglutide (3, 7 and 
14 mg) versus sitagliptin 100 mg once-daily, both in combination with metformin, in subjects with 
T2D. 
Primary endpoint 
Change from baseline to week 26 in HbA1c 
Key secondary endpoints 
• Change from baseline to week 26 in body weight (kg) 
• Change from baseline to week 26 in fasting plasma glucose 
• If a subject after week 26 achieves (yes/no) HbA1c < 7.0 % (53 mmol/mol) (American Diabetes 
Association target)  
• Number of treatment-emergent adverse events during exposure to trial product, assessed up to 
approximately 31 weeks  
• Number of treatment-emergent severe or blood glucose confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 31 weeks  
Trial design: 
This is a 26-week, randomised, double-blinded, double-dummy, active-controlled, four-armed, 
parallel-group, multicentre, multinational trial comparing the efficacy and safety of three once-daily 
dose levels of oral semaglutide versus sitagliptin once-daily in subjects with T2D inadequately 
controlled on metformin. 
Trial population: 
Number of subjects planned to be randomised: 1444 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
11 of 120 
 
 
Inclusion criteria: 
• 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. 
• Male or female, age above or equal to 18 years at the time of signing informed consent. 
For Algeria only: Male or female, age above or equal to 19 years at the time of signing 
informed consent.  
For Taiwan only: Male or female, age above or equal to 20 years at the time of signing 
informed consent 
• Diagnosed with type 2 diabetes mellitus ≥ 60 days prior to day of screening. 
• HbA1c between 7.0-10.5% (53-91 mmol/mol) (both inclusive). 
• Stable daily dose of metformin (≥ 1500 mg or maximum tolerated dose as documented in the 
subject medical record) ≥ 60 days prior to day of screening 
Key exclusion criteria: 
• 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 (adequate contraceptive 
measure as required by local regulation or practice). 
• Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid 
carcinoma (MTC). Family is defined as a first degree relative.  
• History or presence of pancreatitis (acute or chronic). 
• History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).  
• Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.  
• Subjects presently classified as being in New York Heart Association (NYHA) Class IV. 
• Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.  
• Renal impairment measured as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 
as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI).  
• Subjects with alanine aminotransferase (ALT) > 2.5 x upper limit of the normal (ULN). 
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a 
pharmacologically pupil-dilated fundus examination performed by an ophthalmologist or 
another suitably qualified health care provider within the past 90 days prior to screening or in 
the period between screening and randomisation. Fundus examination without dilation is only 
allowed if the digital camera used for fundus photography has this feature. 
• Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. 
Basal and squamous cell skin cancer and any carcinoma in-situ is allowed. 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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Key assessments: 
Efficacy: 
• HbA1c 
• Body weight 
• Fasting plasma glucose 
Safety 
• Adverse events 
• Hypoglycaemic episodes 
Trial product(s): 
Investigational medicinal products: 
• Test product: 
- 
Semaglutide 3 mg, 7 mg and 14 mg tablets 
• Reference therapy:  
- 
Semaglutide placebo tablet 
- 
Sitagliptin (Januvia®), 100 mg tablet 
- 
Sitagliptin (Januvia®) placebo tablet 
  
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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3 
Background information and rationale for the trial 
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2. 
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site. 
3.1 
Background information 
For an assessment of benefits and risks of the trial, see Section 18.1 
3.1.1 
Type 2 diabetes mellitus  
Type 2 diabetes mellitus (T2D) is a progressive metabolic disease primarily characterised by 
abnormal glucose metabolism. The pathogenesis is heterogeneous involving environmental, 
lifestyle and genetic factors leading to chronic hyperglycaemia caused by peripheral tissue insulin 
resistance, impaired insulin secretion due to abnormal beta-cell function and abnormal glucose 
metabolism in the liver3. 
Optimal glycaemic control is the treatment goal in subjects with T2D in order to prevent long-term 
complications associated with chronic hyperglycaemia3. Despite the availability of several 
antidiabetic drugs, a significant proportion of subjects with T2D do not achieve the recommended 
targets for glycaemic control4,5. 
3.1.2 
Glucagon-like peptide-1 
Glucagon-like peptide-1 (GLP-1) is an incretin hormone with a glucose-dependent stimulatory 
effect on insulin and inhibitory effect on glucagon secretion from the pancreatic islets6,7. Subjects 
with T2D have a decreased incretin effect8, 9. However, the insulinotropic action of GLP-1 and thus, 
the ability to lower blood glucose (BG) levels, is preserved when GLP-1 is administered at 
supraphysiological levels10. In addition, supraphysiological levels of GLP-1 induce reduction in 
body weight11. GLP-1 is a physiological regulator of appetite and food intake and GLP-1 receptors 
are present in several areas of the brain involved in appetite regulation12,13. Physiologically, GLP-1 
also has a pronounced inhibitory effect on gastric emptying; however this effect seems to diminish 
upon chronic exposure11,13. These mechanisms of action make GLP-1 receptor agonists (GLP-1 
RA) an attractive pharmacological treatment for T2D14,15. 
3.1.3 
Oral semaglutide 
Semaglutide is a long-acting GLP-1 RA structurally similar to liraglutide (Victoza®), a once-daily 
GLP-1 RA developed by Novo Nordisk and approved worldwide for the treatment of T2D. 
Compared to human native GLP-1, which has a short half-life, the semaglutide molecule has three 
minor but important modifications ensuring protraction of its action: amino acid substitutions at 
position 8 (alanine to alpha-aminoisobutyric acid, a synthetic amino acid) and position 34 (lysine to 
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Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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arginine) and acylation of the peptide backbone with a spacer and C-18 fatty di-acid chain to lysine 
in position 2616. The fatty di-acid side chain and the spacer mediate strong binding to albumin, 
thereby reducing renal clearance. The amino acid substitution at position 8 makes semaglutide less 
susceptible to degradation by dipeptidyl peptidase-4 (DPP-4). The change in position 34 from a 
lysine to an arginine is included to have only one lysine in the sequence whereto a spacer can be 
attached. 
Semaglutide is in development for oral once-daily treatment of T2D. As the bioavailability of GLP-
1 RAs is low when administered orally, semaglutide has been co-formulated with the absorption-
enhancing excipient sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) to increase the 
bioavailability of semaglutide. The absorption-enhancing properties of SNAC co-formulation are 
based on the Eligen® Carrier concept developed by Emisphere Technologies Inc. 
SNAC facilitates the absorption of semaglutide in a strictly time and size dependent manner, 
primarily via the transcellular route. The available data for semaglutide co-formulated with SNAC 
support that the absorption takes place in the stomach in a localised, buffered environment in close 
proximity to the tablet erosion. The absorption process is hampered if dosed with food, liquid or in 
the presence of significant stomach content.  
The absorption enhancement requires co-formulation between semaglutide and SNAC. Throughout 
this document “oral semaglutide” will refer to the drug product, that is, semaglutide co-formulated 
with 300 mg SNAC.  
3.1.4 
Non-clinical data 
3.1.4.1 
Semaglutide 
The non-clinical programme for semaglutide was designed according to the ICH M3 guideline to 
support the clinical development17. The standard non-clinical data package required to support 
phase 3 clinical trials has been completed. In addition, 2-year carcinogenicity studies and a pre- and 
postnatal development toxicity study have been completed. Semaglutide was generally well 
tolerated in animals (mice, rats and cynomolgus monkeys). Two potential safety issues have been 
identified and these are detailed below. 
Thyroid C-cell tumours in rodents 
Treatment-related non-genotoxic proliferative changes in the thyroid C-cells of mice and rats were 
observed in 2-year carcinogenicity studies with semaglutide; thyroid hyperplasia was preceded by 
an increase in serum calcitonin. C-cell changes have not been observed in long-term studies in non-
human primate. The observed pattern of effects in mice and rats and lack of these effects in the non-
human primate and in man suggest that the mechanism by which semaglutide acts on the thyroid C-
cells in rodents is the same as has been demonstrated for other GLP-1 RAs, including liraglutide. 
According to this mechanism, C-cell hyperplasia is mediated by the GLP-1 receptor and is not 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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associated with RET (re-arranged during transfection) gene activation and rodents appear to be 
particularly sensitive, whereas humans are not. The relevance for human subjects is currently 
unknown, but considered to be low18. 
Embryo−foetal development toxicity 
Semaglutide caused embryo-foetal development toxicity in the rat through a GLP-1 receptor 
mediated effect on the inverted yolk sac placenta leading to impaired nutrient supply to the 
developing embryo. Primates do not have an inverted yolk sac placenta which makes this 
mechanism unlikely to be of relevance to humans and cynomolgus monkeys. In the developmental 
toxicity studies in cynomolgus monkey, a marked maternal body weight loss associated with the 
pharmacological effect of semaglutide coincided with increased early foetal loss; however, there 
was no indication of a teratogenic potential of semaglutide in this species. 
A review of the results from the non-clinical studies can be found in the investigator’s brochure (IB) 
for oral semaglutide (NN9924), or any update of this document. 
3.1.4.2 
SNAC 
SNAC was developed as an absorption-enhancing excipient for the oral route of administration. The 
non-clinical programme to support clinical phase 3 development and marketing authorisation 
application submission has been conducted including a 26-week carcinogenicity study in transgenic 
rasH2 mice and a 2-year carcinogenicity study in Sprague-Dawley rats. 
The most common observations related to oral dosing of SNAC were, depending on species, 
salivation, emesis and other clinical signs such as hypoactivity, lethargy, somnolence and ataxia. 
When SNAC was administered at high doses (200 mg/kg/day or more, depending on species) 
mortality has been observed in all toxicology species. The mortality is considered to be due to 
inhibition of cellular respiration, mainly via an inhibition of complex 1 in the electron transport 
chain. The mortality was found to be related to high doses of SNAC and high initial plasma 
concentrations of SNAC in animals. Similar plasma concentrations of SNAC have not been 
observed in clinical trials with oral semaglutide and are not achievable following administration of 
oral semaglutide tablets containing 300 mg SNAC per tablet.  
The carcinogenicity studies demonstrated that SNAC was not carcinogenic to the transgenic rasH2 
mouse or the Sprague-Dawley rat. The doses tested covered total exposures of SNAC in plasma (in 
terms of area under the curve (AUC)) of 2-fold in the mouse and up to 44-fold in the rat when 
compared to the mean total exposure of SNAC in humans following a clinical dose of 300 mg 
SNAC/day. 
A review of the SNAC results from the non-clinical studies can be found in the IB for oral 
semaglutide (NN9924), or any updates hereof. 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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3.1.5 
Clinical data for oral semaglutide 
A comprehensive clinical pharmacology programme including 12 trials has been completed, as well 
as a 26-week phase 2 dose-finding trial involving more than 600 subjects with T2D. 
For details on the individual trials, please see the IB for oral semaglutide (NN9924)19 or any 
updates hereof. 
3.1.5.1 
Pharmacokinetics 
In the multiple-dose trial (NN9924-3991), oral semaglutide has demonstrated a long mean terminal 
half-life (t½) ranging from 153 to 161 hours (~1 week) and a median time to reach maximum 
observed concentration (tmax) ranging from 1 to 2 hours in healthy subjects.  
In multiple-dose pharmacokinetics trials, the exposure to oral semaglutide increased with increasing 
dose. Overall, the pharmacokinetic properties of semaglutide appeared similar in healthy subjects 
and in subjects with T2D. 
Exposure to semaglutide exhibits a substantially greater dose-to-dose variation following oral 
administration compared to s.c. administration. However, when administered orally once-daily the 
pharmacokinetic properties of semaglutide, i.e. low clearance and long half-life, will limit the 
variation in exposure at steady state. 
Data obtained following investigation of different dosing conditions for oral semaglutide have 
demonstrated that subjects should take the oral semaglutide tablet in the morning in a fasting state 
and at least 30 minutes before the first meal of the day.  
Drug-drug interaction investigations have explored the effect of oral semaglutide on the exposure to 
lisinopril, warfarin, metformin and digoxin as well as the effect of omeprazole on oral semaglutide 
and SNAC. It was demonstrated that oral semaglutide did not change the exposure to lisinopril, 
warfarin or digoxin, but increased the exposure to metformin when taken simultaneously. The 
increase in exposure to metformin may be related to delayed gastric emptying caused by 
semaglutide as observed for other GLP-1 RAs. Based on the wide therapeutic index of metformin, 
the increased exposure to metformin was however not considered clinically relevant. Further, it was 
demonstrated that the exposure to semaglutide appeared to be slightly higher when administered 
with omeprazole in comparison to semaglutide alone, but the effect was not statistically significant 
or considered clinically relevant. 
In subjects with mild to end-stage renal impairment, the exposure to semaglutide appeared similar 
in subjects with normal and impaired renal function, whereas the exposure to SNAC was greater in 
subjects with impaired renal function than in subjects with normal renal function. The Cmax of 
SNAC appeared similar in subjects with normal and impaired renal function. The renal clearance of 
all SNAC metabolites was decreased in subjects with renal impairment.  
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Date: 
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Version: 
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Status: 
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In subjects with mild to severe hepatic impairment, the exposure to semaglutide appeared to be 
unaffected by the degree of hepatic impairment, whereas the exposure to SNAC (in terms of both 
AUC and Cmax) was increased for subjects with hepatic impairment as compared to subjects with 
normal hepatic function. 
All tablets of oral semaglutide contain 300 mg of SNAC regardless of the semaglutide dose. SNAC 
is rapidly absorbed with a median tmax ranging from 0.35−0.5 hours in healthy subjects and from 
0.52−1.43 hours in subjects with T2D. It is extensively metabolised and no accumulation of SNAC 
has been observed in clinical trials.  
3.1.5.2 
Efficacy 
The efficacy of oral semaglutide in adult subjects with T2D was investigated in a 26-week phase 2 
dose-finding trial (NN9924-3790). In this trial, placebo or one of the following doses of oral 
semaglutide were administered once-daily: 2.5, 5, 10, 20 and 40 mg. 
Results from the trial showed that oral semaglutide effectively lowered glycosylated haemoglobin 
(HbA1c) and body weight. Placebo-adjusted reductions in HbA1c were dose-dependent and 
statistically significant for all oral semaglutide treatment arms at week 26 (range: -0.40% to -
1.59%). Placebo-adjusted reductions in body weight were dose-dependent and statistically 
significant for oral semaglutide treatment doses of 10 mg and above at week 26 (range: -3.61 kg to -
6.98 kg).  
3.1.5.3 
Safety 
In the clinical trials completed so far, no unexpected safety findings have been identified for oral 
semaglutide administered up to 40 mg once-daily. Consistent with other GLP-1 RAs, commonly 
reported adverse events (AEs) included nausea and vomiting, most of them were mild to moderate 
in severity. In line with findings for other GLP-1 RAs, an increase in heart rate and serum levels of 
lipase and amylase has also been observed in subjects exposed to oral semaglutide. 
In addition to the 13 completed clinical trials with oral semaglutide, SNAC has been investigated in 
the programme of orally administrated heparin in combination with SNAC (heparin/SNAC). The 
heparin/SNAC programme (Emisphere Technologies, Inc.) included 29 phase 1 trials (SNAC doses 
ranged from 0.172-10.5 g). In three of these trials, SNAC alone was investigated (to a maximum 
dose of 10.5 g). The trials covered formulation development, food effect, hepatic and renal 
impairment, age-effect and drug-drug interaction. The programme also included a total of three 
phase 2 and 3 trials in which the effects of orally delivered heparin solution (with >1.5 g SNAC 
three times a day) was investigated. The overall safety profile of oral semaglutide and 
heparin/SNAC indicates that SNAC is safe and well-tolerated. 
For further details, please see the IB for oral semaglutide (NN9924)19, or any updates hereof. 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
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3.1.6 
Sitagliptin 
The selected active comparator in this trial is sitagliptin, an oral antidiabetic drug (OAD) of the 
DPP-4 inhibitor class suitable for once-daily oral administration. Sitagliptin was developed by 
Merck & Co and has been marketed since 2006 under the trade name Januvia®. The net effects of 
inhibition of DPP-4 are increased insulin secretion and reduced release of glucagon20. 
Further information can be obtained in the locally approved Januvia® label added (Chinese 
prescribing information21 and EU Summary of Product Characteristics (SmPC)22)  
3.2 
Rationale for the trial 
Many patients with T2D are not in glycaemic control with the currently marketed OADs. 
Nevertheless, treatment with more efficacious injectable therapies such as GLP1-RAs and insulin 
are rarely added during the early stages of the disease. Oral semaglutide is the first GLP-1 RA in 
development in a tablet formulation and it has the potential of becoming a new attractive treatment 
option early in the treatment cascade due to its effects on both hyperglycaemia and body weight.  
The purpose of the present trial is to compare three dose levels of oral semaglutide with sitagliptin, 
an established OAD within the drug class of DPP4-inhibitors, in terms of glycaemic control, weight 
loss and other efficacy and safety parameters in subjects with T2D inadequately controlled on 
metformin. 
This trial resembles trial NN9924-4222 (PIONEER 3) in the PIONEER programme (i.e. the global 
clinical phase 3a development programme for oral semaglutide). The rationale for the trial is to 
confirm the results of PIONEER 3 in a trial mainly including subjects from China. The design has 
been adjusted to fulfil the requirements to support registrations of oral semaglutide in China. 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
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4 
Objectives and endpoints 
4.1 
Objectives 
4.1.1 
Primary objective 
To compare the effect of three once-daily dose levels of oral semaglutide (3, 7 and 14 mg) versus 
sitagliptin 100 mg once-daily, both in combination with metformin, on glycaemic control in 
subjects with T2D. 
4.1.2 
Secondary objectives 
To compare the effect of three once-daily dose levels of oral semaglutide (3, 7 and 14 mg) versus 
sitagliptin 100 mg once-daily, both in combination with metformin, on body weight in subjects with 
T2D. 
To compare the safety and tolerability of three once-daily dose levels of oral semaglutide (3, 7 and 
14 mg) versus sitagliptin 100 mg once-daily, both in combination with metformin, in subjects with 
T2D. 
4.2 
Endpoints 
4.2.1 
Primary endpoint 
Change from baseline to week 26 in HbA1c 
4.2.2 
Secondary endpoints 
4.2.2.1 
Confirmatory secondary endpoints 
Change from baseline to week 26 in body weight (kg) 
4.2.2.2 
Supportive secondary endpoints 
Supportive secondary efficacy endpoints 
• Change from baseline to week 26 in: 
- 
Fasting plasma glucose (FPG) 
- 
7 point self-measured plasma glucose (SMPG) profile 
 Mean 7-point profile 
 Mean postprandial increment (over all meals) 
- 
Body weight (%) 
- 
Body mass index (BMI) 
- 
Waist circumference 
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Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
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- 
Fasting lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, 
very-low-density lipoprotein (VLDL) cholesterol, high-density lipoprotein (HDL) 
cholesterol, triglycerides, free fatty acids) 
- 
Patient-reported outcome 
 Short Form-36 version 2 (SF-36v2™) (acute version) health survey  
• If a subject after week 26 achieves (yes/no): 
- 
HbA1c < 7.0 % (53 mmol/mol) (American Diabetes Association (ADA) target) 
- 
HbA1c ≤ 6.5 % (48 mmol/mol) (American Association of Clinical Endocrinologists 
(AACE) target) 
- 
HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) 
- 
Body weight loss ≥ 3 % 
- 
Body weight loss ≥ 5 % 
- 
Body weight loss ≥ 10 % 
- 
HbA1c < 7.0 % (53 mmol/mol) without hypoglycaemia (treatment-emergent severe 
or BG confirmed symptomatic hypoglycaemic episodes) and no body weight gain 
- 
HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) and body weight loss ≥ 3 % 
• Time to event: 
- 
Time to rescue medication 
Supportive secondary safety endpoints 
• Number of treatment-emergent adverse events (TEAEs) during exposure to trial product, 
assessed up to approximately 31 weeks 
• Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic 
episodes during exposure to trial product, assessed up to approximately 31 weeks  
• Treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 31 weeks (yes/no)  
• Change from baseline to week 26 in: 
- 
Haematology 
- 
Biochemistry 
- 
Calcitonin 
- 
Pulse rate 
- 
Systolic blood pressure 
- 
Diastolic blood pressure 
- 
Electrocardiogram (ECG) category 
- 
Physical examination category 
- 
Eye examination category 
 
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Pr ot oc ol
Date:
2 8 Ja n u ar y 2 0 1 9
N o v o N or di s k
Trial I D: N N 9 9 2 4 -4 3 0 9
V ersi o n:
3. 0
U T N: U 1 1 1 1 -1 1 8 8 -1 2 5 6
Stat us:
Fi n al
E u dra C T n o.: 2 0 1 8 -0 0 2 5 8 9 -3 8 
P a ge:
2 5 of 1 2 0
5
Tri al desi g n
5. 1 
T y pe of tri al 
T his is a 2 6- wee k, ra n d o mise d, d o u ble- bli n de d, d o u ble- d u m m y, acti ve-c o ntr olle d, f o ur-ar me d, 
parallel - gr o u p, m ultice ntre, m ulti nati o nal trial c o m pari n g t he effi cac y a n d safet y of t hree o nce-dail y 
d ose le vels of or al se ma gl uti de vers us sita gli pti n o nce- dail y i n s u bjects wit h T 2 D i na de q uatel y 
c o ntr olle d o n metf or mi n.
S u bjects will be ra n d o mise d i n a 1: 1: 1: 1 rati o t o recei ve o n e of t he f oll o wi n g treat me nts: 
•
oral se ma gl uti de 3 m g a n d sita gli pti n place b o
•
oral se ma gl uti de 7 m g a n d sita gli pti n place b o
•
oral se ma gl uti de 1 4 m g a n d sita gli pti n place b o
•
sita gli pti n 1 0 0 m g a n d or al se ma gl uti de place b o 
T he ra n d o misati o n will be stratifie d acc or di n g t o w het her t he s u bject is fr o m t he C hi na re gi o n 
(i ncl u di n g T ai wa n a n d H o n g K o n g) or n ot. 
T otal trial d urati o n f or t h e i n di vi d ual s u bject will be u p t o 3 3 wee ks. T h e trial i ncl u des a 2- w ee k 
scree ni n g p eri o d, f oll o we d b y a 2 6- wee k ra n d o mis e d treat me nt peri o d a n d a f oll o w- u p peri o d of 5 
wee ks. T he tri al desi g n is ill ustrate d i n Fi g ure 5 – 1 . 
Fi g ure 5– 1  Tri al Desi g n
5.2 
R ati o n ale f or tri al desi g n 
T he trial has bee n desi g n e d as a parallel- gr o u p, f o ur-ar me d trial t o e ns ure a direct c o m paris o n 
bet wee n t hr ee d ose l e vels of oral se ma gl uti de a n d t he acti ve c o m parat or sit a gli pti n. S u bjects will be 
ra n d o mise d bet wee n t he f o ur treat me nt ar ms a n d t he trial will be d o u ble- bli n de d t o mi ni mise bias. 
Si nce oral se ma gl uti de a n d sita gli pti n are n ot vis u all y i de ntical a d o u ble- d u m m y desi g n will be 
a p plie d t o mai ntai n t he bli n di n g of t he trial. A cc or di n gl y, s u bjects ra n d o mise d t o oral se ma gl uti de 
will als o recei ve sita gli pti n place b o a n d s u bjects ra n d o mise d t o sita gli pti n will als o recei ve oral 
se ma gl uti de place b o.
  Pr ot oc ol  v 3 c o ns ol
4 3 0 9
N N 9 9 2 4
0
 |
V V- T M F- 6 9 8 7 3 2
1 4 5
 of
2 5
-
 |
1
 |
C O N FI D E N TI A L


Protocol 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38 
Page: 
26 of 120 
 
Randomisation will be stratified to ensure an even distribution of the four treatment arms within 
each stratum.  
The treatment duration of 26 weeks is considered adequate to evaluate the effect of oral semaglutide 
versus sitagliptin and furthermore, for the assessment of safety and tolerability. The 5-week follow-
up period is included to allow for wash-out of semaglutide. 
5.3 
Treatment of subjects 
Treatment of subjects is summarised in Table 5–1. 
Oral semaglutide treatment arm 
Oral semaglutide is a long-acting GLP-1 RA to be administered orally once daily. All subjects 
randomised to oral semaglutide will initiate treatment with 3 mg once daily. Subjects randomised to 
a treatment dose of 7 and 14 mg will follow a fixed 4-week dose escalation regimen. The 
maintenance dose of 7 mg once daily will be reached after 4 weeks on 3 mg once daily. The 
maintenance dose of 14 mg once daily will be reached after 4 weeks on 3 mg, followed by 4 weeks 
on 7 mg once daily (Table 5–1). All dose levels, including the dose-escalation, will be blinded (see 
Section 9.1). To mitigate the risk of gastrointestinal (GI) AEs, it is important to follow the fixed 4-
week dose-escalation intervals. The dose of oral semaglutide must not be changed during the trial 
once the maintenance dose has been reached. In addition, all subjects randomised to oral 
semaglutide will receive sitagliptin placebo once daily. 
Sitagliptin treatment arm 
The selected active comparator in this trial is sitagliptin, an OAD of the DPP4-inhibitor class 
suitable for once-daily administration. Subjects randomised to sitagliptin will receive 100 mg once 
daily throughout the trial. In addition, all subjects randomised to sitagliptin will receive oral 
semaglutide placebo once daily. 
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In addition, the background medication (metformin): 
• is considered to be non-investigational medicinal product 
• will not be provided by Novo Nordisk A/S unless required by local law and should be purchased 
or otherwise delivered to subjects in accordance with local health plans  
• should be used in accordance with standard of care or local label in the individual country  
5.4 
Treatment after discontinuation of trial product 
When discontinuing trial products, either at the scheduled end-of-treatment (EOT) visit (see Section 
8.1.4) or if trial product is discontinued prematurely (see Section 8.1.5), the subject should be 
switched to a suitable marketed product at the discretion of the investigator (for Brazil only: or it 
will be made available according to local regulations). After discontinuation of trial product, GLP-
1 RAs are not allowed before completion of the follow-up visit 5 weeks after the last date on trial 
product. Throughout the protocol, last date on trial product is defined as date of the subject’s last 
dosage of trial product. 
As this trial is a phase 3a trial, oral semaglutide will not be available for prescription until after 
marketing authorisation. 
5.5 
Rationale for treatment 
For oral semaglutide, the three dose levels (3, 7 and 14 mg), treatment initiation with the lowest 
dose and the 4-week dose escalation steps have been chosen based on data from the phase 2 dose-
finding trial (NN9924-3790). This regimen is expected to have the optimal benefit-risk for 
treatment of T2D.  
Sitagliptin has been chosen as the active comparator because it is an established OAD of the DPP4-
inhibitor drug class.  
There will be strict glycaemic rescue criteria in place to ensure acceptable glycaemic control during 
the trial for all treatment arms.  
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Date: 
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6 
Trial population 
6.1 
Number of subjects  
Number of subjects planned to be screened: 2063 
Number of subjects planned to be randomised: 1444 
For China only: 1084 subjects from the China region (including Hong Kong and Taiwan) are 
planned to be randomised with an approximate equal distribution across the 4 treatment arms 
Number of subjects expected to complete the trial on or off trial product: 1300 
6.2 
Inclusion criteria 
For an eligible subject, all inclusion criteria must be answered “yes”.  
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.  
For Algeria only: Male or female, age above or equal to 19 years at the time of signing 
informed consent.  
For Taiwan only: Male or female, age above or equal to 20 years at the time of signing 
informed consent. 
3. Diagnosed with type 2 diabetes mellitus ≥ 60 days prior to day of screening. 
 
4. HbA1c between 7.0-10.5% (53-91 mmol/mol) (both inclusive).  
5. Stable daily dose of metformin (≥ 1500 mg or maximum tolerated dose as documented in the 
subject medical record) ≥ 60 days prior to day of screening. 
The criteria will be assessed at the investigator’s discretion unless otherwise stated 
6.3 
Exclusion criteria 
For an eligible subject, all exclusion criteria must be answered “no”. 
1. Known or suspected hypersensitivity to trial products or related products. 
2. Previous participation in this trial. Participation is defined as signed informed consent. 
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3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method. 
For more information on requirements, see Appendix C 
4. Receipt of any investigational medicinal product within 90 days before screening. 
5. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol. 
6. Family or personal history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid 
carcinoma (MTC). Family is defined as a first degree relative.  
7. History or presence of pancreatitis (acute or chronic). 
8. History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery).  
9. Any of the following: myocardial infarction, stroke, hospitalization for unstable angina or 
transient ischaemic attack within the past 180 days prior to the day of screening and 
randomisation.  
10. Subjects presently classified as being in New York Heart Association (NYHA) Class IV. 
11. Planned coronary, carotid or peripheral artery revascularisation known on the day of screening.  
12. Renal impairment measured as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 
as per Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI).  
13. Subjects with alanine aminotransferase (ALT) > 2.5 x upper limit of the normal (ULN). 
14. Treatment with once-weekly Glucagon-like peptide 1 (GLP-1) receptor agonist or 
thiazolidinedione within the past 90 days prior to the day of screening. 
15. Treatment with any medication for the indication of diabetes or obesity other than stated in the 
inclusion criteria within the past 60 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. 
 
16. Use of non-herbal Chinese medicine or other non-herbal local medicine with unknown or 
unspecified content. Herbal traditional Chinese medicine or other local herbal medicines may, at 
the Investigator's discretion, be continued throughout the trial  
 
17. 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 
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screening and randomisation. Pharmacological pupil-dilation is a requirement unless using a 
digital fundus photography camera specified for non-dilated examination 
 
18. Presence or history of malignant neoplasms within the past 5 years prior to the day of screening. 
Basal and squamous cell skin cancer and any carcinoma in-situ is allowed. 
The criteria will be assessed at the investigator’s discretion unless otherwise stated. 
6.4 
Rescue criteria 
Subjects with persistent and unacceptable hyperglycaemia should be offered treatment 
intensification. To allow time for dose escalation and to observe the expected effect of trial 
treatment on glycaemic parameters, rescue criteria will be applied from week 8 (visit 5) and 
onwards. If any of the FPG values (including fasting SMPG) exceed the limits outlined below and 
no intercurrent cause of the hyperglycaemia can be identified, a confirmatory FPG (at central 
laboratory) should be obtained by calling the subject for a re-test. If the confirmatory FPG also 
exceeds the value described below, the subject should be offered rescue medication (i.e. 
intensification of existing antidiabetic background medication and/or initiation of new antidiabetic 
medication): 
• 14.4 mmol/L (260 mg/dL) from week 8 to end of week 13 
• 13.3 mmol/L (240 mg/dL) from week 14 to EOT 
It is important for trial integrity that only subjects actually needing treatment intensification (as 
defined above) are started on rescue medication. Subjects started on rescue medication should 
continue to follow the protocol-specified visit schedule. Rescue medication should be prescribed at 
investigators’s discretion as add-on to randomised treatment and according to ADA/European 
Association for the Study of Diabetes guidelines23, 24 (excluding GLP-1 RAs, DPP-4 inhibitors and 
amylin analogues) and the local label of sitagliptin. 
Rescue medication and any changes hereto should be captured on the concomitant medication form 
in the electronic case report from (eCRF) (see Section 8.2.4). 
6.5 
Criteria for premature discontinuation of trial product  
All efforts should be made to keep the subject on trial product. However, the subject may be 
prematurely discontinued from trial product at the discretion of the investigator due to a safety 
concern. For additional guidance regarding acute pancreatitis, hepatic events and hypersensitivity 
see Appendix B.  
The subject must be prematurely discontinued from trial product if the following applies: 
1. Safety concern related to trial product or unacceptable intolerability  
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2. Included in the trial in violation of the inclusion and/or exclusion criteria 
3. Pregnancy 
4. Intention of becoming pregnant 
5. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product. 
6. Calcitonin ≥ 100 ng/L 
If a criterion for premature discontinuation of trial product is met, trial product should not be re-
initiated but subjects should continue with the scheduled site contacts. 
See Section 8.1.5 for procedures to be performed for subjects discontinuing trial product 
prematurely. 
6.6 
Withdrawal from trial 
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. A subject who does not complete the trial is also considered 
withdrawn from the trial. Hence a subject is considered withdrawn if the following applies: 
• Subject is lost to follow up (only to be used if there is no contact with the subject by the time of 
the subject’s last scheduled visit (see Section 8.1.4 – 8.1.6.1)) 
• Subject withdraws consent  
• Death 
See Section 8.1.6 for procedures to be performed for subjects withdrawing consent. 
6.7 
Subject replacement 
Subjects who withdraw from trial or discontinue trial product prematurely will not be replaced. 
6.8 
Rationale for trial population  
The trial population will include subjects with T2D, treated with stable doses of metformin for at 
least 60 days prior to screening, since changes in background OAD medication shortly before trial 
participation may potentially impact data interpretation. The HbA1c limits of 7.0-10.5% 
(53-91 mmol/mol) have been chosen to include subjects needing intensification of their antidiabetic 
treatment. The upper limit will ensure that subjects with severely dysregulated T2D are not enrolled 
in the trial.  
Subjects with abnormal liver parameters (ALT >2.5 x ULN) will be excluded to avoid potential 
confounding of liver safety assessments.  
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Subjects with moderate, severe or end-stage renal impairment will be excluded in this trial, due to 
restrictions in the labels of sitagliptin and metformin. The safety and efficacy of oral semaglutide in 
subjects with moderate renal impairment are addressed in a global phase 3a clinical trial (trial 
NN9924-4234).  
In addition, subjects with recent cardiovascular disease (myocardial infarction (MI), stroke, 
hospitalisation for unstable angina or transient ischaemic attack within the past 180 days prior to the 
day of screening and randomisation) will be excluded to avoid potential confounding of 
cardiovascular safety assessments. The cardiovascular safety of oral semaglutide is investigated in a 
global phase 3a cardiovascular outcomes trial (trial NN9924-4221). 
Overall, the eligibility criteria will allow for enrolment of a relatively broad trial population, 
resembling the target population in common practice. 
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7 
Milestones 
Planned duration of recruitment period (first subject first visit – last subject first visit) is 18 months. 
End of trial is defined as last subject last visit. 
Recruitment: 
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects screened during the recruitment period 
and found eligible for randomisation can be randomised within the timelines specified in the flow 
chart (see Section 2). 
Trial registration: 
Information of the trial will be disclosed at clinicaltrials.gov, chinadrugtrials.org.cn and 
novonordisk-trials.com. According to the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure25, it will also be disclosed according to other applicable requirements such as those of 
the International Committee of Medical Journal Editors (ICMJE)26, the Food and Drug 
Administration Amendment Act (FDAAA)27, European Commission Requirements28,29 and other 
relevant recommendations or regulations including requirements by China Food and Drug 
administration (CFDA). If a subject requests to be included in the trial via the Novo Nordisk e-mail 
contact at these web sites, Novo Nordisk may disclose the investigator’s contact details to the 
subject. As a result of increasing requirements for transparency, some countries require public 
disclosure of investigator names and their affiliations.  
Primary Completion Date is the last assessment of the primary endpoint, and is for this protocol last 
subject first visit + 28 weeks corresponding to Visit 8. If the last subject is withdrawn/dropout early 
the Primary Completion Date is the date when the last subject would have completed Visit 8. The 
Primary Completion Date determines the deadline for results disclosure at Clinicaltrials.gov 
according to FDAAA. 
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8 
Methods and assessments 
8.1 
Visit procedures 
The following sections describe the assessments and procedures. These are also included in the flow 
chart (see Section 2). Informed consent must be obtained before any trial related activity (see 
Section 18.2). 
All subjects must be provided with a copy of their own signed and dated informed consent form. 
Refer to flowchart (see Section 2) for number and timing of visits and specific assessments to be 
performed.  
Each subject will attend 8 site visits and 1 phone contact. It is the responsibility of the investigator 
to ensure that all site visits occur according to the flow chart. 
Planned visits can be conducted and re-scheduled within the allowed visit window. If a visit is 
missed and it is not possible to re-schedule, every effort should be made to ensure information is 
collected at a telephone contact (within the visit window) and entered into the eCRF. Subjects will 
be invited for the next scheduled visit according to the visit schedule. 
The investigator must keep a log of staff and a delegation of task(s) list at site. Investigator must 
sign the log of staff and the delegation of task(s) at site prior to the delegation of tasks. 
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log. 
8.1.1 
Screening, visit 1 
At screening, subjects will be provided with a card stating that they are participating in a trial and 
giving contact address(es) and telephone number(s) of relevant trial site staff. Subjects should be 
instructed to return the card to the investigator at the last trial visit or to destroy the card after the 
last visit. 
A screening session must be made in the IWRS. Each subject will be assigned a unique 6-digit 
subject number which will remain the same throughout the trial.  
In- or exclusion criteria must not be ticked “Yes” or “No” in the eCRF before source data is 
available. In case source data is not available “Result pending” must be chosen. This is particularly 
relevant for lab samples and eye examination results. Once all data relating to visit 1 have been 
obtained, these must be reviewed, dated and signed by the investigator and/or documented in 
medical records to assess that the subject is eligible to continue in the trial. 
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Screening failures 
For screening failures the screening failure form in the eCRF must be completed with the reason for 
not continuing in the trial. Serious adverse events (SAEs) from screening failures must be 
transcribed by the investigator into the eCRF. Follow-up on SAEs must be carried out according to 
Section 12. 
A screening failure session must be made in the IWRS. The casebook must be signed.  
Re-screening 
Re-screening is NOT allowed if the subject has failed one of the inclusion or exclusion criteria, this 
includes re-sampling if the subject has failed one of the inclusion or exclusion criteria related to 
laboratory parameters. However, in case laboratory samples are lost (e.g. haemolysed or displaced), 
re-sampling is allowed.  
8.1.2 
Fasting visits 
The subjects must attend several visits in a fasting state (see Section 2).  
Fasting for blood sampling is defined as no food or liquid within the last 8 hours prior to blood 
sampling, however water is allowed up until 2 hours prior to blood sampling. 
Trial products must be taken after blood sampling (see Section 5.3.1 for dosing instructions). Other 
oral medication can be taken 30 minutes after trial products. Injectable medications can be 
administered after blood sampling.  
In case a subject attends a fasting visit in a non-fasting state, all non-fasting measurements should 
be performed. The subject should return to the site in a fasting state to have the fasting blood 
samples done within the visit window for the relevant visit and at visit 2 before randomisation to 
trial product. 
Fasting samples: 
• FPG 
• fasting lipid profile (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, 
triglycerides, free fatty acids) 
8.1.3 
Randomisation and trial product administration 
Eligible subjects will be randomised into one of four treatment arms. The randomisation session 
must be performed in the IWRS which will allocate the dispensing unit number (DUN) of trial 
product to be dispensed to the subject. A drug accountability session confirming dispensing of 
allocated trial products should also be performed when dispensing trial products. 
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All visit 2 assessments, including ECG, must be performed before administration of first dose of 
trial product. Additionally, all in- and exclusion criteria should be checked at visit 2 prior to 
randomisation. 
Trial products (see Section 9) will be dispensed to the subject by the site, hospital pharmacy or 
equivalent at each site visit during the trial from randomisation to last visit before the EOT visit (see 
Section 2). The investigator must document that subjects are trained in the dosing instructions, 
according to Section 2 and 5.3.1. 
Date of first administration of trial product will be captured in the eCRF.  
8.1.4 
End-of-treatment (visit 8) and Follow-up (visit 9) 
Subjects, who stay on trial product throughout the trial, must attend the EOT visit (visit 8) 26 weeks 
after randomisation and the Follow-up visit (visit 9) 5 weeks after the last date on trial product. 
Visit 9 has a +3 days visit window. A completion call must be performed in the IWRS after 
completion of visit 8 (see Section 10). 
At visit 8 the subject should be reminded about the importance of attending the follow-up visit 
(visit 9). Should the subject, nonetheless, miss to attend visit 9, the site should make efforts to 
obtain contact with the subject within the visit window.  
Treatment period completion is defined as when randomised subject has received the required 
treatment, and attended the EOT visit (visit 8). 
A trial completer is defined as a subject who attends, or is in contact with the site, at the subject’s 
last scheduled visit. For subjects who complete treatment, the last scheduled visit is visit 9. (For 
subjects who discontinue trial product, see Section 8.1.5) 
8.1.5 
Premature discontinuation of trial product and follow-up (visits 8A and 9A) 
Subjects, who discontinue trial product prematurely, should attend visit 8A scheduled to take place 
on the day of discontinuation of trial product (+ 3 days visit window). Visit 9A should be scheduled 
5 weeks (+3 days visit window) after the last date on trial product.  
The primary reason for premature discontinuation of trial product must be specified in the eCRF, 
and final drug accountability must be performed. A treatment discontinuation session must be made 
in the IWRS. 
If premature discontinuation of trial product is decided during a scheduled visit, the visit will be 
converted into a visit 8A and trial procedures must be performed accordingly. 
Subjects should perform the 7-point SMPG profile and other visit 8A assessments before initiating 
new antidiabetic treatment.  
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Subjects should continue with the originally scheduled site contacts after visit 9A and up to and 
including visit 8 (week 26). If necessary, in order to retain the subject in the trial, site visits can be 
replaced by phone contacts after visit 9A. However, if a subject is unable or unwilling to attend 
subsequent visit(s), the investigator should at least aim to have the subject attend the EOT visit 
(visit 8) (week 26) as this visit should be performed for all subjects, if at all possible (except 
subjects who withdraw consent (see Section 8.1.6)). It should be documented in the medical records 
if subject refuses to attend a visit from visit 8A and onwards. 
A subject who prematurely discontinued trial product is still considered a trial completer if the 
subject attends or is in contact with the site, at the subject’s last scheduled visit. For subjects who 
prematurely discontinue trial product, the last scheduled visit is visit 8 (26 weeks after the 
randomisation visit) (or visit 9A if it is scheduled after visit 8). The site should in due time prepare 
for establishing contact with the subject within the visit window of the scheduled visit 8, if the 
subject has agreed to attend this visit. 
In summary, subjects should stay in the trial irrespective of lack of adherence to randomised 
treatment, lack of adherence to visit schedule, missing assessments or trial product discontinuation 
for any reason. Only subjects who decline any further contact with the site in relation to the trial 
should be considered as having withdrawn consent (for withdrawal procedures, see Section 8.1.6).  
8.1.6 
Withdrawal 
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 8A as soon as possible and visit 9A should be scheduled 5 weeks (+3 days visit window) 
after the last date on trial product, if the subject agrees to it.  
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS. The casebook must be signed.  
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, 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 withdrawing consent must be specified in 
the end-of-trial form in the eCRF. 
8.1.6.1 
Lost to follow-up 
In case contact to the subject is lost during the trial, the site should immediately undertake efforts to 
re-establish contact. If the subject cannot be reached (by clinic visit or phone contact) and the 
subject has consented to it, the site should consult the contacts provided by the subject (e.g. close 
relatives), relevant physicians, medical records and locator agencies (if allowed according to local 
law) in an attempt to regain contact with the subject or to obtain relevant safety information from 
other sources. Efforts to regain contact should continue until the end of the subject’s last scheduled 
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visit: visit 9 for subjects who have completed treatment, whereas for subjects who have 
discontinued trial product prematurely the last visit is visit 8 (or visit 9A if it is scheduled after visit 
8). Only if contact with the subject is not regained by the end of the visit window of the last 
scheduled visit can the subject be considered lost to follow up (see Section 6.6).  
8.1.7 
Investigator assessments 
Review of diaries, patient-reported outcomes (PROs), laboratory reports, ECGs and eye 
examinations must be documented either on the documents or in the subject’s medical record. The 
documents must be retained at the site as source documentation. 
If clarification of entries or discrepancies in the diary or PRO is needed, the subject must be 
questioned and a conclusion made in the subject’s medical record. Care must be taken not to bias 
the subject. 
For ECGs, physical examinations and eye examinations, the evaluations must follow the categories: 
• Normal 
• Abnormal 
- 
Was the result clinically significant? (yes/no) 
The evaluation should be based on investigator’s judgement. 
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not clinically significant. All laboratory printouts must be signed 
and dated by the investigator prior to the following visit. The signed laboratory report is retained at 
the site as source documentation. 
In case of abnormal clinically significant findings found as a result of screening procedures 
conducted at visit 1 or trial procedures revealing baseline conditions at visit 2, the investigator must 
state a comment in the subject’s medical record and record this in the concomitant illness/medical 
history form in the eCRF.  
The investigator or his/her delegate must collect and review the PROs and diaries for completeness 
and to ensure that AEs are reported.  
8.2 
Subject related information/assessments  
8.2.1 
Demography 
Demography will be recorded in the eCRF at screening and consists of: 
• Date of birth (according to local regulation) 
• Sex 
• Ethnicity (according to local regulation) 
• Race (according to local regulation) 
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8.2.2 
Diabetes history and diabetes complications  
Diabetes history and diabetes complications will be recorded on a disease specific form in the eCRF 
at screening and consists of: 
• Date of diagnosis of T2D 
• Information regarding diabetes complications including date of onset 
- 
Diabetic retinopathy 
- 
Diabetic neuropathy 
- 
Diabetic nephropathy 
Please note that macroangiopathy (including peripheral arterial disease) should be reported on the 
disease specific form History of cardiovascular disease (see Section 8.2.3). 
8.2.3 
Concomitant illness and medical history 
A concomitant illness is any illness that is present at the start of the trial (visit 1) 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 has experienced in the past. Only relevant 
medical history as judged by the investigator should be reported. 
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable. 
The following must be recorded in the eCRF on the disease specific forms only, i.e. not on the 
medical history/concomitant illness form: 
• History of cardiovascular disease (e.g. ischaemic heart disease, MI, heart failure incl. NYHA 
class, hypertension, stroke, peripheral arterial disease) 
• History of gallbladder disease (e.g. gallstone, cholecystitis, cholecystectomy) 
• History of gastrointestinal disease (e.g. gastroesophageal reflux disease, ulcer disease, chronic 
gastritis) 
Any change to a concomitant illness should be recorded during the trial. A clinically significant 
worsening of a concomitant illness must be reported as an AE(see Section 12.2). 
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigators own practice; the investigator must make 
reasonable effort to obtain a copy of subject’s medical record from relevant party e.g. primary 
physician. The investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested and who has been contacted. 
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8.2.4 
Concomitant medication 
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening, treatment and follow-up periods. 
Details of any concomitant medication must be recorded at the first visit. Changes in concomitant 
medication must be recorded at each visit as they occur.  
The information collected for each concomitant medication includes  
• trade name or generic name 
• indication  
• start date and stop date or continuation 
• only applicable for antidiabetic medication: total daily dose 
If a change is due to an AE, then this must be reported according to Section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed. 
8.2.5 
Childbearing potential 
It must be recorded in the eCRF whether female subjects are of childbearing potential.  
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
Section 8.4.7. Female subjects of childbearing potential must be instructed to use highly effective 
contraceptive methods throughout the trial and until 5 weeks after EOT. For more information on 
requirements see Appendix C. 
Female of non-childbearing potential is defined as: 
• Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal ligation  
• Postmenopausal defined as no menses for 12 months without an alternative medical cause 
• Other medical reasons preventing childbearing potential  
8.2.6 
Tobacco use  
Details of tobacco use must be recorded at visit 1. Smoking is defined as smoking at least one 
cigarette or equivalent daily.  
Smoking status: 
• Never smoked 
• Previous smoker, smoking stop date 
• Current smoker 
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Date: 
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8.3 
Efficacy assessments 
8.3.1 
Laboratory assessments for efficacy 
For overall laboratory process see Section 8.5. 
Blood samples will be drawn according to flow chart (see Section 2) and will be analysed at the 
central laboratory to determine levels of the following efficacy laboratory parameters (for fasting 
see Section 8.1.2): 
Glucose metabolism: 
• HbA1c 
• FPG 
Fasting lipid profile:  
• Total cholesterol 
• LDL cholesterol 
• VLDL cholesterol  
• HDL cholesterol 
• Triglycerides 
• Free fatty acids 
Fasting plasma glucose 
FPG is measured at the central laboratory in order to evaluate glycaemic control. The subject must 
attend these visits fasting (see Section 8.1.2). 
A central laboratory FPG result ≤ 3.9 mmol/L (70 mg/dL) in relation to planned fasting visits 
should not be reported as a hypoglycaemic episode but as a clinical laboratory adverse event 
(CLAE) at the discretion of the investigator (see Section 12.1.1). 
8.3.2 
Self-measured plasma glucose (SMPG)  
At visit 1 subjects will be provided with a BG meter including auxiliaries as well as instructions for 
use. The subjects will be instructed in how to use the device and the instructions will be repeated as 
necessary during the trial. In case a hypoglycaemic episode is suspected, the provided BG meter 
should be used for SMPG measurement. 
The BG meters use test strips calibrated to plasma values. Therefore, all measurements performed 
with capillary blood are automatically calibrated to plasma equivalent glucose values, which will be 
shown on the display.  
Only the BG meter provided by Novo Nordisk should be used for the measurements required in the 
protocol.  
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Subjects should be instructed in how to record the results of the SMPG values in the diaries. The 
record of each SMPG value should include date, time and value. All data from the diary must be 
transcribed into the eCRF during or following the contact. If obtained via phone and a discrepancy 
is later detected, between the diary and the SMPG data obtained at the phone contact, the values in 
the eCRF must be corrected. 
Occasional review by the investigator of the values stored in the memory of the BG meter and 
correct reporting of these in the diary is advised in order to ensure adequacy of the data reported in 
the trial database.  
8.3.2.1 
7-point self-measured plasma glucose profile 
The subject will be instructed to perform a 7-point SMPG profile twice during the trial period (see 
Section 2) using the BG meter provided for the trial. The 7-point SMPG profile should be 
performed on a day where the subject does not anticipate unusual strenuous exercise. The 7-point 
profile should preferably be taken within a week prior to the visit. 
The record of each SMPG measurement should include the following seven time points: 
• before breakfast 
• 90 minutes after start of breakfast 
• before lunch 
• 90 minutes after start of lunch 
• before dinner 
• 90 minutes after start of dinner 
• at bedtime 
8.3.3 
Body weight and height 
Body weight must be measured and recorded in the eCRF in kilogram or pound (kg or lb), with one 
decimal (with an empty bladder, without shoes and only wearing light clothing). The body weight 
should be assessed on the same calibrated weighing scale equipment throughout the trial, if 
possible. 
Height is measured without shoes in centimetres or inches and recorded in the eCRF to nearest 
½ cm or ¼ inch. 
8.3.4 
Waist circumference 
The waist circumference is defined as the minimal abdominal circumference located midway 
between the lower rib margin and the iliac crest. 
The measurement of waist circumference must be performed and recorded in the eCRF. Waist 
circumference is measured in the horizontal plane and rounded up or down to the nearest ½ cm or ¼ 
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inches using a non-stretchable measuring tape. The same measuring tape should be used throughout 
the trial. 
The circumference should be measured when the subject is in a standing position, with an empty 
bladder and wearing light clothing. The subject should be standing, feet together with arms down 
their side and waist accessible. The tape should touch the skin but not compress soft tissue and 
twists in the tape should be avoided. The subject should be asked to breathe normally and the 
measurement should be taken when the subject is breathing out gently. 
8.3.5 
Patient-reported outcome questionnaire 
Following PROs will be assessed : 
• SF-36v2 (acute version) health survey30, 31, 32, 33, 34 
The questionnaire must be completed by the subject as specified in the flow chart (see Section 2), 
preferably before any other trial-related activities for that visit. It takes approximately fifteen 
minutes to complete the questionnaire. Subjects should be given the opportunity to complete the 
questionnaire by themselves without interruption. The completed questionnaire must be reviewed 
for potential AEs and missing data while the subject is still at the site. All results from the PRO 
questionnaires must be transferred into the eCRF. 
The questionnaire SF-36v2™ is commonly used PRO instrument, also in the T2D area.  
All the questionnaires will be translated to local languages, and also be linguistically validated 
before being handed out to the subjects participating in the trial.  
SF-36 acute version 
SF-36v2™ acute version measures the individual overall health related quality of life on 8 domains; 
Physical functioning, Role physical, Bodily pain, General health, Vitality, Social functioning, Role 
emotional and Mental health. The acute version’s questions are based on a recall period of one 
week. SF-36v2™ contains 36 itemsSafety assessments 
8.3.6 
Adverse events 
AEs must be reported at each visit in accordance with the procedures outlined in Section 12 and 
Appendix B. 
8.3.6.1 
Adverse events requiring additional data collection 
For the following AEs additional data collection is required and specific event forms must be 
completed in the eCRF in addition to the AE form:  
• Acute coronary syndrome (MI or unstable angina pectoris requiring hospitalisation) 
• Acute gallstone disease 
• Cerebrovascular event (stroke or transient ischaemic attack) 
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• Heart failure  
• Hypersensitivity reaction 
• Neoplasm (excluding thyroid neoplasm) 
• Pancreatitis 
• Renal Event 
• Thyroid disease (including thyroid neoplasm) 
• Medication error 
• Lactic acidosis 
• Creatine kinase (CK) > 10x ULN 
• Hepatic event defined as: 
- 
ALT or AST > 5x ULN and total bilirubin ≤ 2x ULN 
- 
ALT or AST > 3x ULN and total bilirubin > 2x ULN* 
- 
Hepatic event leading to trial product discontinuation. 
• Diabetic retinopathy and related complications 
*Please note that in case of a hepatic event defined as ALT or AST >3 x ULN and total bilirubin >2 x ULN, where no 
alternative aetiology exists (Hy's law), this must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable. 
See Section 12.1.4.1 and Appendix B for details about the additional information to report.  
Note that additional assessments may be required according to Appendix B in case of:  
• suspicion of acute pancreatitis 
• suspicion of hypersensitivity reaction 
• increased levels of creatine kinase 
• increased levels of aminotransferase 
In case any of these events fulfil the criteria for a SAE, please report accordingly (see Section 12). 
8.3.7 
Physical examination 
A physical examination will be performed by the investigator according to local procedure (see 
Section 2 and 8.1.7). A physical examination must include: 
• General appearance 
• Head, ears, eyes, nose, throat, neck 
• Thyroid gland* 
• Respiratory system 
• Cardiovascular system 
• GI system including mouth 
• Musculoskeletal system 
• Central and peripheral nervous system 
• Skin 
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•
Lymph node palpation
*Please note that the diagnostic evaluation of thyroid nodules should be in accordance with the American Thyroid
Association Management Guidelines or any updates hereof 35 adapted to local treatment guidelines if applicable.
8.3.8 
Vital signs 
Systolic and diastolic blood pressure 
Systolic and diastolic blood pressure should be measured in a sitting position after the subject has 
been resting for at least 5 minutes and by using the standard clinical practice at the site. The data 
must be recorded in the eCRF. The actual value of the blood pressure measurement should be 
recorded in the eCRF (without rounding). The same equipment should be used throughout the trial. 
Pulse rate 
Pulse rate (beats per minute) must be recorded in the eCRF at site visits after the subject has been 
resting for 5 minutes in a sitting position. 
8.3.9 
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) and performed with 
pharmacologically dilated pupils. 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 above must be performed as per 
the flowchart in section 2. The investigator should indicate the outcome of each eye examination. 
Relevant findings prior to randomisation must be recorded as concomitant illness/medical history. 
While relevant findings occurring after randomisation should be reported as an AE. 
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8.3.10 
Electrocardiogram (12-lead) 
12-lead ECG will be performed as per flowchart (see Section 2) and the assessment must be 
reviewed as described in Section 8.1.7 by the investigator. The baseline ECG at visit 2 must be 
performed before administration of first dose of trial product. 
If the ECG evaluation of a baseline ECG is suggestive of a prior MI, the investigator should 
consider if an update of the History of cardiovascular disease form is required. 
Additional ECG recordings can be performed at the investigator’s site at investigator’s discretion at 
other visits than the planned ECG visits. The reason for additional ECG assessments should be 
documented and an AE should be reported if applicable. 
All findings suggestive of a new MI should be reported as an AE or SAE for adjudication at the 
investigator's discretion and according to section 12. 
8.3.11 
Laboratory assessments for safety 
For overall laboratory process see Section 8.5. 
Blood samples will be drawn according to flow chart (see Section 2) and will be analysed at the 
central laboratory to determine levels of the following safety laboratory parameters: 
Haematology: 
• Haemoglobin 
• Haematocrit 
• Leucocytes 
• Thrombocytes 
• Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes) 
Biochemistry:  
• ALT 
• Albumin 
• Alkaline phosphatase 
• Amylase 
• AST 
• Bilirubin, total 
• Calcium, total 
• Creatinine  
• eGFR per CKD-EPI36 
• CK 
• Lipase 
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Date: 
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• Potassium 
• Sodium 
• Urea 
At visit 1, only ALT, creatinine and eGFR will be measured as part of biochemistry. 
Hormones: 
• Calcitonin 
In case any calcitonin value at any time during the trial is ≥ 10 ng/L, the algorithm in Appendix A 
must be followed.  
8.3.12 
Pregnancy testing 
Females of childbearing potential will have a urine dip-stick pregnancy test performed at site as 
specified in Section 2 or as required by local law. For definition of female of non-childbearing 
potential and contraceptive methods see Section 8.2.5 
In case a menstrual period is missed or if pregnancy is suspected between the scheduled visits, a 
urine pregnancy test should be performed. Investigator should instruct the subject to contact the site 
in case the pregnancy test is positive. At visit 2, females of childbearing potential will be provided 
with a urine dip-stick pregnancy test. 
8.3.13 
Hypoglycaemic episodes 
Plasma glucose (PG) should always be measured and recorded when a hypoglycaemic episode is 
suspected.  
All PG values: 
• ≤ 3.9 mmol/L (70 mg/dL) or  
• > 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms  
should be reported in the diary according to the instructions below throughout the trial from visit 1 
to end of trial by the subject. In case a subject is not able to fill in the diary, (e.g. in case of 
hospitalisation), then investigator should report the hypoglycaemic episode in the eCRF. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines37. 
A SMPG value ≤ 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms will per default be considered as one hypoglycaemic episode until a succeeding SMPG 
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value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved. One hypoglycaemic 
episode form is to cover these measurements and/or symptoms.  
In case of several low SMPG values within the hypoglycaemic episode, the lowest value is the one 
that will be reported as the SMPG value for the hypoglycaemic episode but the start time of the 
episode will remain as the time for the first SMPG value and/or symptom. 
The record should include the following information: 
• Start date and time of the hypoglycaemic episode  
• Stop date and time of the hypoglycaemic episode (stop time is the first time the PG value is >3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved). If a stop date and time is not 
reported, a hypoglycaemic episode will cover a period of 60 minutes. 
• The PG level before treating the episode (if available) and any follow up measurements.  
• The lowest value measured during the hypoglycaemic episode will be reported as the PG value 
for the episode, the remaining values will be kept as source data in the diary. 
• Whether the episode was symptomatic (Yes/No) 
• A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode. 
• Whether the subject was able to treat him/herself. 
If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported, reflecting the most severe degree of hypoglycaemia. 
• Date and time of last trial product administration and for selected antidiabetic medications 
administered prior to the episode, date and time as well as dose must also be collected 
• Date and time of last main meal (not including snacks) prior to the episode 
• Whether the episode occurred in relation to physical activity 
• Change in any concomitant illness 
• Any sign of fever and/or other acute disease  
• Whether the subject was asleep when the episode occurred 
- 
If yes, whether the symptoms of the episode woke up the subject 
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring 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 concentration37. 
Oral carbohydrates must not be given if the subject is unconscious. 
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If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject: 
• Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person)? 
• Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not) 
• Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, IV glucose or 
other) 
• Were symptoms alleviated after administration of treatment? 
• Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. , mix-up between products, incorrect use of device), overdose and other factors not 
listed or unknown) 
• Did the subject experience seizure? 
• Was the subject unconscious/comatose? 
• Did the subject experience any of the following symptoms38(layman term used in the diary is 
specified in brackets if different from the protocol term)?  
- 
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat) 
- 
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate 
movement) 
- 
General malaise: headache or malaise (feeling discomfort/unease) 
• Other symptoms  
The investigator must review the diary for low SMPG values not reported as hypoglycaemic 
episodes (see Section 2 for relevant visits). The subject must be questioned whether any of the low 
values were severe, i.e. whether the subject was able to self-treat or not. If the subject was not able 
to self-treat, it has to be reported as a severe hypoglycaemic episode on a hypoglycaemic episode 
form. 
Low SMPG values for non-severe hypoglycaemic episodes not having a hypoglycaemic episode 
form completed within 7 days since the SMPG measurement should be reported on a 
hypoglycaemic episode form with as much information as possible. Novo Nordisk will not query 
for additional data except for the start date, SMPG value and whether the subject was able to self-
treat due to decreased validity of such data39, 40. 
The subject must be re-trained in how to report hypoglycaemic episodes if the investigator identifies 
low SMPG values not reported as hypoglycaemic episodes. 
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in (see Section 12). 
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8.4 
Laboratory assessments 
The laboratory analyses will mainly be performed by a central laboratory. For some of the analyses 
related to suspicion of acute pancreatitis and hypersensitivity, see Appendix B. 
The handling, transportation and storage of biological samples are described in the laboratory 
manual (for central and special laboratory details see Attachment I). 
Samples will be coded in order to keep subject identity anonymous. 
Laboratory samples not drawn on the day of the actual visit should preferably be drawn on another 
day within the visit window stated in the flow chart (see Section 2). Please note that a laboratory 
sample pertaining to a specific visit must always be reported to that visit. 
For some of the samples drawn during the trial, subjects will be asked to attend the site visits fasting 
(fasting for blood sampling is defined in Section 8.1.2). 
The central laboratory will provide laboratory results to the investigator on an ongoing basis.  
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units. 
Laboratory samples will be destroyed at the latest at the completion of the CTR, or according to 
local regulations. 
8.5 
Other assessments 
8.5.1 
Subject diary 
The diaries should be handed out at the visits described in the flow chart (see Section 2). The 
recordings must be reviewed as described in Section 8.1.7 and transcribed to the eCRF at the 
following visit. 
Entries in the diaries are only to be made by the subject, unless otherwise specified. 
The investigator should instruct the subject in recording the following data in the diary: 
• date of first trial product administration 
• hypoglycaemic episodes 
• changes in concomitant medication 
• AEs 
• SMPG 7-point profile (prior to selected site visits (see Section 8.3.2.1)) 
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8.6 
Subject compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 
Treatment compliance:  Will be assessed by monitoring of drug accountability and by discussing 
treatment compliance and dosing conditions with the subject . The subject will be asked to return all 
used, partly used and unused trial product including empty packaging material during the trial as 
instructed by the investigator. The investigator must assess the amount of trial products returned 
compared to what was dispensed at the previous visit and, in case of discrepancies, question the 
subject. If a subject is found to be non-compliant, the investigator will remind the subject of the 
importance of following the instructions given including taking the trial products as prescribed and 
should document this discussion in the subject’s medical record. 
Compliance is defined as taking between 80%-120% of the dose as prescribed between visits. If the 
subject has been off treatment for more than 10 consecutive days, then Novo Nordisk should be 
contacted for guidance regarding continuation of trial medication.. 
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Date: 
28 January 2019 
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levels. Semaglutide and both placebo products are manufactured and supplied by Novo Nordisk, 
Denmark. Sitagliptin 100 mg is packed for use in clinical trials and supplied by Novo Nordisk, 
Denmark. 
9.2 
Labelling 
The trial products will be labelled in accordance with Annex 1341, local regulations and trial 
requirements. 
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS. Trial product will be distributed to the trial sites according to enrolment 
and randomisation. 
9.3 
Storage  
Storage conditions of the trial products are outlined in Trial Materials Manual (TMM). 
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the trial materials manual. 
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage. 
9.4 
Drug accountability and destruction 
Drug accountability of all trial products received at site is the responsibility of the investigator. 
Subjects must be instructed to return all used, partly used and unused trial products including empty 
packaging material as instructed by the investigator. 
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored outside controlled temperature areas, separated from non-allocated trial product. 
Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site. 
Drug accountability is performed by using the IWRS. Drug accountability must be done on tablet 
level. 
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of 
products must be documented in the IWRS. 
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9.5 
Auxiliary supplies 
The following will be provided by Novo Nordisk in accordance with the trial materials manual: 
• BG meter and BG meter auxiliaries 
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10  Interactive voice/web response system 
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons.  
IWRS is used for:  
• Medication arrival 
• Screening 
• Screening failure 
• Randomisation 
• Dispensing 
• Dispensing verification (when barcode scanner is used) 
• Treatment discontinuation  
• Completion 
• Code break 
• Drug accountability 
• Data change 
IWRS user manuals will be provided to each trial site.  
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11 Randomisation procedure and breaking of blinded codes 
The trial is a double-blinded trial. A randomisation session will be carried out for all subjects using 
the IWRS.  
At the randomisation visit (visit 2), subjects meeting all eligibility criteria will be randomised to one 
of four parallel treatment arms as described in Section 5.1. 
Randomisation will be stratified according to whether a subject is from the China region (including 
Taiwan and Hong Kong) or not.  
• Region: 
- 
China 
- 
Non-China 
11.1 
Breaking of blinded codes 
The IWRS will notify Novo Nordisk (monitor and the Global Safety department) immediately after 
the code is broken. 
The code for a particular subject may be broken in a medical emergency if knowing the actual 
treatment would influence the treatment of the subject. Whenever a code is broken the person 
breaking the code must print the Code Break Confirmation Notification generated by the IWRS, 
record the reason, and sign and date the document. 
When the code is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of code break the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I. If the code has been 
broken by investigator, the subject must discontinue treatment with trial product but be asked to 
continue in the trial (see Section 8.1.5). A treatment discontinuation session must be completed in 
IWRS. 
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12 Adverse events, technical complaints and pregnancies 
12.1 
Definitions 
12.1.1 
Adverse event  
An AE is any untoward medical occurrence in a subject administered a medicinal product, and 
which does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product.  
An AE includes: 
• A clinically significant worsening of a concomitant illness. 
• A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality. 
The following should not be reported as AEs: 
• Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness). 
• Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent. 
• Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form (see Section 8.4.9). 
The following three definitions are used when assessing an AE: 
• Severity  
– Mild – no or transient symptoms, no interference with the subject’s daily activities. 
– Moderate – marked symptoms, moderate interference with the subject’s daily activities. 
– Severe – considerable interference with the subject’s daily activities; unacceptable. 
• Causality  
Relationship between an AE and the relevant trial product(s):  
– 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 trial product. 
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• Final outcome  
– Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent. 
– Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE. 
– 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. 
– Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE. 
– Unknown - This term is only applicable if the subject is lost to follow-up. 
12.1.2 
Serious adverse event 
A SAE is an AE that fulfils at least one of the following criteria: 
• Death. 
• A life-threateninga experience. 
• In-patient hospitalisationb or prolongation of existing hospitalisation. 
• A persistent or significant disability or incapacityc. 
• A congenital anomaly or birth defect. 
• Important medical events that may not result in death, be life threateninga or require 
hospitalisationb may be considered an SAE when - based on appropriate medical judgement - 
they may jeopardise the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the definition of SAEd.  
a. The term “life threatening” in the definition of SAE 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 was more severe. 
b. The term “hospitalisation” is used when a subject:  
– Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or  
– Stays at the hospital for treatment or observation for more than 24 hours 
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
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not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs. 
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life). 
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse. 
The following AEs must always be reported as an SAE using the important medical event criterion 
if no other seriousness criteria are applicable: 
• suspicion of transmission of infectious agents via the trial product  
• risk of liver injury defined as ALT or AST >3 x ULN and total bilirubin >2 x ULN, where no 
alternative aetiology exists (Hy's law) 
Additional assessments should be made for events meeting the criterion of Hy’s law as stated above 
(see Appendix B). 
12.1.3 
Non-serious adverse event 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
12.1.4 
Medication errors 
A medication error42 is an unintended failure in the trial drug 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 lower or higher dose than intended. The administered dose must 
deviate from the intended dose to an extent where clinical consequences for the trial subject were 
likely to happen as judged by the investigator, although they did not necessarily occurMedication 
errors must be reported on an AE form and a specific event form (see Section 12.1.4.1 and 
Appendix B). 
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Date: 
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Neoplasm (excluding thyroid neoplasm) 
 
Yes 
Yes (only if 
malignant) 
Thyroid disease (including thyroid neoplasm) 
Yes 
Yes, (only if 
malignant thyroid 
neoplasm or C-cell 
hyperplasia) 
Pancreatitis 
Yes 
Yes (only if acute 
pancreatitis) 
Renal Event 
Yes 
Yes (only if acute 
kidney injury) 
Death 
No 
Yes 
Medication error 
Yes 
No 
Abuse and misuse of trial product  
Yes 
No 
Lactic acidosis 
Yes 
Yes 
CK > 10x ULN 
Yes 
No 
Hepatic event defined as: 
• ALT or AST > 5x ULN and total bilirubin ≤ 2x ULN 
• ALT or AST > 3x ULN and total bilirubin > 2x ULN* 
• Hepatic event leading to trial product discontinuation. 
Yes 
No 
Diabetic retinopathy and related complications 
 
Yes 
No 
* Please note that in case of a hepatic event defined as ALT or AST > 3 x ULN and total bilirubin > 2 x ULN, where no 
alternative aetiology exists (Hy's law), this must be reported as an SAE using the important medical event criterion if no 
other seriousness criteria are applicable. 
For details about specific event forms, see Section 8.4.1.1, and Appendix B. 
12.1.6 
Technical complaints 
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: 
• The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination) 
• All packaging material including labelling 
Only technical complaints related to AEs will be reported in the CTR.  
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12.2 
Reporting of adverse events 
All events meeting the definition of an AE must be collected and reported. This includes events 
occurring from the first trial-related activity after the subject has signed the informed consent until 
the end of the post-treatment follow-up period (visit 9) for subjects on trial product OR until the end 
of trial (visit 8 or visit 9A, whichever comes last) for the subjects who have discontinued trial 
product prematurely. Events for withdrawn subjects will be collected and reported until last trial 
related contact with the subject. The events must be recorded in the applicable eCRF forms in a 
timely manner (see timelines below and 
Figure 12–1 
Figure 12–1). 
During each contact with the trial site staff, the subject must be asked about AEs and technical 
complaints, for example by asking: “Have you experienced any problems since the last contact?” 
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated.  
All AEs must be recorded by the investigator in the eCRF AE form. The investigator should report 
the diagnosis, if available. If no diagnosis is available, the investigator should record each sign and 
symptom as individual AEs using separate AE forms in the eCRF. 
For SAEs, a safety information form (SIF) must be completed in addition to the AE form. A SIF is 
a form to collect supplementary clinical information. If several symptoms or diagnoses occur as part 
of the same clinical picture, one safety information form can be used to describe all the SAEs.  
AEs requiring additional data collection must be reported using both the AE form and the specific 
event form. A specific event form is a form tailored to collect specific information related to the 
individual event. See Appendix B for details about the events and the additional information to 
report.  
In case any of these events fulfil the criteria for seriousness in Section 12.1, then the event should 
be reported as serious. 
Some events will undergo event adjudication by the Event Adjudication Committee (EAC), please 
refer to Section 12.7.2. For AEs qualifying for event adjudication, the adjudication form will also 
have to be completed in the eCRF. The adjudication form is a checklist of clinical data to be 
collected and uploaded by site to the adjudication database. 
For an overview of AEs requiring additional data collection and AEs that will undergo event 
adjudication, please see Table 12–1. 
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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. 
Timelines for initial reporting of AEs: 
The investigator must complete the following forms in the eCRF within the specified timelines: 
• SAEs: The AE form within 24 hours and the SIF within 5 calendar days of the investigator’s 
first knowledge of the SAE. 
Both forms must be signed within 7 calendar days from the date the information was entered in 
the eCRF. 
• For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE. 
• Events for Adjudication: The adjudication form should be completed within 14 calendar days 
of the investigator’s first knowledge of the AE (see Section 12.7.2).The investigator should 
preferably provide the medical documentation within 4 weeks of event identification according 
to instructions in the event adjudication site manual.  
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file.  
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Date: 
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Novo Nordisk products used as concomitant medication or non-investigational medicinal 
product: 
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
non-investigational medicinal product or concomitant medication in the trial, it is important that the 
suspected relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the 
safety information form. Novo Nordisk may need to report this AE to relevant regulatory 
authorities. 
12.3 
Follow-up of adverse events 
The investigator must record follow-up information by updating the medical records and the forms 
in the eCRF.  
Follow-up information must be reported to Novo Nordisk according to the following: 
• SAEs: All SAEs must be followed until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover. 
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs.  
• Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover. 
• Events for adjudication: If new information becomes available for events in scope for 
adjudication, this must be uploaded to the adjudication database in order for the EAC to 
evaluate if re-adjudication is needed.  
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event. 
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Queries or follow-up requests from Novo Nordisk or event adjudication vendor must be responded 
to within 14 calendar days from the date of receipt of the request, unless otherwise specified in the 
follow-up request. 
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
ended the trial, the investigator should report this SAE within the same timelines as for SAEs 
during the trial.  
12.4 
Technical complaints and technical complaint samples 
12.4.1 
Reporting of technical complaints  
All technical complaints on any of the following products: 
• semaglutide 3 mg/7 mg/14 mg or placebo  tablets, dose-pack 
• sitagliptin 100 mg or placebo  tablets, dose-pack 
which occur from the time of first usage of the product until the time of the last usage of the 
product, must be collected and reported to Customer Complaint Center, Novo Nordisk. 
Contact details (fax, e-mail and address) are provided in Attachment I to the protocol. 
The investigator must assess whether the technical complaint is related to any AEs or SAEs. 
Technical complaints must be reported on a separate technical complaint form: 
• One technical complaint form must be completed for each affected DUN  
• If DUN is not available, a technical complaint form for each code or batch number must be 
completed  
The investigator must complete the technical complaint form in the eCRF within the following 
timelines of the trial site obtaining knowledge of the technical complaint: 
• Technical complaint assessed as related to an SAE within 24 hours 
• All other technical complaints within 5 calendar days 
If the eCRF is unavailable or when reporting a technical complaint that is not subject related, the 
information must be provided on a paper form by fax, e-mail or courier to Customer Complaint 
Center, Novo Nordisk, within the same timelines as stated above. When the eCRF becomes 
available again, the investigator must enter the information on the technical complaint form in the 
eCRF. 
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12.4.2 
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 and DUN and and notify the monitor within 5 calendar days of obtaining the 
sample at trial site. The monitor must coordinate the shipment to Customer Complaint Center, Novo 
Nordisk (the address is provided in Attachment I) and ensure that the sample is sent as soon as 
possible. A copy of the technical complaint form must be included in the shipment of the sample. If 
several samples are shipped in one shipment, the  sample and the corresponding technical complaint 
form should be kept together. 
The investigator must ensure that the technical complaint sample contains the code or batch number 
and, if available, the DUN. All parts of the DUN should be returned. 
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable.  
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product. 
12.5 
Pregnancies in female subjects  
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s). 
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age. 
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant. 
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier: 
1. Reporting of pregnancy information 
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively.  
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
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information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner.  
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.  
2. Reporting of AE information 
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE. 
Forms and timelines for reporting AEs: 
Non-serious AEs:  
• AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE. 
SAEs:  
• AE forma within 24 hours of the investigator’s first knowledge of the SAE. 
• SIF within 5 calendar days of the investigator’s first knowledge of the SAE. 
• SAE follow-up information to the AE form and/or safety information form within 24 hours of 
the investigator’s first knowledge of the follow-up information. 
a  It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and safety information form. 
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request. 
12.6 
Precautions and/or overdose 
There are no specific antidotes to semaglutide. Treatment of an overdose should be symptomatic. 
There is a potential risk of hypoglycaemia during dosing with semaglutide. The typical signs and 
symptoms of a non-severe hypoglycaemia include: hunger, slight headache, nausea, light-
headedness, palpitations and sweating. Symptoms of non-severe hypoglycaemia should be treated 
by ingestion of carbohydrates.  
Severe hypoglycaemia resulting in loss of consciousness should be treated according to best 
available medical practise.  
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One case of accidental overdose of oral semaglutide was reported in the NN9924-3692 trial. The 
subject accidentally took the trial product twice the same day and was thus treated with 20 mg of 
oral semaglutide. The subject did not report any symptoms and treatment was continued without 
any change. 
One case of accidental overdose has been reported in subjects treated with s.c. semaglutide once 
weekly. The subject inadvertently injected 4 mg of semaglutide instead of 0.4 mg, which 
corresponds to a 2.5-fold higher dose than the maximum dose included in that trial. After 4−5 hours 
the subject felt nauseated, vomited and had a headache. The subject was instructed to drink 
sufficient amounts of fluids. Symptoms had improved within one day of dosing and the subject 
wished to continue in the trial. No symptoms of hypoglycaemia or any other symptoms or signs 
were noted. 
For further details please see the current edition of the IB for oral semaglutide (NN9924)43, and any 
updates hereof. 
12.7 
Committees related to safety 
12.7.1 
Novo Nordisk safety committee 
Novo Nordisk will constitute an internal oral semaglutide safety committee to perform ongoing 
safety surveillance. The oral semaglutide safety committee may recommend unblinding of any data 
for further analysis, and in this case an independent ad hoc group will be established in order to 
maintain the blinding of the trial personnel. 
12.7.2 
Event adjudication committee 
An independent external EAC is established to perform validation of selected AEs according to pre-
defined diagnostic criteria. The validation is based on review of pre-defined clinical data related to 
the specific AE. Pre-defined clinical data consist of copies of source documents collected and 
delivered by the investigational sites. 
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk.  
The events are reviewed by the EAC in a blinded manner. The EAC will have no authorisations to 
impact on trial conduct, trial protocol or amendments. 
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee. 
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The events outlined in Table 12–2 have been selected for adjudication in order to obtain an external 
independent validation of the diagnosis. In addition, cardiovascular events are being adjudicated 
according to U.S. Food and Drug Administration (FDA) requirements45. 
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
reports and death certificates). The investigator must provide medical documentation as soon as 
possible, when they receive the request from Novo Nordisk or the event adjudication vendor.  
The AEs for adjudication are listed in Table 12–2: 
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Thyroid disease, if malignant 
thyroid neoplasm or C-cell 
hyperplasia 
Malignant thyroid neoplasms are defined as  
• thyroid neoplasms in which abnormal cells 
divide without control and can invade nearby 
tissues and/or spread to other parts of the body 
through the blood and lymph systems 
C-cell hyperplasia is defined as  
• hyperplasia of the parafollicular C-cells of the 
thyroid gland 
• Malignant thyroid 
neoplasm 
• C-cell hyperplasia 
Acute kidney injury 
Acute kidney injury47 is defined as any of the 
following (not graded): 
• Increase in serum creatinine by ≥ 0.3 mg/dL 
(≥ 26.5 μmol/L) within 48 hours, or 
• Increase in serum creatinine to ≥ 1.5 times 
baseline, which is known or presumed to have 
occurred within the prior 7 days, or 
• Urine volume < 0.5 mL/kg/h for 6 hours 
• Acute kidney injury 
Lactic acidosis 
• Lactic acidosis is characterised by increased 
blood lactate level in association with metabolic 
acidosis 
• Lactic acidosis 
*Death is not a separate event, but an outcome 
There are different processes for capturing events for adjudication: 
• Direct reporting by investigator: 
- 
All AEs need to be assessed by the investigator if any AE category is applicable. If 
the selected AE category is in scope for adjudication, the relevant adjudication form 
for the specific event will be populated for site to complete 
- 
AEs with fatal outcome 
• Screening:  
- 
All AEs will be screened by Novo Nordisk for potential missed events for 
adjudication and if needed, the investigator will be asked to provide additional 
information EAC identified events: 
- 
The EAC can decide to have an event adjudicated even if not initially reported as an 
event for adjudication by the investigator. 
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures.  
AEs for adjudication must be reported according to Section 12.2. In addition the specific 
adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual. 
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The assessment made by the EAC will be included in the CTR as well as the assessments made by 
the investigator. However, the adjudication made by the EAC, given its independent analysis of 
each event, will be attributed with greater importance of the two.  
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13 Case report forms  
Novo Nordisk will provide a system for the eCRF. This system and support services to the system 
will be provided by an external supplier. 
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions. 
The following will be provided as paper case report forms (CRFs): 
• Pregnancy forms 
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable: 
• AE forms  
• Safety information forms  
• Technical complaint forms (also to be used to report complaints that are not subject related (e.g. 
discovered at trial site before allocation)  
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF. 
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the casebook in the eCRF, the investigator confirms that the information in 
the eCRF and related forms is complete and correct. 
13.1 
Corrections to case report forms  
Corrections to the eCRF data may be made by the investigator or the investigator’s delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction. 
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the casebook, the casebook must be signed and dated again by the investigator. 
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13.2 
Case report form flow  
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes. 
At the end of the trial, the investigator must ensure that all remaining data have been entered into 
the eCRF no later than 3 days after last subject last visit at the site in order to ensure the planned 
lock of the database. 
Site specific eCRF data (in an electronic readable format) will be provided to the trial site before 
access to the eCRF is revoked. This data must be retained at the trial site. When the final CTR is 
available, the data will be archived by Novo Nordisk A/S. 
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14 Monitoring procedures  
Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring and visits to trial sites. 
During the course of the trial, the monitor will visit the trial site to ensure that the protocol is 
adhered to, that all issues have been recorded, to perform source data verification and to monitor 
drug accountability. The first monitoring visit will be performed as soon as possible after first 
subject first visit at the trial site and no later than 4 weeks after. The monitoring visit intervals will 
depend on the outcome of the centralised monitoring of the eCRFs (remote assessment of data by 
Novo Nordisk), the trial site's recruitment rate and the compliance of the trial site to the protocol 
and Good Clinical Practice (GCP), but will not exceed 12 weeks until last subject last visit at the 
trial site (for sites with active subjects (defined as subjects in screening, treatment or follow-up)). 
The monitor must be given direct access to all source 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 trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone). 
All data must be verifiable in source documentation other than the eCRF. 
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element. 
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction. 
The original of the completed diaries and/or PROs must not be removed from the trial site, unless 
they form part of the eCRF and a copy is kept at the site. 
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected. 
The following data will be source data verified for screening failures:  
• Date for obtaining informed consent. 
• Screening failure date and reason  
• Date of visit 
• Demography (date of birth, sex and race (according to local regulation)) 
• Eligibility criteria 
• SAEs 
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Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs) 
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these. 
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. This should address any action to be taken. 
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15 Data management 
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a Contract Research Organisation (CRO).  
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks.  
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer. 
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements. 
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16 Computerised systems 
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented. 
Investigators working on the trial may use their own electronic systems to capture source data.  
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17 Statistical considerations 
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock. 
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked. 
Data from all sites will be analysed and reported together.  
China including Taiwan and Hong Kong will be considered as a separate region unless otherwise 
specified. The information regarding region (China/non-China) will be included based on country 
details from the IWRS.  
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. 
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. Number of 
values below LLoQ by treatment and visit will be summarised if deemed relevant. 
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below three comparisons with associated two-sided 95% confidence intervals and 
p-values corresponding to two-sided tests of no difference: 
• oral semaglutide 14 mg vs. sitagliptin 100 mg 
• oral semaglutide 7 mg vs. sitagliptin 100 mg 
• oral semaglutide 3 mg vs. sitagliptin 100 mg 
If no statistical analysis is specified, data will be presented using relevant summary statistics. 
Primary and secondary estimands 
Two estimands addressing different aspects of the trial objective will be defined; a primary 
‘Hypothetical’  estimand and a secondary ‘Treatment-policy  estimand:  
• Primary estimand – ‘Hypothetical’ 
- 
 Treatment difference at week 26 for all randomised subjects if all subjects adhered 
to treatment and did not initiate rescue medication 
The hypothetical estimand assesses the glycaemic benefit a future subject is expected to achieve if 
initiating and continuing treatment with oral semaglutide as compared to sitagliptin. It is considered 
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a clinically relevant estimand as it provides information to treating clinicians about the expected 
glycaemic efficacy of oral semaglutide compared to sitagliptin for purposes of treating individual 
subjects. Generalisation of this estimand depends among other things on the extent to which the 
adherence to trial product administration in this trial reflects the behaviour of the target population. 
Accordingly, only data collected prior to discontinuation of trial product or initiation of rescue 
medication will be used to draw inference. This will avoid confounding from rescue medication. 
• Secondary estimand  ‘Treatment-policy’ 
- 
Treatment difference at week 26 for all randomised subjects regardless of adherence 
to randomised treatment and initiation of rescue medication. 
The treatment policy estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s) as compared to initiating treatment with sitagliptin including potential rescue 
medication(s). Generalisation of this estimand depends among other things on the extent to which 
the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.  
The confirmation of the confirmatory hypotheses will be based on the primary analysis results for 
the primary  estimand (hypothetical). However, to address a different aspect of the trial objective 
and to be able to compare the trial results with the global trial (PIONEER 3), the secondary 
estimand (treatment-policy) has been included as well. 
Missing data considerations at week 26 
When estimating the primary estimand, data collected after discontinuation of trial product or 
initiation of rescue medication(s) will be set to missing. Across treatment arms the main reasons for 
missing data are expected to be early treatment discontinuation due to GI AEs and initiation of 
rescue medication. The proportion of missing data is expected to be 20% based on the sitagliptin 
phase 3 trials48, the oral semaglutide phase 2 trial (NN9924-3790) that indicated that a low starting 
dose with gradual dose escalation diminishes GI AEs compared with more aggressive dosing 
regimens. Initiation of rescue medication is expected to be more frequent in the sitagliptin arm and 
in the oral semaglutide 3 mg arm than for the two highest dose levels of oral semaglutide. A higher 
proportion of subjects are expected to discontinue treatment due to AEs in the oral semaglutide 14 
mg arm compared to the other treatment arms. So, overall, the frequency of missing data is 
expected to be similar across treatment arms. 
When estimating the secondary estimand, the proportion of missing data, i.e., data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s) is expected to be maximum 10% based on the oral semaglutide phase 2 trial 
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(NN9924-3790). Thus, missing data will mainly be due to withdrawal from trial or lost to follow-
up. 
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm. 
17.1 
Sample size calculation 
The primary endpoint is change from baseline to week 26 in HbA1c. For HbA1c, both non-inferiority 
and superiority versus sitagliptin are planned to be tested at each dose level. The confirmatory 
secondary endpoint is change from baseline to week 26 in body weight (kg). For body weight, 
superiority versus sitagliptin is planned to be tested at each dose level. The sample size calculation 
is made for the primary estimand and ensuresa power of at least 85% for testing the below three out 
of the nine pre-specified confirmatory hypotheses shown in Figure 17–1. The closed testing 
procedure described in Bretz et al 201149 is used to control the overall type I error at a nominal two-
sided 5% level. The three hypotheses are: 
• HbA1c superiority of semaglutide 14 mg vs. sitagliptin 100 mg 
• HbA1c superiority of semaglutide 7 mg vs. sitagliptin 100 mg  
• HbA1c non-inferiority of semaglutide 3 mg vs. sitagliptin 100 mg (margin of 0.3%-point) 
The statistical testing strategy is based on the following two principles: 
• Within a dose level, glycaemic effect must be established in terms of HbA1c non-inferiority 
before testing for added benefits in terms of superiority for HbA1c and/or superiority of body 
weight.  
• Glycaemic effect in terms of HbA1c non-inferiority must be established on all higher dose levels 
before continuing testing hypotheses on lower dose levels. 
The sample size is calculated using the calcPower function in the R package, gMCP50 using 10000 
simulations. All of the nine pre-specified confirmatory tests are assumed to be independent. Since 
positive correlations among the tests are expected, the assumption of independence is viewed as 
conservative. 
The sample size assumptions for treatment effects (TE), adjusted TE and the common standard 
deviations (SD) used across dose levels are given in Table 17–1. These are based on the oral 
semaglutide phase 2 results (NN9924-3790), sitagliptin phase 3a trial results48 and supported by 
results from the s.c. semaglutide phase 2 trial (NN9535-1821). 
An adjustment in TE will be implemented for the 20% of subjects who are expected to have missing 
data. The TE used in the sample size calculation will be adjusted according to a 50% smaller effect 
in these subjects. The adjusted treatment effect is defined as 0.8×TE + 0.2×TE×0.50.  
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Definition of analysis sets                                                                                                                                      
The following analysis sets will be defined: 
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”. 
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period where they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”. 
Per protocol (PP) analysis set: Includes all subjects in the FAS who fulfil the following criteria: 
• have not violated any inclusion criteria 
• have not fulfilled any exclusion criteria 
• have a baseline HbA1c measurement 
• is exposed to trial product and have at least one valid HbA1c measurement while on treatment 
without rescue medication at or after week 14  
Subjects in the PP analysis set will, as in the SAS, contribute to the analysis “as treated”. 
Data selections and observation periods 
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including: 
• the follow-up visit (visit 9) for subjects on trial product 
• the latest occurring visit of the EOT visit (visit 8) or the follow-up premature discontinuation 
visit (visit 9A), for subjects who have discontinued trial product prematurely 
Subjects and data to be used in an analysis will be selected in a two-step manner: 
• Firstly, subjects will be selected based on the specified analysis set 
• Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period 
Definition of the observation periods: 
In-trial: This observation period represents the time period where subjects are considered to be 
in the trial, regardless of discontinuation of trial product or initiation of rescue medication. The 
in-trial observation period starts at randomisation (as registered in the IWRS) and ends at the 
date of:  
- 
the last direct subject-site contact, which is scheduled to take place 5 weeks after 
planned last dose of trial product at the follow-up visit  
- 
withdrawal for subjects who withdraw their informed consent 
- 
the last subject-investigator contact as defined by the investigator for subjects who 
are lost to follow-up 
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- 
death for subjects who dies before any of the above 
On-treatment: This observation period represents the time period where subjects are 
considered treated with the trial product. The observation period is a subset of the in-trial 
observation period. It starts at the date of first dose of trial product. Two slightly different end 
dates will be needed to cover all assessments appropriately. For adjudicated events, ECGs, eye 
examination category, and AEs including hypoglycaemic episodes, the observation period ends 
at the first date of:  
- 
the follow-up visit (visit 9) 
- 
the follow-up prematurely discontinuation visit (visit 9A) 
- 
the last date on trial product + 38 days  
- 
the end-date for the in-trial observation period 
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product 
corresponding to approximately five half-lives of oral semaglutide. The visit window for the 
follow-up visit is + 3 days. 
For efficacy and other safety assessments (laboratory assessments, physical examination and 
vital signs) the observation period ends at the last date on trial product + 3 days. This will be 
used in order to ensure specificity to reversible effects of treatment. 
On-treatment without rescue medication: This observation period is a subset of the on-
treatment observation period, where subjects are considered treated with trial product, but have 
not initiated any rescue medications. Specifically it starts at date of first dose of trial product 
and the observation period ends at the first date of: 
- 
the last dose of trial product +3 days 
- 
initiation of rescue medication 
The on-treatment without rescue medication observation period will be the primary observation 
period when estimating the primary estimand (hypothetical). The in-trial observation period will be 
the primary observation period when estimating the secondary estimand (treatment-policy Safety 
will be evaluated based on the in-trial and the on-treatment observation periods. 
Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date. 
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
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 
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exclusion must be documented and signed by those responsible before database lock. The subjects 
and observations excluded from analysis sets, and the reason for this, will be described in the CTR. 
Confirmatory hypotheses  
For the primary HbA1c endpoint and the secondary confirmatory body weight endpoint, the 
following three confirmatory one-sided hypotheses are planned to be tested at each dose level of 
oral semaglutide versus sitagliptin. Let the mean treatment difference at week 26 be defined as μ = 
(oral semaglutide minus sitagliptin): 
• HbA1c, non-inferiority, using a non-inferiority margin of 0.3%-point 
- 
H0: μ ≥ 0.3%-point against Ha: μ < 0.3-point% 
• HbA1c superiority 
- 
H0: μ ≥ 0.0%-point against Ha: μ < 0.0%-point 
• Body weight superiority 
- 
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg 
Operationally the hypotheses will be evaluated by two-sided tests at the 5% significance level.  
Multiplicity and criteria for confirming hypotheses 
The type I error for testing the nine confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using the weighted Bonferroni-
based closed testing procedure described in Bretz et al 2011 and outlined in Figure 17–1.  
The first hypothesis to be tested is non-inferiority of HbA1c at the highest dose level. 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 edges 
going from the confirmed hypothesis to the next hypotheses as specified in Figure 17–1. Each of the 
following hypotheses will be tested at their updated local significance level (α-local). This process 
will be repeated until no further hypotheses can be confirmed. 
Non-inferiority and/or 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 of the primary estimand is strictly below its local two-sided significance level as defined by 
the closed testing procedure in Figure 17–1. This is equivalent to using a one-sided p-value 
(nominal α= 0.025) and a one-sided 2.5% overall significance level in the closed testing procedure.  
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Date: 
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17.2 
Primary endpoint 
The primary endpoint is change from baseline to week 26 in HbA1c. 
17.2.1 
Primary analysis for the primary estimand  
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 26 from the on-treatment without rescue medication observation period. The 
primary analysis for the primary estimand will be a Mixed Model for Repeated Measurements 
(MMRM). A restricted maximum likelihood (REML) will be used. The model will include all post-
baseline HbA1c measurements collected at scheduled visits up to and including week 26 as 
dependent variables. The independent effects included in the model will be treatment 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. For subjects who do not have post-baseline 
assessments for planned visits available in the on-treatment without rescue medication period, the 
baseline value will be carried forward to the first planned visit to ensure that all randomised subjects 
will contribute to the statistical analysis. 
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is missing at random (MAR). Under 
this assumption, the statistical behaviour of the missing data (given the observed responses and 
model fixed effects and covariates) is assumed to be same as for the observed data.  
17.2.2 
Primary analysis for the secondary estimand 
The secondary estimand will be estimated based on the FAS using week-26 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 MAR 
within the groups used for imputation. Imputation of missing data at week 26 will be done within 8 
groups of subjects defined by randomised treatment arm, and whether subjects at week 26; (i) have 
discontinued treatment or initiated rescue medication or (ii) are still on treatment and have not 
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 26 are 
similar in terms of randomised treatment arm and treatment adherence/rescue status. 
Missing values for each group will be imputed as follows: 
• An analysis of covariance (ANCOVA) with region as categorical fixed effects and baseline 
HbA1c measurement as a covariate will be fitted to observed values of the change from baseline 
in HbA1c at week 26. 
• The estimated parameters for location and dispersion will be used to impute 1000 values for 
each subject with missing week-26 data based on region as categorical and baseline HbA1c. 
Thus, 1000 complete data sets will be generated including observed and imputed values. 
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Analysis used for superiority versus sitagliptin at week 26: 
For each of the 1000 (now complete) imputed data sets, the change in HbA1c from baseline to week 
26 will be analysed using an ANCOVA with treatment and region as categorical fixed effects and 
baseline HbA1c as covariate. The results obtained from analysing the data sets will be combined 
using Rubin’s rule51 to draw inference. 
Analysis used for non-inferiority versus sitagliptin at week 26: 
Prior to analysing the data using the same model and approach as used for superiority (see above), a 
value of 0.3% (the non-inferiority margin) will be added to imputed values at week 26 for the oral 
semaglutide treatment arms only52. For evaluating non-inferiority versus sitagliptin unadjusted two 
sided p-values for testing no difference from the non-inferiority margin will be presented. 
17.2.3 
Sensitivity analyses 
To investigate the sensitivity of the primary analysis results, a complementary and separate analysis 
will be performed for the primary and secondary estimand. In line with European Medicines 
Agency (EMA) recommendations53 and with a report from the US National Research Council54, 
these analyses will primarily evaluate the sensitivity of the results due to the impact of missing data. 
Since conservatism, i.e. avoiding bias in favour of oral semaglutide, depends on the context, 
separate sensitivity analyses will be made for non-inferiority and superiority testing. 
The evaluation of the robustness of the primary analysis results will  be based on a pattern mixture 
model approach using multiple imputation. The pattern mixture model sensitivity analyses aim to 
stress-test the primary HbA1c results by changing the assumptions for the missing data in the oral 
semaglutide treatment arms, while maintaining the MAR data assumption for the sitagliptin 
Additiomally a sensitivity analysis for the primary analysis will be described that is not based on the 
pattern mixture model approach (see Section 17.2.3.1). 
Sensitivity analyses for the primary estimand 
The estimation of the primary estimand will be repeated using a tipping-point multiple imputation 
analysis based on FAS using the on-treatment without rescue medication observation period: 
 
In this sensitivity analysis, missing data will first be imputed using a sequential multiple imputation 
approach assuming MAR. The imputation will be done as described below: 
• 
Intermittent missing values in the on-treatment without rescue medication 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 
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be used to impute missing values at each planned visit. The model will include region as 
categorical effect and baseline and post-baseline values prior to the visit in question as 
covariates. 
Secondly, for all oral semaglutide treatment arms a penalty will be added to the imputed values at 
week 26. The approach is to gradually increase this penalty until all confirmed HbA1c conclusions 
from the primary analysis are reversed. For each hypothesis tested the specific value of the penalty 
that reverses the conclusion will be used to evaluate the robustness of the primary analysis results. 
  
Sensitivity analyses for the secondary estimand 
The estimation of the secondary estimand will be repeated using a tipping-point multiple imputation 
analysis based on FAS using the in-trial observation period. For all oral semaglutide treatment arms 
a penalty will be added to the imputed values at week 26 from the primary analysis for the 
secondary estimand. The approach is to gradually increase this penalty until all confirmed HbA1c 
conclusions from the primary analysis are reversed. For each hypothesis tested the specific value of 
the penalty that reverses the conclusion will be used to evaluate the robustness of the primary 
analysis results. 
17.2.3.1 
Other sensitivity analyses 
• Per-protocol analysis: This sensitivity will be based on the per-protocol analysis set. Data from 
the on-treatment without rescue medication observation period will be analysed using the 
primary MMRM analysis approach for the primary estimand. This sensitivity analysis will be 
used to evaluate the robustness of the HbA1c non-inferiority conclusions. 
17.2.4 
Chinese subgroup analyses 
Subgroup analyses for the primary endpoint and the confirmatory secondary endpoint will be 
performed by region with the aim to assess the TE in China region. They will be performed in a 
combined model using all data similar to the main analysis of the respective parameter but with an 
interaction between treatment and region. In addition, the safety in China region will be assessed. 
17.3 
Secondary endpoints 
17.3.1 
Confirmatory secondary endpoints  
Change from baseline to week 26 in body weight (kg) will be a confirmatory secondary endpoint.  
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint. Body weight will only be tested for superiority. Baseline body weight 
will be used as a covariate instead of baseline HbA1c in both the MMRM and the multiple 
imputation analysis models. 
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Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the primary estimand is 
strictly below its local two-sided significance level resulting from the closed testing procedure in 
Figure 17–1. Sensitivity analyses similar to the ones pre-specified for testing superiority for the 
primary HbA1c endpoint will be made to evaluate the robustness of the body weight results. 
17.3.2 
Supportive secondary endpoints 
17.3.2.1 
Efficacy endpoints 
The below supportive secondary efficacy endpoints will be evaluated for: 
• the primary estimand based on FAS using the on-treatment without rescue medication 
observation period. For endpoints where the first planned visit falls later than 8 weeks after 
randomisation, the baseline will not be carried forward 
•  the secondary estimand based on FAS using the in-trial observation period 
No sensitivity analyses are planned for these.  
Continuous efficacy endpoints 
Change from baseline to week 26 in: 
• FPG 
• Body weight (%) 
• BMI 
• Waist circumference 
• Fasting lipid profiles (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, 
triglycerides, free fatty acids) 
BMI will be calculated based on body weight and height based on the formulae: 
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703]) 
Change from baseline to week 26 in the below derived endpoints from the 7-point SMPG profile: 
• Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time 
• Mean post prandial increment (over all meals) 
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. Fasting lipid profile 
endpoints will be log-transformed prior to analysis with the associated log-transformed baseline 
value as a covariate. 
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Binary efficacy endpoints 
If a subject after week 26 achieves (yes/no): 
• HbA1c < 7.0 % (53 mmol/mol) (ADA target) 
• HbA1c ≤ 6.5 % (48 mmol/mol) (AACE target) 
• Body weight loss ≥ 5 % 
• Body weight loss ≥ 10 % 
• HbA1c < 7.0 % (53 mmol/mol) without hypoglycaemia ( severe or BG confirmed symptomatic 
hypoglycaemia) and no body weight gain 
• HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) and body weight loss ≥ 3 % 
When addressing the treatment-policy estimand the ‘without hypoglycaemia’ component of the 
composite endpoint will also include non-treatment-emergent events of severe or BG-confirmed 
symptomatic hypoglycaemia as data collected regardless of discontinuation of trial product or 
initiation of rescue medication(s) is used.  
Missing data for the above six binary endpoints will be accounted for using multiple imputation 
techniques. For the treatment-policy estimand the binary endpoints will be calculated as 
dichotomisations of the 1000 multiple imputations underlying the primary MI analysis. For the 
hypothetical estimand the model will be implemented using a sequential imputation approach as in 
the tipping-point sensitivity analysis. The binary endpoints will be derived as dichotomisations of 
the 1000 imputed complete data sets from the sequential imputation. 
The imputed complete data sets will be analysed using a logistic regression model with treatment 
and region as categorical fixed effects and baseline response as covariate (i.e. baseline HbA1c for 
binary HbA1c endpoints, baseline weight for binary weight endpoints and both baseline HbA1c and 
body weight for the binary endpoints that combines both parameters). Inference comparing 
treatments will be drawn using Rubin’s rule51. 
For the composite endpoints involving both HbA1c and body weight the imputed data sets will be 
combined by imputation number. 
Time to event endpoint 
• 
Time to additional anti-diabetic medication (to support the treatment policy estimand) 
• 
Time to rescue medication (to support the hypothetical estimand) 
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. 
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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 to be considered as ‘anti-
diabetic medication’. This threshold is set to ensure that the short-term durations (i.e. ≤ 21 days) of 
anti-diabetic medication (e.g. in connection with concurrent illnesses) are not included because such 
intensifications are not likely to affect the effect endpoints. 
Treatment policy estimand: Time to additional anti-diabetic medication 
The treatment policy estimand is addressed for the FAS using the in-trial observation period and 
additional anti-diabetic medication will be considered an event regardless of whether or not subjects 
prematurely discontinued treatment. Time from randomisation to additional anti-diabetic 
medication will be analysed using a Cox proportional hazards model with treatment and 
stratification factor as categorical fixed effects and baseline HbA1c as a covariate. From this analysis 
the estimated Hazard ratios between each of the oral semaglutide dose levels and placebo together 
with associated two-sided 95% CIs and unadjusted two-sided p-values will be presented. The 
analysis aims to address the need of additional anti-diabetic medication regardless of this is due to 
lack of effect or tolerability. Switch to other anti-diabetic treatment is therefore also considered an 
event and withdrawn subjects or subject lost to follow-up will be considered as having an event on 
the day of withdrawal. Subjects will be censored on the day before planned end of treatment visit.  
Hypothetical estimand: Time to rescue medication 
The hypothetical estimand is addressed for the FAS using the on-treatment without rescue 
medication observation period. Time from first dose of trial product to initiation of rescue 
medication will be analysed using the same model as described above. The analysis aims to address 
lack of effect and only initiation of rescue medication as add-on to randomised treatment is 
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considered an event. Switch to other anti-diabetic treatment is not considered an event and as a 
consequence subjects will be censored on the day before date of last trial product. Potential events 
occurring between randomisation and first date on trial product will be included in the analysis as 
events at day 0, in order to count all events of rescue medication.  
17.3.2.2 
Safety endpoints 
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on SAS using the in-trial observation period unless otherwise stated. The following endpoints 
are used to support the safety objectives: 
Adverse events  
• Number of TEAEs during exposure to trial product, assessed up to approximately 31 weeks 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.  
A TEAE is defined as an AE with onset in the on-treatment observation period (see definition of 
observation periods in Section 0). 
TEAEs will be summarised in terms of the number of subjects with at least one event (N), the 
percentage of subjects with at least one event (%), the number of events (E) and the event rate per 
100 patient-years of observation time (R) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
GI AEs will be evaluated by the use of graphical methods.  
Other safety endpoints 
Change from baseline to week 26 in: 
• Amylase 
• Lipase 
• Pulse rate 
• 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 on-treatment observation period and using the primary analysis for the 
secondary estimand based on SAS using the in-trial observation period. Endpoints will be analysed 
separately as described above for continuous efficacy endpoints. Results at week 26 will be 
presented. Amylase and lipase endpoints will be log-transformed prior to analysis with the 
associated log-transformed baseline value as a covariate. 
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Change from baseline to week 26 in: 
• ECG category 
• Physical examination category 
• Eye examination category 
•  
Safety assessments 
Change from baseline to week 26 in: 
• Haematology  
• Biochemistry (except for amylase and lipase) 
• Calcitonin 
The above safety endpoints and assessments will be summarised descriptively by treatment arm and 
visit. Categorical safety endpoints will be summarised as counts and relative frequencies. Calcitonin 
will also be presented by gender.  
Hypoglycaemia 
• Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 31 weeks 
• Treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 31 weeks (yes/no)  
Classification of Hypoglycaemia: 
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only. 
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 0). 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.  
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17–2). 
Novo Nordisk classification of hypoglycaemia 
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L (56 
mg/dL)55. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-off 
point in the definition of BG confirmed hypoglycaemia. 
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Novo Nordisk uses the following classification in addition to the ADA classification: 
• Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification55 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with 
symptoms consistent with hypoglycaemia.  
ADA classification37 of hypoglycaemia  
• Severe hypoglycaemia: An episode requiring 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. 
• Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL). 
• Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL). 
• Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level. 
• Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a PG determination but that was presumably caused by a PG 
concentration ≤ 3.9 mmol/L (70 mg/dL). 
 
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Date: 
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Version: 
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Status: 
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17.5 
Patient-reported outcomes 
PRO endpoints 
Change from baseline to week 26 in: 
•
SF-36v2 (acute version) health survey: Scores from the 8 domains, the physical component
summary score and mental component summary score
The PRO endpoints will be evaluated using the primary analysis for the primary estimand based on 
FAS using the on-treatment without rescue medication period and using the primary analysis for the 
secondary estimand based on FAS using the in-trial observation period. Scores will be analysed 
separately as the other continuous efficacy endpoints with the associated baseline response as a 
covariate. 
17.5.1 
SF-36v2® (acute version) health survey 
The SF-36v2® Health Survey (SF-36v2) (acute version) instrument is a commonly used generic 
instrument measuring health-related quality of life (HRQoL)/general health status across disease 
areas including diabetes. The SF-36v2 (acute version) for adults with a 1-week recall period 
contains 36 items. 
A total of 35 items measure eight domains of functional health and well-being as well as two 
component summary scores: physical functioning (10 items), role limitation due to physical health 
problems (4 items), bodily pain (2 items), general health perceptions (5 items), vitality (4 items), 
social functioning (2 items), role limitations due to emotional problems (3 items) and general 
mental health (5 items), mental component summary (MCS) score, physical component summary 
(PCS) score. There is an additional single item giving information on health change over the past 
week. 
Domain scores 
Norm-based scores (NBS) will be derived using the QualityMetric Health Outcomes™ Scoring 
Software1 including the 2009 US general population norm. The most recent version of the 
QualityMetric Health Outcomes™ Scoring Software available at time of licensing was used for the 
specific trial. Table 17–3 provides an overview of the domains. NBS standardises domain and 
component scores into T-scores using the means and standard deviations from the US general 
population. Higher scores on all domains and component summary measures (PCS and MCS) 
indicate better HRQoL/general health status. Item 2 (i.e. Question 2 in CRF) is not included in any 
score.  
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Table 17–3 
Overview of domains for SF-36v2 (acute version) 
Domain 
Items numbers of items 
included in domain 
Comment 
Physical Functioning (PF) 
Items 3a-j 
Role Limitations Due to Physical Health (Role-Physical; 
RP) 
Items 4a-d 
Bodily Pain (BP) 
Items 7, 8 
Both item scores reversed  
General Health Perceptions (General Health; GH) 
Items 1, 11a-d 
Item scores 1, 11b and 11d reversed 
Vitality (VT) 
Items 9a, 9e, 9g, 9i 
Item scores 9a and 9e reversed  
Social Functioning (SF) 
Items 6, 10 
Item score 6 reversed  
Role Limitations Due To Emotional Problems (Role-
Emotional; RE) 
Items 5a-c 
Mental Health (MH) 
Items 9b, 9c, 9d, 9f, 9h 
Item scores 9d and 9h reversed  
Physical component summary (PCS) 
NA 
The PCS score is a weighted average of 
the 8 domain scores.  
Mental component summary (MCS) 
NA 
The MCS score is also a weighted average 
of the 8 domain scores. Weights differ 
from PCS to MCS.  
Missing data at instrument level will be handled using the Maximum Data Recovery method: The 
method applies a value to a domain item rendered missing if at least one of the items in that domain 
has valid data. A domain score is considered missing if all item values in the domain are missing. 
PCS and MCS are calculated when at least seven of the eight domains have valid data, either actual 
or estimated. However, to calculate PCS, the PF domain must be one of the seven domains having 
valid data. Also, to calculate MCS, the MH domain must be one of the seven domains having valid 
data. 
Responder threshold values 
The responder threshold values, in terms of T-score points for change from baseline are defined in 
Table 17–4. 
Table 17–4 
Responder thresholds for SF-36v2 (acute version) 
Domain 
Responder threshold 
Physical Functioning (PF) 
4.3 
Role Limitations Due to Physical Health (Role-Physical; RP) 
4.0 
Bodily Pain (BP) 
5.5 
General Health Perceptions (General Health; GH) 
7.0 
Vitality (VT) 
6.7 
Social Functioning (SF) 
6.2 
Role Limitations Due To Emotional Problems (Role-Emotional; RE) 
4.6 
Mental Health (MH) 
6.7 
Physical component summary (PCS) 
3.8 
Mental component summary (MCS) 
4.6 
Responder analyses will be based on the responder threshold values and are described in 
Section 17.5.2. 
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17.5.2 
Responder analyses 
Responder analyses will be conducted for both estimands and separately for each score. 
For descriptive statistics the following subject responder categorization is applied for all relevant 
time points and scores: 
•
Responder - improvement: Individual change from baseline in score ≥ positive responder
threshold
•
Non-responder - no change: Individual change from baseline in score  > negative responder
threshold value and < positive responder threshold value
•
Non-responder - worsening: Individual change from baseline in score  ≤ negative responder
threshold value
The following binary subject responder definition is applied for all relevant time points and scores: 
•
Responder: Individual change from baseline in score ≥ positive responder threshold
•
Non-responder: Individual change from baseline in score < positive responder threshold
The binary responder endpoints will be analysed as the other supportive secondary binary efficacy 
endpoints. Estimated proportions and differences in proportions will be reported in addition to odds 
and odds ratios. 
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18 Ethics 
18.1 
Benefit-risk assessment of the trial 
18.1.1 
Risks and precautions 
18.1.1.1 
Oral semaglutide 
The non-clinical safety programme of oral semaglutide has not revealed any safety issues 
precluding use in humans.  
The sections below describe the important identified and potential risks and precautions associated 
with oral semaglutide treatment. These are based on findings in non-clinical studies and clinical 
trials with oral semaglutide as well as other GLP-1 RAs. For each of these risks and precautions, 
mitigating actions have been implemented to minimise the risks for subjects enrolled in this trial. 
Identified risks 
Gastrointestinal adverse events 
Consistent with findings with other GLP-1 RAs, the most frequently reported AEs in clinical trials 
with oral semaglutide have been GI disorders (nausea, vomiting, diarrhoea, dyspepsia and 
constipation). Clinical trials have indicated that a low starting dose and gradual dose escalation 
mitigates the risk of GI AEs. Consequently, a low starting dose and dose escalation with 4 week 
dose-escalation steps have been implemented in the trial.  
Potential risks 
Medullary thyroid cancer 
The human relevance of the proliferative C-cell changes found in rodents treated with GLP-1 RAs 
is unknown, but data suggest that rodents are more sensitive to the mode of action of GLP-1 RAs 
for induction of C-cell tumours. However, as a precaution, subjects with a family or personal 
history of multiple endocrine neoplasia type 2 (MEN 2) or medullary thyroid carcinoma (MTC) will 
not be enrolled in the trial. During the trial, calcitonin will be measured on a regular basis, and 
guidance for investigators on further evaluation and action on elevated calcitonin concentrations is 
included in Appendix A. 
Acute pancreatitis 
Acute pancreatitis has been reported in subjects treated with GLP-1 RAs including oral 
semaglutide. As a precaution, subjects with a history of acute or chronic pancreatitis will not be 
enrolled in the trial. Also, subjects will be informed about the symptoms of acute pancreatitis and 
serum levels of lipase and amylase will be monitored throughout the trial. 
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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 or clinical trials or post-marketing data that GLP-1-
based therapies increase the risk of pancreatic cancer. However, pancreatic cancer has been 
included as a separate potential risk due to the scientific debate surrounding a potential association 
to GLP-1-based therapies and the unknown long-term effects of stimulation of β-cells and 
suppression of α-cells. Pancreatic cancer has been classified as a potential class risk of GLP-1 RAs 
by European Medicines Agency (EMA). 
Allergic reactions 
As in the case with all protein-based pharmaceuticals, treatment with oral semaglutide may evoke 
allergic reactions. These may include urticaria, rash, pruritus as well as anaphylactic reactions. As a 
precaution, subjects with known or suspected hypersensitivity to trial product(s) or related products 
will not be enrolled in the 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. 
Hypoglycaemia 
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
sulphonylurea or insulin. The risk for development of hypoglycaemia with oral semaglutide in 
combination with sulphonylurea and insulin is currently unknown.  
Acute renal impairment 
In subjects treated with GLP-1 RAs, including oral semaglutide, GI AEs such as nausea, vomiting 
and diarrhoea may lead to significant dehydration and secondary acute renal impairment. Subjects 
with GI AEs are recommended to drink plenty of fluids to avoid volume depletion. Also, serum 
creatinine and other markers of kidney function will be monitored throughout the trial. 
Impaired renal function may increase the risk of metformin-associated lactic acidosis when GLP-1 
RAs are co-administered with metformin. As a precaution, serum creatinine will be measured 
regularly. In subjects treated with metformin who experience prolonged or severe nausea and 
vomiting, the investigator should monitor serum creatinine, and if clinically indicated, withhold 
metformin until resolution of renal dysfunction. 
The use of the background medication should be used in accordance with standard of care or local 
label in the individual country. 
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Other safety considerations 
Diabetic retinopathy complications 
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment56,57,58. Risk factors for these events 
include long-standing poor glycaemic control and presence of proliferative retinopathy, and initial 
large improvements in BG may be an additional aggravating factor. Several studies have, however, 
documented long-term beneficial effects of intensive glycaemic treatment in reducing retinopathy 
progression59,60 even in intensively treated patients who experienced early worsening57. In a 
cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of events 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo61. As a 
precaution in this trial, all subjects are required to have a fundus photography or dilated fundoscopy 
performed before enrolment into the trial; moreover, subjects with proliferative retinopathy or 
maculopathy requiring acute treatment will be excluded. As part of good diabetes management the 
investigator is encouraged to ensure adequate monitoring and treatment of diabetic retinopathy in 
subjects enrolled into the trial62. 
Teratogenicity (embryo-foetal development toxicity) 
Semaglutide caused embryo-foetal malformations in the rat through a GLP-1 receptor mediated 
effect on the inverted yolk sac placenta leading to impaired nutrient supply to the developing 
embryo. Primates do not have an inverted yolk sac placenta which makes this mechanism unlikely 
to be of relevance to humans. However, as a precaution, females who are pregnant, breast-feeding 
or intend to become pregnant or are of childbearing potential and not using an adequate 
contraceptive method will not be enrolled in the trial. In addition, pregnancy tests will be performed 
at all visits, including screening and follow-up and at any time during the trial if a menstrual period 
is missed, or as required by local law. 
General precautions  
All subjects will be included after a thorough evaluation with regards to in- and exclusion criteria 
defined in order to ensure that subjects are eligible for trial treatment. There are also strict 
glycaemic rescue criteria in place to ensure acceptable glycaemic control during the trial. If rescue 
medication is required, it should be in accordance with ADA/European Association for the Study of 
Diabetes23, 24 (excluding GLP-1 RAs, DPP-4 inhibitors and amylin analogues) and the local label of 
sitagliptin 
It is the responsibility of the investigator to ensure the best possible care according to the principles 
outlined in Diabetes Care 2017 Standards of Medical Care in Diabetes62. In addition to ensuring 
glycaemic control, appropriate risk factor modification also includes optimal treatment of 
hypertension, dyslipidaemia and other cardiovascular risk factors, as well as regular monitoring and 
treatment of diabetic kidney disease and diabetic retinopathy62. 
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Further details with regards to safety of oral semaglutide are described in the current edition of the 
IB for oral semaglutide (NN9924)43, or any updates thereto. 
18.1.1.2 
Sitagliptin 
The most commonly reported side effects associated with sitagliptin are upper respiratory tract 
infection, nasopharyngitis and headache. Also acute pancreatitis, acute renal failure, 
hypersensitivity reactions and hypoglycaemia have been reported. Please consult the EU SmPC or 
locally approved label of Januvia® for information on warnings and precautions/risks48.  
18.1.2 
Benefits 
Randomised subjects will receive a trial product that is anticipated to be equally or more efficacious 
than the treatment they receive at trial entry. Based on the results of the phase 2 dose-finding trial, 
oral semaglutide is expected to provide clinically relevant improvements in glycaemic control and 
body weight in subjects with T2D. 
Similarly, treatment with sitagliptin is expected to provide clinically significant improvements in 
glycaemic control48. 
In addition, it is expected that all subjects, will benefit from participation through close contact with 
the trial site, with close follow-up of their T2D and a careful medical examination; all of which will 
most likely result in an intensified management of their T2D. 
All subjects in this trial will receive trial products and auxiliary supplies free of charge. 
18.1.3 
Risk and benefit conclusion  
The safety profile for oral semaglutide generated from the clinical and non-clinical development 
programme has not revealed any safety issues that would prohibit administration of oral 
semaglutide in accordance with the planned clinical trial. 
The phase 2 results indicate that oral semaglutide will provide clinically relevant improvements in 
glycaemic control and body weight. Sitagliptin is already a marketed drug approved for the use in 
subjects with T2D.  
Safety and efficacy will be monitored regularly and acceptable glycaemic control will be reinforced 
at all times during the trial. 
In conclusion, the potential risk to the subjects in this trial is considered low and acceptable in view 
of the anticipated benefits associated with oral semaglutide/sitagliptin in subjects with T2D. 
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18.2 
Informed consent  
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP44 and the requirements in the Declaration of 
Helsinki2. 
Before any trial-related activity, the investigator must give the subject verbal and written 
information about the trial and the procedures involved in a form that the subject can read and 
understand. 
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products. 
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity. 
The responsibility for 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. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity. 
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained. 
In order to avoid missing data, the subjects will be informed about the importance of completing the 
trial also if the subjects discontinue trial product. 
18.3 
Data handling 
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows: 
• Data already collected and any data collected at the end-of-trial visit including follow up visits 
will be retained by Novo Nordisk, entered into the database and used for the CTR.  
• Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements. 
If data is used, it will always be in accordance with local regulations and IRBs/IECs. 
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18.4 
Information to subjects during trial 
The subject may receive a “welcome to the trial letter” and a “thank you for your participation 
letter” after completion of the trial. Further the subject may receive letters 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. 
18.5 
Premature termination of the trial and/or trial site 
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained. 
If the trial is suspended or prematurely 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.  
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described. 
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19 Protocol compliance 
19.1 
Protocol deviations 
Deviations from the protocol should be avoided. 
If deviations do occur, the investigator must inform the monitor 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.  
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file. 
19.2 
Prevention of missing data 
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites.  
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial.  
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites.  
The investigator will make every effort to ensure that all assessments are performed and data is 
collected. If missing data does occur the reason will be collected via the protocol deviation process 
(see Section 19.1). Novo Nordisk will monitor protocol deviations on an on-going basis throughout 
the trial followed by appropriate actions (e.g. re-training of site staff). 
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20 Audits and inspections 
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial. 
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21 Critical documents 
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk: 
• Regulatory approval and/or acknowledgement of notification as required  
• Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials 
• List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance) 
• Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate) 
• Signed receipt of Investigator’s Brochure for oral semaglutide 
• Signed and dated Agreement on Protocol 
• Signed and dated Agreement on Protocol Amendment, if applicable 
• Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk 
• Source document agreement 
• Central laboratory certification and normal ranges 
• Insurance statement, if applicable 
• Financial disclosure form from investigator and sub-investigator(s) 
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial. 
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP44, 
applicable regulatory requirements and the Declaration of Helsinki2.  
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations. 
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22 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 trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects. 
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions. 
The investigator will follow instructions from Novo Nordisk when processing data. 
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 no unauthorized persons can get access to the 
data.  
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
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23 Reports and publications 
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 physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One or two investigators will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators. The signatory investigator(s) will be 
appointed based upon the criteria defined by the ICMJE for research publications63.  
23.1 
Communication of results 
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
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, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure64. 
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. All authors will be given the relevant 
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statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication. 
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication. 
23.1.1 
Authorship 
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors63 (sometimes referred to as the Vancouver 
Criteria).Novo Nordisk will appoint investigator(s) to prepare publications in collaboration with 
Novo Nordisk. 
23.1.2 
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. It is a Novo Nordisk policy that 
such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial. 
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.  
23.2 
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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24 Retention of clinical trial documentation and human biosamples 
24.1 
Retention of clinical trial documentation 
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice. 
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files. 
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk. 
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest. 
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
Section 7, or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
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Date: 
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Status: 
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities 
IRB/IEC: 
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial. 
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to IB, unexpected SAEs 
where a causal relationship cannot be ruled out, protocol amendments according to local 
requirements, deviations to the protocol implemented to eliminate immediate hazards to the 
subjects, new information that may affect adversely the safety of the subjects or the conduct of the 
trial (including new benefit-risk analysis in case it will have an impact on the planned follow-up of 
the subjects), annually written summaries of the trial status, and other documents as required by the 
local IRB/IEC. 
The investigator must ensure submission of the CTR synopsis to the IRB/IEC. 
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects. 
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk. 
Regulatory Authorities: 
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the CTR according to national requirements. 
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26 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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27 References 
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for Good Clinical Practise E6(R2), Step 4. 09 Nov 2016.
2.
World Medical Association. Declaration of Helsinki. Ethical Principles for Medical
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Fortaleza, Brazil. October 2013.
3.
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am.
2004;88(4):787-835, ix.
4.
Chuang LM, Tsai ST, Huang BY, Tai TY, Diabcare-Asia Study Group. The status of
diabetes control in Asia--a cross-sectional survey of 24 317 patients with diabetes mellitus
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5.
Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among U.S. adults
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Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus.
Mol Cell Endocrinol. 2009;297(1-2):127-36.
7.
Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20(6):876-913.
8.
Bagger JI, Knop FK, Lund A, Vestergaard H, Holst JJ, Vilsboll T. Impaired regulation of
the incretin effect in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96(3):737-
45.
9.
Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in
normal and diabetic sujbjects. J Clin Invest. 1967;46(12):1954-62.
10.
Hojberg PV, Vilsboll T, Rabol R, Knop FK, Bache M, Krarup T, et al. Four weeks of near-
normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and
glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia.
2009;52(2):199-207.
11.
Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.
Nat Rev Endocrinol. 2012;8(12):728-42.
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Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and
suppresses energy intake in humans. J Clin Invest. 1998;101(3):515-20.
13.
Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, et al. Glucagon-like
peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy
humans. Am J Physiol. 1997;273(5 Pt 1):E981-8.
14.
Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of
fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-
insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741-4.
15.
Toft-Nielsen MB, Damholt MB, Madsbad S, Hilsted LM, Hughes TE, Michelsen BK, et al.
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic
patients. J Clin Endocrinol Metab. 2001;86(8):3717-23.
16.
Nauck MA, Petrie JR, Sesti G, Mannucci E, Courreges JP, Atkin S, et al. The once-weekly
human GLP-1 analogue semaglutide provides significant reductions in HbA1c and body
weight in patients with type 2 diabetes. EASD abstract. 2012.
17.
EMA. ICH guideline M3(R2) on non-clinical safety studies for the conduct of human
clinical trials and marketing authorisation for pharmaceuticals
(EMA/CPMP/ICH/286/1995). 2009 2009.
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Date: 
28 January 2019 
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Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
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34. 
Hill AJ, Heaton-Brown L. The experience of food craving: a prospective investigation in 
healthy women. J Psychosom Res. 1994;38(8):801-14. 
35. 
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 
American Thyroid Association Management Guidelines for Adult Patients with Thyroid 
Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines 
Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-
133. 
36. 
National Kidney F. KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 
Update. Am J Kidney Dis. 2012;60(5):850-86. 
37. 
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. 
38. 
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705. 
39. 
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development to 
Support Labeling Claims. December 2009. 
40. 
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. 
41. 
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products. Brussels, February 2010. 
42. 
European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) 
Module VIII - Post-authorisation safety studies (EMA/813938/2011 Rev 3). 2017. 
43. 
Investigators brochure for oral semaglutide (NN9924), edition 7 or any updates hereof. 2016 
2016. 
44. 
International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. 
Guideline for Good Clinical Practice E6(R1), Step 4. 10 June 1996. 
45. 
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(Draft). 20 Aug 2014. 
46. 
Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, et al. 2017 
Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Circulation. 
2018;137(9):961-72. 
47. 
KDIGO. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney international 
supplements. 2012;2(1):1-138. 
48. 
Merck Sharp & Dohme Limited. JANUVIA - European Summary of Product Characteristics 
Annex 1. 26 May 2015. 
49. 
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. 
50. 
Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 3 Oct 2014. 
51. 
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987. 
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Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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52. 
Koch GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med. 2008;27(3):333-42. 
53. 
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 
Rev. 1). 2 Jul 2010. 
54. 
National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010. 
55. 
Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of 
glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81. 
56. 
Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid 
tightening of blood glucose control leads to transient deterioration of retinopathy in insulin 
dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811-
5. 
57. 
The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic 
retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 
1998;116(7):874-86. 
58. 
Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic 
control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin 
Pract. 2014;103(3):e37-9. 
59. 
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional 
treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK 
Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53, Erratum 
1999; 354: 602. 
60. 
The Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye 
Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On 
(ACCORDION) Study Group. Persistent Effects of Intensive Glycemic Control on 
Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in Diabetes 
(ACCORD) Follow-On Study. Diabetes Care. 2016;39(7):1089-100. 
61. 
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016;375:1834-
44. 
62. 
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 
2017;40 (Suppl. 1):S1-S135. 
63. 
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. 
64. 
Novo Nordisk A/S. http://www.novonordisk-trials.com/website/content/how-we-disclose-
trial-information.aspx. 
 
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Protocol - Appendix A 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
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Appendix A 
Monitoring of Calcitonin 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
2 of 6 
 
 
1 
Background 
Treatment with glucagon-like peptide-1 receptor agonists has shown to be associated with thyroid 
C-cell changes in rodents but not in non-human primates. The human relevance of this finding is 
unknown. However, based on the findings in rodents, monitoring of serum calcitonin (a sensitive 
biomarker for C-cell activation) is currently being performed in clinical trials with semaglutide. 
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is 
less clear with regards to indication of disease. 
There are several known confounding factors affecting calcitonin levels, e.g.: 
• renal dysfunction 
• smoking 
• autoimmune thyroiditis 
• several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and 
glucocorticoids) 
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells. 
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Protocol - Appendix A 
 
Date: 
28 January 2019 
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Trial ID: NN9924-4309 
Version: 
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UTN: U1111-1188-1256 
Status: 
Final 
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product). The subject should remain in the trial, however, all medications suspected to relate to this 
condition must be discontinued until diagnosis has been established. 
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease1. All of these patients were diagnosed with medullary thyroid carcinoma resulting 
in a positive predictive value of 100 %. 
Diagnostic evaluation should include: 
• thyroid ultrasound examination 
• fine needle aspiration of any nodules > 1 cm  
• potentially surgery with neck dissection 
In case a subject is diagnosed with medullary thyroid carcinoma, it is common clinical practice to 
explore the family history of medullary thyroid carcinoma or multiple endocrine neoplasia and 
perform a genetic test for RET proto-oncogene mutation. 
2.2 
Calcitonin ≥ 50 and < 100 ng/L 
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist.  
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease1. Two of these subjects were diagnosed with medullary thyroid carcinoma and two 
were diagnosed with C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly 
of 50%. 
Diagnostic evaluation should include:  
• thyroid ultrasound examination  
• if available and there are no contraindication, a pentagastrin stimulation test should be done. For 
subjects with positive pentagastrin stimulation test, surgery should be considered.  
• if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration 
biopsy may add important clinical information about the need for surgery. 
2.3 
Calcitonin ≥ 10 and < 50 ng/L 
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol. 
If the value is from the last sample taken in the trial, the subject should be referred to a thyroid 
specialist for further evaluation. 
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Date: 
28 January 2019 
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Version: 
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UTN: U1111-1188-1256 
Status: 
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Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low. 
For calcitonin values between 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient 
out of the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell 
hyperplasia at surgery. Two other studies used a cut-off of calcitonin > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal calcitonin > 10 and < 
20 ng/L to allow conclusions2,3. 
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Date: 
28 January 2019 
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Trial ID: NN9924-4309 
Version: 
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UTN: U1111-1188-1256 
Status: 
Final 
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3 
References 
 1  Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with 
thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455. 
 2  Scheuba C, Kaserer K, moritz A, drosten R. Sporadic hypercalcitoninemia: clinica and therapeutic consequences. 
Endocrine Related Cancer 2009; 16(1):243-253. 
 3  Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and molecular studies in 
patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 
14(2):393-403. 
 
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Protocol - Appendix B 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
1 of 8 
 
 
Appendix B 
Adverse events requiring additional data collection 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
2 of 8 
 
 
1 
Adverse events requiring additional data collection 
For the following adverse events (AEs) additional data collection is required and specific event 
forms must be completed in the electronic case report form (eCRF) in addition to the AE form: 
• Acute coronary syndrome (myocardial infarction or unstable angina pectoris requiring 
hospitalisation) 
• Acute gallstone disease 
• Cerebrovascular event (stroke or transient ischaemic attack) 
• Heart failure 
• Hypersensitivity reaction 
• Neoplasm (excluding thyroid neoplasm) 
• Thyroid disease (including thyroid neoplasm) 
• Pancreatitis 
• Renal event 
• Medication error (concerning trial products): 
• 
Administration of wrong drug.  
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error. 
• 
Wrong route of administration. 
• 
Accidental administration of a higher dose than intended. A higher dose is a dose of at least 
one tablet more than the intended dose; however 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. 
• Abuse and misuse of trial product 
Abuse is defined as: 
Persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied 
by harmful physical or psychological effects (e.g. overdose with the intention to cause harm). 
Misuse is defined as: 
Situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the protocol.  
• Lactic acidosis 
• Creatine kinase (CK) > 10 x upper limit of the normal (ULN) 
• Hepatic event defined as: 
• 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x ULN and total 
bilirubin ≤ 2 x ULN 
• 
ALT or AST >3 x ULN and total bilirubin > 2 x ULN* 
• 
Hepatic event leading to trial product discontinuation 
• Diabetic retinopathy and related complications 
*Please note that in case of a hepatic event defined as ALT or AST > 3 x ULN and total bilirubin 
> 2 x ULN, where no alternative aetiology exists (Hy's law), this must be reported as an serious 
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Protocol - Appendix B 
 
Date: 
28 January 2019 
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Trial ID: NN9924-4309 
Version: 
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UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
3 of 8 
 
 
adverse event (SAE) using the important medical event criterion if no other seriousness criteria are 
applicable. 
In case any of these events fulfil the criteria for a SAE, please report accordingly, see protocol 
Section 12.1.2. 
Some of these events will undergo event adjudication by the event adjudication committee (EAC), 
see protocol Section 12.7.2 and protocol Table 12-1 and Table 12-2.  
1.1 
Acute coronary syndrome 
If an event of acute coronary syndrome (ranging from unstable angina pectoris requiring 
hospitalisation to myocardial infarction) is observed during the trial, the following additional 
information must be reported if available: 
• Duration of symptoms 
• Changes in electrocardiogram (ECG) 
• Collection of cardiac biomarkers 
• Cardiac imaging 
• Cardiac stress testing 
• Angiography 
• Use of thrombolytic drugs 
• Revascularisation procedures 
1.2 
Acute gallstone disease 
If an event of acute gallstone disease or clinical suspicion of this is observed during the trial, the 
following additional information must be reported if available: 
• Signs and symptoms of acute gallstone disease 
• Specific laboratory tests supporting a diagnosis of gallstone 
• Imaging performed and consistency with gallstone disease 
• Treatment given for the condition 
• Relevant risk factors for acute gallstone disease 
• Family history of gallstones 
1.3 
Cerebrovascular event 
If a cerebrovascular event (e.g. transient ischaemic attack, stroke) is observed during the trial, the 
following additional information must be reported if available: 
• Type of event (e.g. transient ischaemic attack, stroke) 
• Contributing condition 
• Neurologic signs and symptoms 
• History of neurologic disease 
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Protocol - Appendix B 
 
Date: 
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Version: 
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Status: 
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• Imaging supporting the condition 
• Treatment given for the condition 
1.4 
Heart failure 
If an event of heart failure is observed during the trial, the following additional information must be 
reported if available: 
• Signs and symptoms of heart failure 
• New York Heart Association (NYHA) Class 
• Supportive imaging 
• Supportive laboratory measurements 
• Initiation or intensification of treatment for this condition 
1.5 
Hypersensitivity reaction 
All events of hypersensitivity reactions must be reported and the following additional information 
must be reported if available: 
• Signs and symptoms associated to the event 
• Time of appearance after administration of trial drug 
• Relevant immunological tests performed 
• Treatment given for the reaction 
• Previous history of similar reaction 
• Risk or confounding factors identified 
1.5.1 
Assessments in case of suspicion of hypersensitivity reaction 
If suspicion of a hypersensitivity reaction occurs, the subjects should be instructed to contact the 
site staff as soon as possible. 
In case of suspicion of a severe immediate systemic hypersensitivity reaction3 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
Section 6.5 and 8.1.5). 
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended  to test 
tryptase locally (total and/or mature tryptase) within 3 hours of reaction. Moreover, a baseline 
tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual variation in tryptase baseline concentration. Tryptase concentrations, if available, 
should be included in the specific event form when reporting the AE. 
Tryptase measurements are not required at the follow up visits. 
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Protocol - Appendix B 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
5 of 8 
 
 
In case of suspicion of immune complex disease3, the subject must be discontinued from trial 
product but should remain in the trial (see protocol Section 6.5 and 8.1.5). It is recommended to 
draw a blood sample for local assessment of complement levels (C3 and C4) to assist in the 
diagnostic evaluation. Complement level results should be included in the specific event form when 
reporting the AE. 
1.6 
Neoplasm 
All events of neoplasms (excluding thyroid neoplasm, which will be reported under thyroid disease) 
must be reported during the trial and the following additional information must be reported if 
available: 
• Type of neoplasm 
• Symptoms leading to identification of event 
• Diagnostic imaging 
• Pathological examination results 
• Treatment for the event 
• Participation in screening programs 
• Risk factors associated to the event 
1.7 
Thyroid disease 
If an event of thyroid disease, including any thyroid neoplasms, is observed during the trial, the 
following additional information must be reported if available: 
• History of thyroid disease 
• Signs and symptoms leading to investigations of thyroid disease 
• Specific laboratory tests describing thyroid function 
• Diagnostic imaging performed and any prior imaging supporting the disease history  
• Pathologic examinations 
• Treatment given for the condition 
• Risk factors identified 
• Family history of thyroid disease 
1.8 
Pancreatitis 
For all confirmed events of pancreatitis the following additional information must be reported if 
available: 
• Signs and symptoms of pancreatitis 
• Specific laboratory test supporting a diagnosis of pancreatitis 
• Imaging performed and consistency with pancreatic disease 
• Treatment for and complications of the event 
• Relevant risk factors for pancreatic disease 
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Protocol - Appendix B 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
6 of 8 
 
 
• Family history of pancreatic disease 
1.8.1 
Assessments in case of suspicion of acute pancreatitis 
Most patients with acute pancreatitis experience severe abdominal pain that is located generally in 
the epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 min, it is frequently unbearable and characteristically persists for more than 
24 hours without relief1. The pain is often associated with nausea and vomiting. Physical 
examination usually reveals severe upper abdominal tenderness at times associated with guarding. 
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
lipase does not correlate with the severity of acute pancreatitis1. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis. 
In case of suspicion of acute pancreatitis, trial product treatment should be promptly interrupted. 
Appropriate additional examinations must be performed, including measurement of amylase and 
lipase. 
The diagnosis of acute pancreatitis requires two of the following three features2: 
• 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 
the normal 
• characteristic findings of acute pancreatitis on imaging. 
If acute pancreatitis is ruled out, trial product should be re-initiated. 
If acute pancreatitis is confirmed, appropriate treatment and careful monitoring of the subject 
should be initiated. The subject must be discontinued from trial product (treatment discontinuation 
call), but should remain in the trial (see protocol Section 6.5 and 8.1.5). 
1.9 
Renal event  
If a renal event is observed during the trial, the following additional information must be reported if 
available: 
• Signs and symptoms of renal failure 
• Specific laboratory tests supporting the diagnosis 
• Imaging performed supporting the diagnosis 
• Kidney biopsy results 
• Risk or confounding factors identified including exposure to nephrotoxic agents 
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Protocol - Appendix B 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
7 of 8 
 
 
1.10 
Medication error 
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form (see Section 8.4.1.1 
and 12.1.5): 
• Trial product(s) involved 
• Classification of medication error 
o Wrong drug(s) administered 
o Administration of an overdose 
• Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error 
• Suspected primary reason for the medication error 
For definition of medication error, see protocol Section 12.1.4. 
1.11 
Lactic acidosis 
If an event of lactic acidosis is observed during the trial, the following additional information must 
be reported if available: 
• Signs and symptoms of lactic acidosis 
• Specific laboratory tests describing the event 
• Possible cause(s) of the event 
1.12 
Creatine kinase > 10 x ULN 
If an event of CK > 10 x ULN is observed during the trial, the following additional information 
must be reported if available: 
• Signs and symptoms associated to the event  
• Recent physical activity 
• Possible cause(s) of the event 
1.12.1 
Assessments in case of increased levels of creatine kinase 
In case of CK > 10 x ULN, prompt repeat testing (at central laboratory) of CK should be done. 
Repeat testing (at central laboratory) should be done regularly until CK levels return to normal or 
baseline state. Additional clinical information should be gathered to seek the possible cause of the 
observed CK elevation. 
1.13 
Hepatic event 
• ALT or AST > 5 x ULN and total bilirubin ≤ 2 x ULN 
• ALT or AST >3 x ULN and total bilirubin > 2 x ULN* 
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Protocol - Appendix B 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
8 of 8 
 
 
• Hepatic event leading to trial product discontinuation 
*Please note that risk of liver injury defined as ALT or AST > 3 x ULN and total 
bilirubin > 2 x ULN, where no alternative aetiology exits (Hy’s law), should also be reported as a 
SAE (important medical event, according to protocol Section 12.1.2). 
If one of the above events is observed during the trial, the following additional information must be 
reported if available: 
• Signs and symptoms associated to the event 
• Risk factors 
• Relevant laboratory test results 
• Diagnostic imaging performed 
• Possible cause(s) of the event 
1.13.1 
Assessments in case of increased levels of aminotransferases 
Both events should prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
phosphatase (ALP) and total bilirubin and discontinuation of trial product should be considered. 
Thereafter, repeat testing (at central laboratory) of ALT, AST, ALP and total bilirubin should be 
done regularly until the abnormalities return to normal or baseline state. Additional clinical 
information such as related symptoms, risk factors and contributing conditions (e.g. viral hepatitis, 
autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic disorders) should be gathered 
to seek a possible cause of the observed laboratory test abnormalities. 
1.14 
Diabetic retinopathy and related complications 
If an event of diabetic retinopathy or related complications is observed during the trial the following 
additional information must be reported, if available: 
• Signs and symptoms associated with the event 
• Results of the eye examination  
• Treatment for and complications of the event 
• Contributing conditions  
2 
References 
1. 
Banks PA, Freeman ML, Practice Parameters Committee of the American College of G. 
Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400. 
2. 
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. 
3. 
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry: Immunogenicity Assessment for Therapeutic Protein Products. August 2015. 
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Protocol - Appendix C 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
1 of 4 
 
 
Appendix C 
Contraceptive guidance and collection of pregnancy 
information 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix C 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
2 of 4 
 
 
 
Contraceptive guidance and collection of pregnancy information 
It must be recorded in the eCRF whether female subjects are of childbearing potential  
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
Women in the following categories are not considered WOCBP 
1. Premenarcheal  
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview. 
3. Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high Follicle Stimulating Hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal contraception or 
Hormonal Replacement Therapy (HRT). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.  
 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrolment. 
Contraception guidance 
Male subjects 
No contraception measures are required for male subjects as 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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Protocol - Appendix C 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
3 of 4 
 
 
Table 1 
Highly effective contraceptive methods 
Highly effective contraceptive methods that are user dependent a and b 
Failure rate of <1% per year when used consistently and correctly.  
Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation   
• 
oral  
• 
intravaginal  
• 
transdermal  
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
oral  
• 
injectable  
Highly effective methods that are user independent b  
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 product. 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. 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation  
• 
Intrauterine Device (IUD) 
• 
Intrauterine hormone-releasing System (IUS) 
• 
Bilateral tubal occlusion 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
Notes:  
a Failure rates may differ from < 1% per year, if not used consistently and correctly. Use should be consistent with local 
regulations regarding the use of contraceptive methods for subjects participating in clinical trials.  
b Contraception should be utilised during the treatment period and for at least 35 days after the last dose of trial product. 
Pregnancy testing 
• WOCBP should only be included in the trial after a negative urine pregnancy test at visit 1 and 
at visit 2. 
• Urine pregnancy tests should be performed throughout the trial in accordance with the protocol 
flowchart, section 2. WOCBP needs the last urine pregnancy test at the end of trial visit (visit 9).  
• Pregnancy testing should be performed whenever a menstrual period is missed or when 
pregnancy is otherwise suspected. 
• Additional urine pregnancy testing should be performed during the treatment period, if required 
locally.  
 
 
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Protocol - Appendix C 
 
Date: 
28 January 2019 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT no.: 2018-002589-38  
Page: 
4 of 4 
 
 
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. 
• 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. 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 pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial products by the investigator will be reported to Novo Nordisk as described in 
section 12 of the protocol. 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.  
Any female subject who becomes pregnant while participating in the trial must discontinue trial 
product.  
 
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Protocol - Appendix A
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
1 of 6
Appendix A
Monitoring of Calcitonin
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix A
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
2 of 6
1
Background
Treatment with glucagon-like peptide-1 receptor agonists has shown to be associated with thyroid 
C-cell changes in rodents but not in non-human primates. The human relevance of this finding is
unknown. However, based on the findings in rodents, monitoring of serum calcitonin (a sensitive
biomarker for C-cell activation) is currently being performed in clinical trials with semaglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) as likely indicative of C-cell neoplasia, the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is 
less clear with regards to indication of disease.
There are several known confounding factors affecting calcitonin levels, e.g.:

renal dysfunction

smoking

autoimmune thyroiditis

several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
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Protocol - Appendix A
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
3 of 6
2
Calcitonin monitoring
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin.
In case a subject has a calcitonin value ≥ 10 ng/L the algorithm outlined in Figure 1 and described 
below should be followed. The algorithm applies for all calcitonin values in the trial.
Calcitonin < 10ng/L
Calcitonin  ≥ 10 ng/L and 
< 50 ng/L
Calcitonin  ≥ 50 ng/L and 
< 100 ng/L
Calcitonin  ≥ 100 ng/L
Evaluation of 
calcitonin results
Calcitonin  ≥ 10 ng/L and 
last measurement in the 
trial
No action
●Investigate potential confounding
factors
●Continue sampling of calcitonin
according to protocol
●Refer to thyroid specialist
●Discontinue trial product
●Refer to thyroid specialist
●Refer to thyroid specialist
Figure 1
Flow of calcitonin monitoring
2.1
Calcitonin ≥ 100 ng/L  
Action: The subject must immediately be referred to a thyroid specialist for further evaluation and 
the trial product must be discontinued (see protocol Section 6.5 premature discontinuation of trial 
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Protocol - Appendix A
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
4 of 6
product). The subject should remain in the trial, however, all medications suspected to relate to this 
condition must be discontinued until diagnosis has been established.
Background: These values were found in 9 (0.15%) of a population of 5817 patients with thyroid 
nodular disease1. All of these patients were diagnosed with medullary thyroid carcinoma resulting 
in a positive predictive value of 100 %.
Diagnostic evaluation should include:

thyroid ultrasound examination

fine needle aspiration of any nodules > 1 cm

potentially surgery with neck dissection
In case a subject is diagnosed with medullary thyroid carcinoma, it is common clinical practice to 
explore the family history of medullary thyroid carcinoma or multiple endocrine neoplasia and 
perform a genetic test for RET proto-oncogene mutation.
2.2
Calcitonin ≥ 50 and < 100 ng/L
Action: The subject should be referred to a thyroid specialist for further evaluation. The subject 
should remain in the trial and continuation on trial product should be based on the evaluation done 
by the thyroid specialist. 
Background: These values were found in 8 (0.14%) of the population of 5817 patients with thyroid 
nodular disease1. Two of these subjects were diagnosed with medullary thyroid carcinoma and two 
were diagnosed with C-cell hyperplasia, resulting in a positive predictive value of a C-cell anomaly 
of 50%.
Diagnostic evaluation should include: 

thyroid ultrasound examination

if available and there are no contraindication, a pentagastrin stimulation test should be done. For
subjects with positive pentagastrin stimulation test, surgery should be considered.

if pentagastrin stimulation test is not available, thyroid ultrasound and fine needle aspiration
biopsy may add important clinical information about the need for surgery.
2.3
Calcitonin ≥ 10 and < 50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol.
If the value is from the last sample taken in the trial, the subject should be referred to a thyroid 
specialist for further evaluation.
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Protocol - Appendix A
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
5 of 6
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease 1. The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low.
For calcitonin values between 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient 
out of the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell 
hyperplasia at surgery. Two other studies used a cut-off of calcitonin > 10 ng/L to screen for C-cell 
disease, but they do not provide sufficient information on patients with basal calcitonin > 10 and < 
20 ng/L to allow conclusions2,3.
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Protocol - Appendix A
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
6 of 6
3
References
1 Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S et al. Predictive value of serum calcitonin 
levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with 
thyroid nodules. J Clin Endocrinol Metab 2007; 92(2):450-455.
2 Scheuba C, Kaserer K, moritz A, drosten R. Sporadic hypercalcitoninemia: clinica and therapeutic consequences. 
Endocrine Related Cancer 2009; 16(1):243-253.
3 Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M et al. Histopathological and molecular studies in 
patients with goiter and hypercalcitoninemia: reactive or neoplastic C-cell hyperplasia? Endocr Relat Cancer 2007; 
14(2):393-403.
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Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
1 of 8
Appendix B
Adverse events requiring additional data collection
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
2 of 8
1
Adverse events requiring additional data collection
For the following adverse events (AEs) additional data collection is required and specific event 
forms must be completed in the electronic case report form (eCRF) in addition to the AE form:

Acute coronary syndrome (myocardial infarction or unstable angina pectoris requiring 
hospitalisation)

Acute gallstone disease

Cerebrovascular event (stroke or transient ischaemic attack)

Heart failure

Hypersensitivity reaction

Neoplasm (excluding thyroid neoplasm)

Thyroid disease (including thyroid neoplasm)

Pancreatitis

Renal event

Medication error (concerning trial products):

Administration of wrong drug. 
Note: Use of wrong dispensing unit number (DUN) is not considered a medication error.

Wrong route of administration.

Accidental administration of a higher dose than intended. A higher dose is a dose of at least 
one tablet more than the intended dose; however 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.

Abuse and misuse of trial product
Abuse is defined as:
Persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied
by harmful physical or psychological effects (e.g. overdose with the intention to cause harm).
Misuse is defined as:
Situations where the medicinal product is intentionally and inappropriately used not in
accordance with the protocol.

Lactic acidosis

Creatine kinase (CK) > 10 x upper limit of the normal (ULN)

Hepatic event defined as:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x ULN and total 
bilirubin ≤ 2 x ULN

ALT or AST >3 x ULN and total bilirubin > 2 x ULN*

Hepatic event leading to trial product discontinuation

Diabetic retinopathy and related complications
*Please note that in case of a hepatic event defined as ALT or AST > 3 x ULN and total bilirubin 
> 2 x ULN, where no alternative aetiology exists (Hy's law), this must be reported as an serious 
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Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
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
Imaging supporting the condition

Treatment given for the condition
1.4
Heart failure
If an event of heart failure is observed during the trial, the following additional information must be 
reported if available:

Signs and symptoms of heart failure

New York Heart Association (NYHA) Class

Supportive imaging

Supportive laboratory measurements

Initiation or intensification of treatment for this condition
1.5
Hypersensitivity reaction
All events of hypersensitivity reactions must be reported and the following additional information 
must be reported if available:

Signs and symptoms associated to the event

Time of appearance after administration of trial drug

Relevant immunological tests performed

Treatment given for the reaction

Previous history of similar reaction

Risk or confounding factors identified
1.5.1
Assessments in case of suspicion of hypersensitivity reaction
If suspicion of a hypersensitivity reaction occurs, the subjects should be instructed to contact the 
site staff as soon as possible.
In case of suspicion of a severe immediate systemic hypersensitivity reaction3 to the trial product, 
the subject must be discontinued from trial product but should remain in the trial (see protocol 
Section 6.5 and 8.1.5).
In the event of a severe systemic hypersensitivity reaction to trial product it is recommended  to test 
tryptase locally (total and/or mature tryptase) within 3 hours of reaction. Moreover, a baseline 
tryptase measurement is necessary 1-2 weeks after the immediate severe hypersensitivity reaction 
due to individual variation in tryptase baseline concentration. Tryptase concentrations, if available, 
should be included in the specific event form when reporting the AE.
Tryptase measurements are not required at the follow up visits.
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Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
5 of 8
In case of suspicion of immune complex disease3, the subject must be discontinued from trial 
product but should remain in the trial (see protocol Section 6.5 and 8.1.5). It is recommended to 
draw a blood sample for local assessment of complement levels (C3 and C4) to assist in the 
diagnostic evaluation. Complement level results should be included in the specific event form when 
reporting the AE.
1.6
Neoplasm
All events of neoplasms (excluding thyroid neoplasm, which will be reported under thyroid disease) 
must be reported during the trial and the following additional information must be reported if 
available:

Type of neoplasm

Symptoms leading to identification of event

Diagnostic imaging

Pathological examination results

Treatment for the event

Participation in screening programs

Risk factors associated to the event
1.7
Thyroid disease
If an event of thyroid disease, including any thyroid neoplasms, is observed during the trial, the 
following additional information must be reported if available:

History of thyroid disease

Signs and symptoms leading to investigations of thyroid disease

Specific laboratory tests describing thyroid function

Diagnostic imaging performed and any prior imaging supporting the disease history 

Pathologic examinations

Treatment given for the condition

Risk factors identified

Family history of thyroid disease
1.8
Pancreatitis
For all confirmed events of pancreatitis the following additional information must be reported if 
available:

Signs and symptoms of pancreatitis

Specific laboratory test supporting a diagnosis of pancreatitis

Imaging performed and consistency with pancreatic disease

Treatment for and complications of the event

Relevant risk factors for pancreatic disease
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Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
6 of 8

Family history of pancreatic disease
1.8.1
Assessments in case of suspicion of acute pancreatitis
Most patients with acute pancreatitis experience severe abdominal pain that is located generally in 
the epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 min, it is frequently unbearable and characteristically persists for more than 
24 hours without relief1. The pain is often associated with nausea and vomiting. Physical 
examination usually reveals severe upper abdominal tenderness at times associated with guarding.
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
lipase does not correlate with the severity of acute pancreatitis1. In general, serum lipase is thought 
to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis.
In case of suspicion of acute pancreatitis, trial product treatment should be promptly interrupted. 
Appropriate additional examinations must be performed, including measurement of amylase and 
lipase.
The diagnosis of acute pancreatitis requires two of the following three features2:

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 
the normal

characteristic findings of acute pancreatitis on imaging.
If acute pancreatitis is ruled out, trial product should be re-initiated.
If acute pancreatitis is confirmed, appropriate treatment and careful monitoring of the subject 
should be initiated. The subject must be discontinued from trial product (treatment discontinuation 
call), but should remain in the trial (see protocol Section 6.5 and 8.1.5).
1.9
Renal event 
If a renal event is observed during the trial, the following additional information must be reported if 
available:

Signs and symptoms of renal failure

Specific laboratory tests supporting the diagnosis

Imaging performed supporting the diagnosis

Kidney biopsy results

Risk or confounding factors identified including exposure to nephrotoxic agents
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Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
7 of 8
1.10
Medication error
If a medication error is observed during the trial, the following information is required and a 
specific event form must be completed in the eCRF in addition to the AE form (see Section 8.4.1.1 
and 12.1.5):

Trial product(s) involved

Classification of medication error
o
Wrong drug(s) administered
o
Administration of an overdose

Whether the subject experienced any hypoglycaemic episode and/or AE(s) as a result of the 
medication error

Suspected primary reason for the medication error
For definition of medication error, see protocol Section 12.1.4.
1.11
Lactic acidosis
If an event of lactic acidosis is observed during the trial, the following additional information must 
be reported if available:

Signs and symptoms of lactic acidosis

Specific laboratory tests describing the event

Possible cause(s) of the event
1.12
Creatine kinase > 10 x ULN
If an event of CK > 10 x ULN is observed during the trial, the following additional information 
must be reported if available:

Signs and symptoms associated to the event 

Recent physical activity

Possible cause(s) of the event
1.12.1
Assessments in case of increased levels of creatine kinase
In case of CK > 10 x ULN, prompt repeat testing (at central laboratory) of CK should be done. 
Repeat testing (at central laboratory) should be done regularly until CK levels return to normal or 
baseline state. Additional clinical information should be gathered to seek the possible cause of the 
observed CK elevation.
1.13
Hepatic event

ALT or AST > 5 x ULN and total bilirubin ≤ 2 x ULN

ALT or AST >3 x ULN and total bilirubin > 2 x ULN*
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Protocol - Appendix B
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
8 of 8

Hepatic event leading to trial product discontinuation
*Please note that risk of liver injury defined as ALT or AST > 3 x ULN and total 
bilirubin > 2 x ULN, where no alternative aetiology exits (Hy’s law), should also be reported as a 
SAE (important medical event, according to protocol Section 12.1.2).
If one of the above events is observed during the trial, the following additional information must be 
reported if available:

Signs and symptoms associated to the event

Risk factors

Relevant laboratory test results

Diagnostic imaging performed

Possible cause(s) of the event
1.13.1
Assessments in case of increased levels of aminotransferases
Both events should prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
phosphatase (ALP) and total bilirubin and discontinuation of trial product should be considered. 
Thereafter, repeat testing (at central laboratory) of ALT, AST, ALP and total bilirubin should be 
done regularly until the abnormalities return to normal or baseline state. Additional clinical 
information such as related symptoms, risk factors and contributing conditions (e.g. viral hepatitis, 
autoimmune hepatitis, alcoholic hepatitis, hepatobiliary or pancreatic disorders) should be gathered 
to seek a possible cause of the observed laboratory test abnormalities.
1.14
Diabetic retinopathy and related complications
If an event of diabetic retinopathy or related complications is observed during the trial the following 
additional information must be reported, if available:

Signs and symptoms associated with the event

Results of the eye examination 

Treatment for and complications of the event

Contributing conditions 
2
References
1.
Banks PA, Freeman ML, Practice Parameters Committee of the American College of G. 
Practice guidelines in acute pancreatitis. Am J Gastroenterol. 2006;101(10):2379-400.
2.
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.
3.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance 
for Industry: Immunogenicity Assessment for Therapeutic Protein Products. August 2015.
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Protocol - Appendix C
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
1 of 4
Appendix C
Contraceptive guidance and collection of pregnancy 
information
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol - Appendix C
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
2 of 4
Contraceptive guidance and collection of pregnancy information
It must be recorded in the eCRF whether female subjects are of childbearing potential 
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
Women in the following categories are not considered WOCBP
1. Premenarcheal 
2. Premenopausal female with one of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview.
3. Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high Follicle Stimulating Hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal contraception or 
Hormonal Replacement Therapy (HRT). However, in the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrolment.
Contraception guidance
Male subjects
No contraception measures are required for male subjects as 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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Protocol - Appendix C
Date:
28 January 2019
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT no.: 2018-002589-38 
Page:
4 of 4
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.

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. 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 pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as such.

Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial products by the investigator will be reported to Novo Nordisk as described in 
section 12 of the protocol. 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. 
Any female subject who becomes pregnant while participating in the trial must discontinue trial 
product. 
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16.1.01 
Protocol Attachment 
 
Protocol Attachment I is located in the Trial Master File. 
If applicable, Protocol Attachment II is also located in the Trial Master File. 
Content: Global key staff and Country key staff. 
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924 4309 (PIONEER 12)
Clinical Trial Report
Appendix 16.1.1
11 February 2022
1.0
Final
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04017832 
Sponsor trial ID: 
NN9924-4309 
Official title of study: 
PIONEER 12 China multi-regional clinical trial: Efficacy and 
safety of oral semaglutide versus sitagliptin in subjects with 
type 2 diabetes mellitus treated with metformin 
Document date*: 
18 November 2021 
 
*Document date refers to the date on which the document was most recently updated. 
Note: The date in the header from Page 2 is the date of compilation of the documents and not of an update to content. 


Link
List of contents
Statistical analysis plan......................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Oral semaglutide
Trial ID: NN9924 4309 (PIONEER 12)
Clinical Trial Report
Appendix 16.1.9
27 December 2021
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
1 of 28 
 
 
Statistical Analysis Plan 
Trial ID: NN9924-4309 
 
PIONEER 12 China multi-regional clinical trial: Efficacy and 
safety of oral semaglutide versus sitagliptin in subjects with 
type 2 diabetes mellitus treated with metformin 
 
Author:  
 
Clinical Medical Regulatory and Quality-
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
Redacted statistical analysis plan 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
2 of 28 
 
 
Table of contents 
 
Table of contents ............................................................................................................................................... 2 
Version History ................................................................................................................................................. 3 
List of abbreviations ......................................................................................................................................... 4 
1 
Introduction ............................................................................................................................................... 6 
1.1 
Trial information ............................................................................................................................ 6 
1.2 
Scope of the statistical analysis plan .............................................................................................. 6 
2 
Statistical considerations .......................................................................................................................... 6 
2.1 
Sample size calculation .................................................................................................................. 8 
2.2 
Definition of analysis sets ............................................................................................................ 12 
2.3 
Primary endpoint .......................................................................................................................... 15 
2.3.1 
Primary analysis for the primary estimand ................................................................ 15 
2.3.2 
Primary analysis for the secondary estimand ............................................................. 15 
2.3.3 
Sensitivity analyses .................................................................................................... 16 
2.3.3.1 
Other sensitivity analyses .................................................................... 17 
2.3.3.2 
Chinese Subpopulation Analyses ........................................................ 18 
2.4 
Secondary endpoints .................................................................................................................... 18 
2.4.1 
Confirmatory secondary endpoints ............................................................................ 18 
2.4.2 
Supportive secondary endpoints ................................................................................ 18 
2.4.2.1 
Efficacy endpoints ............................................................................... 18 
2.4.2.2 
Safety endpoints .................................................................................. 21 
2.5 
Interim analysis ............................................................................................................................ 25 
2.6 
Patient-reported outcomes ........................................................................................................... 25 
2.6.1 
SF-36v2® (acute version) health survey ................................................................... 25 
2.6.2 
Responder analyses .................................................................................................... 27 
3 
Changes to the statistical analyses planned in the protocol ................................................................. 27 
4 
References ................................................................................................................................................ 28 
 
 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
3 of 28 
 
 
Version History 
This Statistical Analysis Plan (SAP) for trial NN9924-4309 is based on the protocol version 3.0 
dated 28JAN2019. 
SAP 
Version Date 
Change 
Rationale 
1.0 
16Feb2017 
Not Applicable 
Original version 
2.0 
09Nov2018 
Detailed description 
Update to align with protocol 
version 2.0 
3.0 
18Nov2021 
Removal of Anti-semaglutide 
antibodies analyses according to 
protocol amendment 2. 
Anti-semaglutide antibodies data 
was not collected. 
Removed IWQOL in Section 2.6.2 
in SAP. 
IWQOL data is not collected. 
Insert description on handling 
sparse data in Section 2.3.2 Primary 
analysis for the secondary estimand. 
Propose alternative statistical 
model when sparse data 
encountered. 
Negative binomial regression and 
logistic regression on severe or BG 
confirmed symptomatic 
hypoglycaemic endpoints that 
described in protocol Section 
2.4.2.2 Safety endpoints are 
replaced by descriptive statistics. 
Too few hypoglycaemic episodes 
were observed in the study. 
Remove statistical modelling on SF-
36 responder binary endpoint 
analyses in Section 2.6.1, keep 
descriptive analyses instead. 
Statistical testing result from SF36 
is not informative in other Pioneer 
trials 
Chinese subgroup analyses has 
changed to Chinese subpopulation 
analyses in Section 2.3.3.1. 
More detailed analyses on Chinese 
subpopulation are performed to 
assess the efficacy and safety 
endpoints on subpopulation and 
document in separate CTR. And 
region factor is removed from 
covariate. 
 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
4 of 28 
 
 
List of abbreviations 
AACE 
American Association of Clinical Endocrinologists 
ADA 
American Diabetes Association 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
BMI 
body mass index 
EAC 
event adjudication committee 
ECG 
electrocardiogram 
EOT 
end-of-treatment 
FAS 
full analysis set 
FPG 
fasting plasma glucose 
GI 
gastrointestinal  
GLP-1 
glucagon-like peptide-1 
HbA1c 
glycosylated haemoglobin 
HDL 
high-density lipoprotein 
IMP 
investigational medicinal product 
LDL 
low-density lipoprotein 
LLoQ 
lower limit of quantification 
MAR 
missing at random 
MI 
myocardial infarction 
MMRM 
mixed model for repeated measurements 
PG 
plasma glucose 
PIONEER 
Peptide InnOvatioN for Early diabEtes tReatment 
PK 
pharmacokinetics 
PRO 
patient-reported outcome 
SAE 
serious adverse event 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
5 of 28 
 
 
SAS 
safety analysis set 
s.c. 
subcutaneous(ly) 
SMPG 
self-measured plasma glucose 
T2D 
type 2 diabetes mellitus 
TE 
treatment effect 
TEAE 
treatment-emergent adverse events 
UTN 
Universal Trial Number 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
6 of 28 
 
 
1 
Introduction 
1.1 
Trial information 
This is a 26-week, randomised, double-blinded, double-dummy, active-controlled, four-armed, 
parallel-group, multicentre, multinational trial comparing the efficacy and safety of three once-daily 
dose levels of oral semaglutide versus sitagliptin once-daily in subjects with T2D inadequately 
controlled on metformin. 
Subjects will be randomised in a 1:1:1:1 ratio to receive one of the following treatments:  
• oral semaglutide 3 mg and sitagliptin placebo 
• oral semaglutide 7 mg and sitagliptin placebo 
• oral semaglutide 14 mg and sitagliptin placebo 
• sitagliptin 100 mg and oral semaglutide placebo 
The randomisation will be stratified according to whether the subject is from the China region 
(including Taiwan and Hong Kong) or not. 
For further details see the trial protocol. 
1.2 
Scope of the statistical analysis plan 
This SAP is based on the statistical analyses in the protocol version 3.0 dated 28JAN2019. 
2 
Statistical considerations 
The blinding of the randomised treatments will be maintained until the database has been released 
for statistical analysis. No interim analyses or other analyses of unblinded data will be performed 
before the database is locked. 
Data from all sites will be analysed and reported together.  
China including Taiwan and Hong Kong will be considered as a separate region unless otherwise 
specified. The information regarding region (China/non-China) will be included based on country 
details from the IWRS.  
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. 
Laboratory values below the lower limit of quantification (LLoQ) will be set to ½LLoQ. Number of 
values below LLoQ by treatment and visit will be summarised if deemed relevant. 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
7 of 28 
 
 
Results from a statistical analysis will as a minimum be presented by the estimated treatment 
contrasts for the below three comparisons with associated two-sided 95% confidence intervals and 
p-values corresponding to two-sided tests of no difference: 
• oral semaglutide 14 mg vs. sitagliptin 100 mg 
• oral semaglutide 7 mg vs. sitagliptin 100 mg 
• oral semaglutide 3 mg vs. sitagliptin 100 mg 
If no statistical analysis is specified, data will be presented using relevant summary statistics. 
Primary and secondary estimands 
Two estimands addressing different aspects of the trial objective will be defined; a primary 
‘Hypothetical’  estimand and a secondary ‘Treatment-policy  estimand:  
Primary estimand – ‘Hypothetical’ 
• 
 Treatment difference at week 26 for all randomised subjects if all subjects adhered to 
treatment and did not initiate rescue medication 
The hypothetical estimand assesses the glycaemic benefit a future subject is expected to achieve if 
initiating and continuing treatment with oral semaglutide as compared to sitagliptin. It is considered 
a clinically relevant estimand as it provides information to treating clinicians about the expected 
glycaemic efficacy of oral semaglutide compared to sitagliptin for purposes of treating individual 
subjects. Generalisation of this estimand depends among other things on the extent to which the 
adherence to trial product administration in this trial reflects the behaviour of the target population. 
Accordingly, only data collected prior to discontinuation of trial product or initiation of rescue 
medication will be used to draw inference. This will avoid confounding from rescue medication. 
Secondary estimand  ‘Treatment-policy’ 
• 
Treatment difference at week 26 for all randomised subjects regardless of adherence to 
randomised treatment and initiation of rescue medication. 
The treatment policy estimand assesses the expected glycaemic benefit in a future population that 
results from subjects initiating treatment with oral semaglutide including potential rescue 
medication(s) as compared to initiating treatment with sitagliptin including potential rescue 
medication(s). Generalisation of this estimand depends among other things on the extent to which 
the use of rescue medication in this trial reflects clinical practice and the adherence to trial product 
administration in this trial reflects the behaviour of the target population. Accordingly, data 
collected regardless of discontinuation of trial product or initiation of rescue medication(s) will be 
used to draw inference.  
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
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The confirmation of the confirmatory hypotheses will be based on the primary analysis results for 
the primary  estimand (hypothetical). However, to address a different aspect of the trial objective 
and to be able to compare the trial results with the global trial (PIONEER 3), the secondary 
estimand (treatment-policy) has been included as well. 
Missing data considerations at week 26 
When estimating the primary estimand, data collected after discontinuation of trial product or 
initiation of rescue medication(s) will be set to missing. Across treatment arms the main reasons for 
missing data are expected to be early treatment discontinuation due to GI AEs and initiation of 
rescue medication. The proportion of missing data is expected to be 20% based on the sitagliptin 
phase 3 trials1, the oral semaglutide phase 2 trial (NN9924-3790) that indicated that a low starting 
dose with gradual dose escalation diminishes GI AEs compared with more aggressive dosing 
regimens. Initiation of rescue medication is expected to be more frequent in the sitagliptin arm and 
in the oral semaglutide 3 mg arm than for the two highest dose levels of oral semaglutide. A higher 
proportion of subjects are expected to discontinue treatment due to AEs in the oral semaglutide 14 
mg arm compared to the other treatment arms. So, overall, the frequency of missing data is 
expected to be similar across treatment arms. 
When estimating the secondary estimand, the proportion of missing data, i.e., data that do not exist 
even though subjects are intended to stay in the trial regardless of treatment status and initiation of 
rescue medication(s) is expected to be maximum 10% based on the oral semaglutide phase 2 trial 
(NN9924-3790). Thus, missing data will mainly be due to withdrawal from trial or lost to follow-
up. 
Descriptive summaries and graphical representation of extent, reason(s) for and pattern of missing 
data will be presented by treatment arm. 
2.1 
Sample size calculation 
The primary endpoint is change from baseline to week 26 in HbA1c. For HbA1c, both non-inferiority 
and superiority versus sitagliptin are planned to be tested at each dose level. The confirmatory 
secondary endpoint is change from baseline to week 26 in body weight (kg). For body weight, 
superiority versus sitagliptin is planned to be tested at each dose level. The sample size calculation 
is made for the primary estimand and ensuresa power of at least 85% for testing the below three out 
of the nine pre-specified confirmatory hypotheses shown in Figure 2–1. The closed testing 
procedure described in Bretz et al 20112 is used to control the overall type I error at a nominal two-
sided 5% level. The three hypotheses are: 
• HbA1c superiority of semaglutide 14 mg vs. sitagliptin 100 mg 
• HbA1c superiority of semaglutide 7 mg vs. sitagliptin 100 mg  
• HbA1c non-inferiority of semaglutide 3 mg vs. sitagliptin 100 mg (margin of 0.3%-point) 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
9 of 28 
 
 
The statistical testing strategy is based on the following two principles: 
• Within a dose level, glycaemic effect must be established in terms of HbA1c non-inferiority 
before testing for added benefits in terms of superiority for HbA1c and/or superiority of body 
weight.  
• Glycaemic effect in terms of HbA1c non-inferiority must be established on all higher dose levels 
before continuing testing hypotheses on lower dose levels. 
The sample size is calculated using the calcPower function in the R package, gMCP3 using 10000 
simulations. All of the nine pre-specified confirmatory tests are assumed to be independent. Since 
positive correlations among the tests are expected, the assumption of independence is viewed as 
conservative. 
The sample size assumptions for treatment effects (TE), adjusted TE and the common standard 
deviations (SD) used across dose levels are given in Table 2–1.These are based on the oral 
semaglutide phase 2 results (NN9924-3790), sitagliptin phase 3a trial results1 and supported by 
results from the s.c. semaglutide phase 2 trial (NN9535-1821). 
An adjustment in TE will be implemented for the 20% of subjects who are expected to have missing 
data. The TE used in the sample size calculation will be adjusted according to a 50% smaller effect 
in these subjects. The adjusted treatment effect is defined as 0.8×TE + 0.2×TE×0.50.  
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
12 of 28 
 
 
The overall significance level of α=0.05 (two-sided) is initially allocated to the HbA1c non-
inferiority test of semaglutide 14 mg vs. sitagliptin 100 mg. The local significance level (α-local) 
will be reallocated if a hypothesis is confirmed according to the weight given by the directed edges 
between nodes (hypotheses). The sample size is based on the hypotheses in the dark boxes. 
2.2 
Definition of analysis sets 
The following analysis sets will be defined: 
Full analysis set (FAS): Includes all randomised subjects. Subjects in the FAS will contribute to 
the evaluation “as randomised”. 
Safety analysis set (SAS): Includes all subjects exposed to at least one dose of trial product. 
Subjects in the SAS will contribute to the evaluation based on the trial product received for the 
majority of the period where they were on treatment. This will be referred to as contributing to the 
evaluation “as treated”. 
Per protocol (PP) analysis set: Includes all subjects in the FAS who fulfil the following criteria: 
• have not violated any inclusion criteria 
• have not fulfilled any exclusion criteria 
• have a baseline HbA1c measurement 
• is exposed to trial product and have at least one valid HbA1c measurement while on treatment 
without rescue medication at or after week 14  
Subjects in the PP analysis set will, as in the SAS, contribute to the analysis “as treated”. 
Data selections and observation periods 
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. The full duration of the trial is defined as up to and including: 
• the follow-up visit (visit 9) for subjects on trial product 
• the latest occurring visit of the EOT visit (visit 8) or the follow-up premature discontinuation 
visit (visit 9A), for subjects who have discontinued trial product prematurely 
Subjects and data to be used in an analysis will be selected in a two-step manner: 
• Firstly, subjects will be selected based on the specified analysis set 
• Secondly, data points on the selected subjects from first step will be selected based on the 
specified observation period 
Definition of the observation periods: 
In-trial: This observation period represents the time period where subjects are considered to be 
in the trial, regardless of discontinuation of trial product or initiation of rescue medication. The 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
13 of 28 
 
 
in-trial observation period starts at randomisation (as registered in the IWRS) and ends at the 
date of:  
- 
The last direct subject-site contact, which is scheduled to take place 5 weeks after 
planned last dose of trial product at the follow-up visit  
- 
Withdrawal for subjects who withdraw their informed consent 
- 
The last subject-investigator contact as defined by the investigator for subjects who 
are lost to follow-up 
- 
Death for subjects who dies before any of the above 
On-treatment: This observation period represents the time period where subjects are 
considered treated with the trial product. The observation period is a subset of the in-trial 
observation period. It starts at the date of first dose of trial product. Two slightly different end 
dates will be needed to cover all assessments appropriately. For adjudicated events, ECGs, eye 
examination category, and AEs including hypoglycaemic episodes, the observation period ends 
at the first date of:  
- 
The follow-up visit (visit 9) 
- 
The follow-up prematurely discontinuation visit (visit 9A) 
- 
The last date on trial product + 38 days  
- 
The end-date for the in-trial observation period 
The follow-up visit is scheduled to take place 5 weeks after the last date on trial product 
corresponding to approximately five half-lives of oral semaglutide. The visit window for the 
follow-up visit is + 3 days. 
For efficacy and other safety assessments (laboratory assessments, physical examination and 
vital signs) the observation period ends at the last date on trial product + 3 days. This will be 
used in order to ensure specificity to reversible effects of treatment. 
On-treatment without rescue medication: This observation period is a subset of the on-
treatment observation period, where subjects are considered treated with trial product, but have 
not initiated any rescue medications. Specifically, it starts at date of first dose of trial product 
and the observation period ends at the first date of: 
- 
the last dose of trial product +3 days 
- 
initiation of rescue medication 
The on-treatment without rescue medication observation period will be the primary observation 
period when estimating the primary estimand (hypothetical). The in-trial observation period will be 
the primary observation period when estimating the secondary estimand (treatment-policy). Safety 
will be evaluated based on the in-trial and the on-treatment observation periods. 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
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Data points collected outside an observation period will be treated as missing in the analysis. 
Baseline data will always be included in an observation period. For adjudicated events, the onset 
date will be the EAC adjudicated onset date. 
Before data are locked for statistical analysis and the randomisation code is broken, a review of all 
data will take place. Any decision to exclude either a subject or single observations from the 
statistical analysis is the joint responsibility of the members of the Novo Nordisk study group. 
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 and signed by those responsible before database lock. The subjects 
and observations excluded from analysis sets, and the reason for this, will be described in the CTR. 
Confirmatory hypotheses  
For the primary HbA1c endpoint and the secondary confirmatory body weight endpoint, the 
following three confirmatory one-sided hypotheses are planned to be tested at each dose level of 
oral semaglutide versus sitagliptin. Let the mean treatment difference at week 26 be defined as μ = 
(oral semaglutide minus sitagliptin): 
• HbA1c, non-inferiority, using a non-inferiority margin of 0.3%-point 
- 
H0: μ ≥ 0.3%-point against Ha: μ < 0.3-point% 
• HbA1c superiority 
- 
H0: μ ≥ 0.0%-point against Ha: μ < 0.0%-point 
• Body weight superiority 
- 
H0: μ ≥ 0.0 kg against Ha: μ < 0.0 kg 
Operationally the hypotheses will be evaluated by two-sided tests at the 5% significance level. 
Multiplicity and criteria for confirming hypotheses 
The type I error for testing the nine confirmatory hypotheses related to the HbA1c and body weight 
endpoints will be preserved in the strong sense at 5% (two-sided) using the weighted Bonferroni-
based closed testing procedure described in Bretz et al 2011 and outlined in Figure 2–1. 
The first hypothesis to be tested is non-inferiority of HbA1c at the highest dose level. 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 edges 
going from the confirmed hypothesis to the next hypotheses as specified in Figure 2–1. Each of the 
following hypotheses will be tested at their updated local significance level (α-local). This process 
will be repeated until no further hypotheses can be confirmed. 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
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Non-inferiority and/or 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 of the primary estimand is strictly below its local two-sided significance level as defined by 
the closed testing procedure in Figure 2–1. This is equivalent to using a one-sided p-value (nominal 
α= 0.025) and a one-sided 2.5% overall significance level in the closed testing procedure.  
2.3 
Primary endpoint 
The primary endpoint is change from baseline to week 26 in HbA1c. 
2.3.1 
Primary analysis for the primary estimand  
The primary estimand will be estimated based on the FAS using post-baseline measurements up to 
and including week 26 from the on-treatment without rescue medication observation period. The 
primary analysis for the primary estimand will be a Mixed Model for Repeated Measurements 
(MMRM). A restricted maximum likelihood (REML) will be used. The model will include all post-
baseline HbA1c measurements collected at scheduled visits up to and including week 26 as 
dependent variables. The independent effects included in the model will be treatment 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. For subjects who do not have post-baseline 
assessments for planned visits available in the on-treatment without rescue medication period, the 
baseline value will be carried forward to the first planned visit to ensure that all randomised subjects 
will contribute to the statistical analysis. 
The MMRM is a well-established method that accounts for the uncertainty pertaining to missing 
data. This analysis assumes that the missing data mechanism is missing at random (MAR). Under 
this assumption, the statistical behaviour of the missing data (given the observed responses and 
model fixed effects and covariates) is assumed to be same as for the observed data.   
2.3.2 
Primary analysis for the secondary estimand 
The secondary estimand will be estimated based on the FAS using week-26 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 MAR 
within the groups used for imputation. Imputation of missing data at week 26 will be done within 8 
groups of subjects defined by randomised treatment arm, and whether subjects at week 26; (i) have 
discontinued treatment or initiated rescue medication or (ii) are still on treatment and have not 
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 26 are 
similar in terms of randomised treatment arm and treatment adherence/rescue status. 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
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Missing values for each group will be imputed as follows: 
• An analysis of covariance (ANCOVA) with region as categorical fixed effects and baseline 
HbA1c measurement as a covariate will be fitted to observed values of the change from baseline 
in HbA1c at week 26. 
• The estimated parameters for location and dispersion will be used to impute 1000 values for 
each subject with missing week-26 data based on region as categorical and baseline HbA1c. 
Thus, 1000 complete data sets will be generated including observed and imputed values. 
• If data is too sparse to fit the above defined imputation model for subjects who have 
discontinued trial treatment or initiated rescue medication, missing week 26 data for these 
subjects will be imputed based on subjects from all four treatment arms, and the model will in 
addition include treatment arm as a factor. If data is still too sparse to fit this imputation model, 
the model will be reduced by removing factors in the following order:  
• Region 
• Treatment arm. 
Analysis used for superiority versus sitagliptin at week 26: 
For each of the 1000 (now complete) imputed data sets, the change in HbA1c from baseline to week 
26 will be analysed using an ANCOVA with treatment and region as categorical fixed effects and 
baseline HbA1c as covariate. The results obtained from analysing the data sets will be combined 
using Rubin’s rule4 to draw inference. 
Analysis used for non-inferiority versus sitagliptin at week 26: 
Prior to analysing the data using the same model and approach as used for superiority (see above), a 
value of 0.3% (the non-inferiority margin) will be added to imputed values at week 26 for the oral 
semaglutide treatment arms only5. For evaluating non-inferiority versus sitagliptin unadjusted two 
sided p-values for testing no difference from the non-inferiority margin will be presented. 
2.3.3 
Sensitivity analyses 
To investigate the sensitivity of the primary analysis results, a complementary and separate analysis 
will be performed for the primary and secondary estimand. In line with European Medicines 
Agency (EMA) recommendations6 and with a report from the US National Research Council7, these 
analyses will primarily evaluate the sensitivity of the results due to the impact of missing data. 
Since conservatism, i.e. avoiding bias in favour of oral semaglutide, depends on the context, 
separate sensitivity analyses will be made for non-inferiority and superiority testing. 
The evaluation of the robustness of the primary analysis results will  be based on a pattern mixture 
model approach using multiple imputation. The pattern mixture model sensitivity analyses aim to 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
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stress-test the primary HbA1c results by changing the assumptions for the missing data in the oral 
semaglutide treatment arms, while maintaining the MAR data assumption for the sitagliptin 
Additionally a sensitivity analysis for the primary analysis will be described that is not based on the 
pattern mixture model approach. 
Sensitivity analyses for the primary estimand 
The estimation of the primary estimand will be repeated using a tipping-point multiple imputation 
analysis based on FAS using the on-treatment without rescue medication observation period: 
 
In this sensitivity analysis, missing data will first be imputed using a sequential multiple imputation 
approach assuming MAR. The imputation will be done as described below: 
• 
Intermittent missing values in the on-treatment without rescue medication 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 region as 
categorical effect and baseline and post-baseline values prior to the visit in question as 
covariates. 
Secondly, for all oral semaglutide treatment arms a penalty will be added to the imputed values at 
week 26. The approach is to gradually increase this penalty until all confirmed HbA1c conclusions 
from the primary analysis are reversed. For each hypothesis tested the specific value of the penalty 
that reverses the conclusion will be used to evaluate the robustness of the primary analysis results. 
Sensitivity analyses for the secondary estimand 
The estimation of the secondary estimand will be repeated using a tipping-point multiple imputation 
analysis based on FAS using the in-trial observation period. For all oral semaglutide treatment arms 
a penalty will be added to the imputed values at week 26 from the primary analysis for the 
secondary estimand. The approach is to gradually increase this penalty until all confirmed HbA1c 
conclusions from the primary analysis are reversed. For each hypothesis tested the specific value of 
the penalty that reverses the conclusion will be used to evaluate the robustness of the primary 
analysis results. 
 
2.3.3.1 
Other sensitivity analyses 
Per-protocol analysis: This sensitivity will be based on the per-protocol analysis set. Data from 
the on-treatment without rescue medication observation period will be analysed using the 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
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primary MMRM analysis approach for the primary estimand. This sensitivity analysis will be 
used to evaluate the robustness of the HbA1c non-inferiority conclusions. 
2.3.3.2 
Chinese Subpopulation Analyses 
The primary endpoint, secondary endpoints, and other analyses defined in this SAP will be 
performed on region China subpopulation. The region will no longer be included in the model. The 
statistical analyses will be the same as that performed on the overall population. The results will be 
included in China subpopulation CTR. 
2.4 
Secondary endpoints 
2.4.1 
Confirmatory secondary endpoints  
Change from baseline to week 26 in body weight (kg) will be a confirmatory secondary endpoint.  
The primary and secondary estimands will be estimated using the same approaches as described for 
the primary HbA1c endpoint. Body weight will only be tested for superiority. Baseline body weight 
will be used as a covariate instead of baseline HbA1c in both the MMRM and the multiple 
imputation analysis models. 
Superiority will be considered confirmed if the mean treatment difference is supporting the 
corresponding hypothesis and the two-sided p-value from the analysis of the primary estimand is 
strictly below its local two-sided significance level resulting from the closed testing procedure in 
Figure 2–1. Sensitivity analyses similar to the ones pre-specified for testing superiority for the 
primary HbA1c endpoint will be made to evaluate the robustness of the body weight results. 
2.4.2 
Supportive secondary endpoints 
2.4.2.1 
Efficacy endpoints 
The below supportive secondary efficacy endpoints will be evaluated for: 
• the primary estimand based on FAS using the on-treatment without rescue medication 
observation period. For endpoints where the first planned visit falls later than 8 weeks after 
randomisation, the baseline will not be carried forward 
•  the secondary estimand based on FAS using the in-trial observation period 
No sensitivity analyses are planned for these.  
Continuous efficacy endpoints 
Change from baseline to week 26 in: 
• FPG 
• Body weight (%) 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
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• BMI 
• Waist circumference 
• Fasting lipid profiles (total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, 
triglycerides, free fatty acids) 
• Patient-reported outcome 
Short Form-36 version 2 (SF-36v2™) (acute version) health survey 
 
BMI will be calculated based on body weight and height based on the formulae: 
BMI kg/m2 = body weight (kg)/(height (m) × height (m)) or (kg/m2 = [lb/in2 × 703]) 
Change from baseline to week 26 in the below derived endpoints from the 7-point SMPG profile: 
• Mean of the 7-point profile, defined as the area under the profile, calculated using the 
trapezoidal method, divided by the measurement time 
• Mean post prandial increment (over all meals) 
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. Fasting lipid profile 
endpoints will be log-transformed prior to analysis with the associated log-transformed baseline 
value as a covariate. 
Binary efficacy endpoints 
If a subject after week 26 achieves (yes/no): 
• HbA1c < 7.0 % (53 mmol/mol) (ADA target) 
• HbA1c ≤ 6.5 % (48 mmol/mol) (AACE target) 
• HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) 
• Body weight loss ≥ 3 % 
• Body weight loss ≥ 5 % 
• Body weight loss ≥ 10 % 
• HbA1c < 7.0 % (53 mmol/mol) without hypoglycaemia ( severe or BG confirmed symptomatic 
hypoglycaemia) and no body weight gain 
• HbA1c reduction ≥ 1 %-point (10.9 mmol/mol) and body weight loss ≥ 3 % 
When addressing the treatment-policy estimand the ‘without hypoglycaemia’ component of the 
composite endpoint will also include non-treatment-emergent events of severe or BG-confirmed 
symptomatic hypoglycaemia as data collected regardless of discontinuation of trial product or 
initiation of rescue medication(s) is used. 
Missing data for the above six binary endpoints will be accounted for using multiple imputation 
techniques. For the treatment-policy estimand the binary endpoints will be calculated as 
dichotomisations of the 1000 multiple imputations underlying the primary MI analysis. For the 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
20 of 28 
 
 
hypothetical estimand the model will be implemented using a sequential imputation approach as in 
the tipping-point sensitivity analysis. The binary endpoints will be derived as dichotomisations of 
the 1000 imputed complete data sets from the sequential imputation. 
The imputed complete data sets will be analysed using a logistic regression model with treatment 
and region as categorical fixed effects and baseline response as covariate (i.e. baseline HbA1c for 
binary HbA1c endpoints, baseline weight for binary weight endpoints and both baseline HbA1c and 
body weight for the binary endpoints that combines both parameters). Inference comparing 
treatments will be drawn using Rubin’s rule4. 
For the composite endpoints involving both HbA1c and body weight the imputed data sets will be 
combined by imputation number. 
Time to event endpoint 
• 
Time to additional anti-diabetic medication (to support the treatment policy estimand) 
• 
Time to rescue medication (to support the hypothetical estimand) 
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 to be considered as ‘anti-
diabetic medication’. This threshold is set to ensure that the short-term durations (i.e. ≤ 21 days) of 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
21 of 28 
 
 
anti-diabetic medication (e.g. in connection with concurrent illnesses) are not included because such 
intensifications are not likely to affect the effect endpoints. 
 
Treatment policy estimand: Time to additional anti-diabetic medication 
The treatment policy estimand is addressed for the FAS using the in-trial observation period and 
additional anti-diabetic medication will be considered an event regardless of whether or not subjects 
prematurely discontinued treatment. Time from randomisation to additional anti-diabetic 
medication will be analysed using a Cox proportional hazards model with treatment and 
stratification factor as categorical fixed effects and baseline HbA1c as a covariate. From this analysis 
the estimated Hazard ratios between each of the oral semaglutide dose levels and placebo together 
with associated two-sided 95% CIs and unadjusted two-sided p-values will be presented. The 
analysis aims to address the need of additional anti-diabetic medication regardless of this is due to 
lack of effect or tolerability. Switch to other anti-diabetic treatment is therefore also considered an 
event and withdrawn subjects or subject lost to follow-up will be considered as having an event on 
the day of withdrawal. Subjects will be censored on the day before planned end of treatment visit. 
Hypothetical estimand: Time to rescue medication 
The hypothetical estimand is addressed for the FAS using the on-treatment without rescue 
medication observation period. Time from first dose of trial product to initiation of rescue 
medication will be analysed using the same model as described above. The analysis aims to address 
lack of effect and only initiation of rescue medication as add-on to randomised treatment is 
considered an event. Switch to other anti-diabetic treatment is not considered an event and as a 
consequence subjects will be censored on the day before date of last trial product. Potential events 
occurring between randomisation and first date on trial product will be included in the analysis as 
events at day 0, in order to count all events of rescue medication.  
2.4.2.2 
Safety endpoints 
The safety endpoints will be evaluated based on SAS using the on-treatment observation period and 
based on SAS using the in-trial observation period unless otherwise stated. The following endpoints 
are used to support the safety objectives: 
Adverse events  
• Number of TEAEs during exposure to trial product, assessed up to approximately 31 weeks 
All AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) coding.  
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
22 of 28 
 
 
A TEAE is defined as an AE with onset in the on-treatment observation period (see definition of 
observation periods in Section 2.2). 
TEAEs will be summarised in terms of the number of subjects with at least one event (N), the 
percentage of subjects with at least one event (%), the number of events (E) and the event rate per 
100 patient-years of observation time (R) for the on-treatment observation period. Supportive 
summaries of AEs will be made for the in-trial observation period. The development over time in 
GI AEs will be evaluated by the use of graphical methods. 
Other safety endpoints 
Change from baseline to week 26 in: 
• Amylase 
• Lipase 
• Pulse rate 
• 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 on-treatment observation period and using the primary analysis for the 
secondary estimand based on SAS using the in-trial observation period. Endpoints will be analysed 
separately as described above for continuous efficacy endpoints. Results at week 26 will be 
presented. Amylase and lipase endpoints will be log-transformed prior to analysis with the 
associated log-transformed baseline value as a covariate. 
Change from baseline to week 26 in: 
• ECG category 
• Physical examination category 
• Eye examination category 
Safety assessments 
Change from baseline to week 26 in: 
• Haematology  
• Biochemistry (except for amylase and lipase) 
• Calcitonin 
The above safety endpoints and assessments will be summarised descriptively by treatment arm and 
visit. Categorical safety endpoints will be summarised as counts and relative frequencies. Calcitonin 
will also be presented by gender.   
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CONFIDENTIAL


Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
23 of 28 
 
 
Hypoglycaemia 
• Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during exposure to trial product, assessed up to approximately 31 weeks 
• Treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes during 
exposure to trial product, assessed up to approximately 31 weeks (yes/no)  
Classification of Hypoglycaemia: 
Hypoglycaemic episodes will be summarised for the SAS and the on-treatment observation period 
only. 
Treatment-emergent: hypoglycaemic episodes will be defined as treatment-emergent if the onset of 
the episode occurs within the on-treatment observation period (see definition of observation periods 
in Section 2.2). 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.  
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 2–2). 
Novo Nordisk classification of hypoglycaemia 
In normal physiology, symptoms of hypoglycaemia occur below a PG level of 3.1 mmol/L (56 
mg/dL)8. Therefore, Novo Nordisk has included hypoglycaemia with PG levels below this cut-off 
point in the definition of BG confirmed hypoglycaemia. 
Novo Nordisk uses the following classification in addition to the ADA classification: 
• Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification9 or BG confirmed by a PG value <3.1 mmol/L (56 mg/dL) with 
symptoms consistent with hypoglycaemia.  
ADA classification9 of hypoglycaemia  
• Severe hypoglycaemia: An episode requiring 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. 
• Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured PG concentration ≤ 3.9 mmol/L (70 mg/dL). 
• Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured PG concentration ≤ 3.9 mmol/L (70 
mg/dL). 
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Statistical Analysis Plan
Date:
18 November 2021
Novo Nordisk
Trial ID: NN9924-4309
Version:
3.0
UTN: U1111-1188-1256
Status:
Final
EudraCT No.: 2018-002589-38 
Page:
24 of 28
•
Pseudo-hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia with a measured PG concentration > 3.9 mmol/L (70 
mg/dL) but approaching that level.
•
Probable symptomatic hypoglycaemia: An episode during which symptoms of 
hypoglycaemia are not accompanied by a PG determination but that was presumably caused 
by a PG concentration ≤ 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG ≤ 3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo- 
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG ≤ 3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia 
(ADA 2013)
Figure 2–2
ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes will be presented in terms of the number of 
subjects with at least one episode, the percentage of subjects with at least one episode (%), the total 
number of episodes and the episode rate per 100 patient years of observation time.
Analysis of severe or BG confirmed symptomatic hypoglycaemic endpoints
The number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
in the on-treatment period will be summarized by descriptive statistics.
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
25 of 28 
 
 
2.5 
Interim analysis 
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked 
2.6 
Patient-reported outcomes 
PRO endpoints 
Change from baseline to week 26 in: 
• SF-36v2 (acute version) health survey: Scores from the 8 domains, the physical component 
summary score and mental component summary score. 
The PRO endpoints will be evaluated using the primary analysis for the primary estimand based on 
FAS using the on-treatment without rescue medication period and using the primary analysis for the 
secondary estimand based on FAS using the in-trial observation period. Scores will be analysed 
separately as the other continuous efficacy endpoints with the associated baseline response as a 
covariate. 
2.6.1 
SF-36v2® (acute version) health survey 
The SF-36v2® Health Survey (SF-36v2) (acute version) instrument is a commonly used generic 
instrument measuring health-related quality of life (HRQoL)/general health status across disease 
areas including diabetes. The SF-36v2 (acute version) for adults with a 1-week recall period 
contains 36 items. 
A total of 35 items measure eight domains of functional health and well-being as well as two 
component summary scores: physical functioning (10 items), role limitation due to physical health 
problems (4 items), bodily pain (2 items), general health perceptions (5 items), vitality (4 items), 
social functioning (2 items), role limitations due to emotional problems (3 items) and general 
mental health (5 items), mental component summary (MCS) score, physical component summary 
(PCS) score. There is an additional single item giving information on health change over the past 
week. 
Domain scores 
Norm-based scores (NBS) will be derived using the QualityMetric Health Outcomes™ Scoring 
Software1 including the 2009 US general population norm. The most recent version of the 
QualityMetric Health Outcomes™ Scoring Software available at time of licensing was used for the 
specific trial. Table 2-3 provides an overview of the domains. NBS standardises domain and 
component scores into T-scores using the means and standard deviations from the US general 
population. Higher scores on all domains and component summary measures (PCS and MCS) 
indicate better HRQoL/general health status. Item 2 (i.e. Question 2 in CRF) is not included in any 
score.  
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
26 of 28 
 
 
Table 2–3 
Overview of domains for SF-36v2 (acute version) 
Domain 
Items numbers of items 
included in domain 
Comment 
Physical Functioning (PF) 
Items 3a-j 
 
Role Limitations Due to Physical Health (Role-Physical; 
RP) 
Items 4a-d 
 
Bodily Pain (BP) 
Items 7, 8 
Both item scores reversed  
General Health Perceptions (General Health; GH) 
Items 1, 11a-d 
Item scores 1, 11b and 11d reversed 
Vitality (VT) 
Items 9a, 9e, 9g, 9i 
Item scores 9a and 9e reversed  
Social Functioning (SF) 
Items 6, 10 
Item score 6 reversed  
Role Limitations Due To Emotional Problems (Role-
Emotional; RE) 
Items 5a-c 
 
Mental Health (MH) 
Items 9b, 9c, 9d, 9f, 9h 
Item scores 9d and 9h reversed  
Physical component summary (PCS) 
NA 
The PCS score is a weighted average of 
the 8 domain scores.  
Mental component summary (MCS) 
NA 
The MCS score is also a weighted average 
of the 8 domain scores. Weights differ 
from PCS to MCS.  
 
Missing data at instrument level will be handled using the Maximum Data Recovery method: The 
method applies a value to a domain item rendered missing if at least one of the items in that domain 
has valid data. A domain score is considered missing if all item values in the domain are missing. 
PCS and MCS are calculated when at least seven of the eight domains have valid data, either actual 
or estimated. However, to calculate PCS, the PF domain must be one of the seven domains having 
valid data. Also, to calculate MCS, the MH domain must be one of the seven domains having valid 
data. 
Responder threshold values 
The responder threshold values, in terms of T-score points for change from baseline are defined in 
Table 2-4. 
Table 2–4 
Responder thresholds for SF-36v2 (acute version) 
Domain 
Responder threshold 
Physical Functioning (PF) 
4.3 
Role Limitations Due to Physical Health (Role-Physical; RP) 
4.0 
Bodily Pain (BP) 
5.5 
General Health Perceptions (General Health; GH) 
7.0 
Vitality (VT) 
6.7 
Social Functioning (SF) 
6.2 
Role Limitations Due To Emotional Problems (Role-Emotional; RE) 
4.6 
Mental Health (MH) 
6.7 
Physical component summary (PCS) 
3.8 
Mental component summary (MCS) 
4.6 
Responder analyses will be based on the responder threshold values and are described in Section 
2.6.2. 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
27 of 28 
 
 
2.6.2 
Responder analyses 
Responder analyses will be conducted for both estimands and separately for each score. 
For descriptive statistics the following subject responder categorization is applied for all relevant 
time points and scores: 
• Responder - improvement: Individual change from baseline in score ≥ positive responder 
threshold  
• Non-responder - no change: Individual change from baseline in score  > negative responder 
threshold value and < positive responder threshold value 
• Non-responder - worsening: Individual change from baseline in score  ≤ negative responder 
threshold value 
 
3 
Changes to the statistical analyses planned in the protocol 
The SAP specifies several changes and clarifications to the statistical analyses that were described 
in the trial protocol. All the changes were finalised and approved before unblinding of trial data at 
DBL. The changes and clarifications are listed below (Table 3-1): 
Table 3–1 
 Change to planned statistical analyses 
 
Change to planned statistical analysis 
Rationale for change and possible 
implications 
Insert description on handling sparse data in 
Section 2.3.2 Primary analysis for the secondary 
estimand. 
Propose alternative statistical model when 
sparse data encountered. 
Remove negative binomial regression and 
logistic regression on severe or BG confirmed 
symptomatic hypoglycaemic endpoints that 
described in protocol Section 17.3.2.2 Safety 
endpoints. 
Too few hypoglycaemic episodes were observed 
in the study. 
Remove statistical modelling on SF-36 
responder binary endpoint analyses in Section 
Statistical testing result from SF36 is not 
informative in other Pioneer trials 
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Statistical Analysis Plan 
 
Date: 
18 November 2021 
Novo Nordisk 
Trial ID: NN9924-4309 
Version: 
3.0 
UTN: U1111-1188-1256 
Status: 
Final 
EudraCT No.: 2018-002589-38  
Page: 
28 of 28 
 
 
Change to planned statistical analysis 
Rationale for change and possible 
implications 
2.6.1, keep descriptive analysis instead. 
Chinese subgroup analyses described in protocol 
Section 17.2.4 changed to SAP Section 2.3.3.2 
as Chinese subpopulation analyses. 
More detailed analyses on Chinese 
subpopulation has performed to assess the 
efficacy and safety on subpopulation and 
document in separate CTR. 
 
4 
References 
 
1. Merck Sharp & Dohme Limited. JANUVIA - European Summary of Product Characteristics 
Annex 1. 26 May 2015. 
2. 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. 
3. Rohmeyer K, Klinglmueller F. gMCP: Graph Based Multiple Test Procedures. R package 
version 0.8-8. 3 Oct 2014. 
4. Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987. 
5. Koch GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med. 2008;27(3):333-42. 
6. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
Guideline on Missing Data in Confirmatory Clinical Trials (EMA/CPMP/EWP/1776/99 Rev. 
1). 2 Jul 2010. 
7. National Academy of Sciences (NAS). The Prevention and Treatment of Missing Data in 
Clinical Trials. Washington D.C.: The National Academies Press. 2010. 
8. Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose 
counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 
1987;79(3):777-81. 
9. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95. 
 
 
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