Clinical trial NCT01923181
Conditions: Diabetes Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2013-12-02; Completion date: 2014-12-11
Enrollment: 632 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial is conducted globally. The aim of the trial is to examine the dose range, escalation and efficacy of oral semaglutide in subjects with type 2 diabetes.

Detailed description:

Arms: arm 1: 2.5 mg for 26 weeks. All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 2: 2.5 mg for 4 weeks, then 5.0 mg for 22 weeks. All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 3: 5.0 mg for 4 weeks, then 10 mg for 22 weeks. All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 4: 5.0 mg for 4 weeks, then 10 mg for 4 weeks, then 20 mg for 18 weeks. All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 5: 5.0 mg for 4 weeks, then 10 mg for 4 weeks, then 20 mg for 4 weeks, then 40 mg for 14 weeks.

All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 6: 5.0 mg for 8 weeks, then 10 mg for 8 weeks, then 20 mg for 8 weeks, then 40 mg for 2 weeks All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 7: 5.0 mg for 2 weeks, then 10 mg for 2 weeks, then 20 mg for 2 weeks, then 40 mg for 20 weeks.

All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 8: All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone. arm 9: 0.25 mg for 4 weeks, then 0.50 mg for 4 weeks, then 1.0 mg for 18 weeks. All arms include 26 weeks of treatment and a 5 week follow-up period. The trial medication will be add-on to metformin therapy or as monotherapy in the case where the subject is treated with diet and exercise alone.
Interventions: intervention 1: semaglutide intervention 2: semaglutide intervention 3: oral placebo
Intervention descriptions: intervention 1: Once-daily oral administration as tablets. intervention 2: Once-weekly,injected s.c./subcutaneously (under the skin) using a pen intervention 3: Once-daily oral administration as tablets.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01923181 
Sponsor trial ID: 
NN9924-3790 
Official title of study: 
Multiple dose trial examining dose range, escalation and efficacy of 
oral semaglutide in subjects with type 2 diabetes 
Document date: 
24 August 2016 
 


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List of contents
Protocol .............................................................................................................................................
Appendix A - Monitoring of Calcitonin .........................................................................................
Appendix B - PRO questionnaires..................................................................................................
Appendix C - MESI..........................................................................................................................
Attachment 1 - Global key staff ......................................................................................................
Attachment 2 - List of key staff and relevant departments..........................................................
Substantial amendment 1 ................................................................................................................
Substantial amendment 2 ................................................................................................................
Substantial amendment 3 ................................................................................................................
CONFIDENTIAL
Date:
1RYR1RUGLVN
Version:
Status:
Oral GLP-1
Trial ID: NN9924-3790
Clinical Trial Report
Appendix 16.1.1
24 August 2016
2.0
Final
16.1.1 Protocol and protocol amendments
CONFIDENTIAL
Redacted protocol 
Lncludes redaction of personal identifiable DQGFRPSDQ\
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. 


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 98
Protocol
Trial ID: NN9924-3790
Multiple dose trial examining dose range, escalation and 
efficacy of oral semaglutide in subjects with type 2 diabetes
Trial phase: 2
Protocol originator: 
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.
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
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 98
Table of contents
Page
Table of contents...............................................................................................................................................2
Table of figures.................................................................................................................................................6
Table of tables...................................................................................................................................................6
List of abbreviations.........................................................................................................................................7
1
Summary..................................................................................................................................................10
2
Flow chart ................................................................................................................................................13
2.1
Flow chart foot notes ...................................................................................................................16
3
Background information and rationale for the trial............................................................................17
3.1
Type 2 diabetes mellitus and glucagon-like peptide-1.................................................................17
3.2
Semaglutide and SNAC...............................................................................................................17
3.2.1
Nonclinical data.........................................................................................................18
3.2.1.1
Thyroid C-cell tumours in rodents ......................................................19
3.2.1.2
Teratogenicity in rats...........................................................................19
3.2.1.3
SNAC toxicology................................................................................19
3.2.2
Nonclinical pharmacology and pharmacokinetics.....................................................20
3.2.3
Clinical data...............................................................................................................21
3.2.3.1
Data from literature.............................................................................21
3.2.3.2
Clinical data of s.c. semaglutide..........................................................21
3.2.3.3
Clinical data of oral GLP-1 .................................................................23
3.2.3.4
Clinical data of SNAC.........................................................................23
3.3
Risks and benefits of the trial ......................................................................................................24
3.4
Rationale for the trial...................................................................................................................25
4
Objective(s) and endpoint(s) ..................................................................................................................26
4.1
Objectives ....................................................................................................................................26
4.1.1
Primary objective.......................................................................................................26
4.1.2
Secondary objectives .................................................................................................26
4.2
Endpoints.....................................................................................................................................26
4.2.1
Primary endpoint........................................................................................................26
4.2.2
Supportive secondary endpoints ................................................................................26
5
Trial design..............................................................................................................................................28
5.1
Type of trial .................................................................................................................................28
5.2
Rationale for trial design..............................................................................................................29
5.3
Treatment of subjects...................................................................................................................29
5.3.1
Dose levels and escalation regimen for oral dosing...................................................30
5.3.2
Dose levels and escalation regimen for s.c. dosing....................................................30
5.4
Treatment after end of trial..........................................................................................................31
5.5
Rationale for treatment ................................................................................................................31
6
Trial population.......................................................................................................................................32
6.1
Number of subjects......................................................................................................................32
6.2
Inclusion criteria ..........................................................................................................................32
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 98
6.3
Exclusion criteria.........................................................................................................................32
6.4
Rescue criteria..............................................................................................................................33
6.5
Withdrawal criteria and discontinuation of trial product.............................................................34
6.5.1
Withdrawal from trial ................................................................................................34
6.5.2
Discontinuation of trial product.................................................................................34
6.6
Rationale for trial population.......................................................................................................35
7
Milestones ................................................................................................................................................36
8
Methods and assessments .......................................................................................................................37
8.1
Visit procedures...........................................................................................................................37
8.1.1
Introduction................................................................................................................37
8.1.2
Visit 1 (Screening).....................................................................................................37
8.1.3
Fasting visits ..............................................................................................................38
8.1.4
Unscheduled visits.....................................................................................................38
8.1.5
Visit 2 (Randomisation).............................................................................................38
8.1.6
Visit numbers.............................................................................................................39
8.1.7
Visits 3-10 (Treatment)..............................................................................................39
8.1.8
Visits 11-12 (End-of-treatment and Follow-up) ........................................................39
8.1.9
Visit 11X (End-of-Trial – premature discontinuation) ..............................................39
8.1.10
Withdrawals...............................................................................................................40
8.1.11
Investigator’s assessment...........................................................................................40
8.2
Subject related information..........................................................................................................41
8.2.1
Concomitant illness and medical history...................................................................41
8.2.2
Concomitant medication............................................................................................41
8.2.3
Demography ..............................................................................................................42
8.2.4
Diagnosis of diabetes.................................................................................................42
8.2.5
Diabetes treatment history .........................................................................................42
8.2.6
History of gallbladder disease....................................................................................42
8.2.7
History of cardiovascular disease ..............................................................................42
8.2.8
Renal impairment history...........................................................................................42
8.2.9
Post-dose fasting routines..........................................................................................43
8.3
Assessments for efficacy .............................................................................................................43
8.3.1
Blood samples............................................................................................................43
8.3.2
Body measurements...................................................................................................43
8.3.3
Patient reported outcomes..........................................................................................44
8.4
Assessments for safety.................................................................................................................45
8.4.1
Hypoglycaemic episodes ...........................................................................................45
8.4.2
Blood samples............................................................................................................45
8.4.3
Pregnancy test............................................................................................................46
8.4.4
Urinalysis...................................................................................................................47
8.4.5
Antibodies..................................................................................................................47
8.4.6
Vital signs ..................................................................................................................47
8.4.7
Electrocardiogram – 12-lead......................................................................................47
8.4.8
Fundoscopy/fundus photography...............................................................................48
8.4.9
Physical examination.................................................................................................48
8.4.10
Pharmacokinetics.......................................................................................................49
8.4.11
Calcitonin...................................................................................................................50
8.5
Laboratory assessments ...............................................................................................................50
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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8.6
Other assessments........................................................................................................................51
8.6.1
Subject diary ..............................................................................................................51
8.6.2
Additional safety assessments ...................................................................................51
8.6.2.1
Thyroidectomy, tissue sample and genetic testing..............................51
8.6.2.2
Assessments in case of suspicion of acute pancreatitis.......................52
8.6.2.3
Assessments in case of suspicion of severe hypersensitivity..............53
8.7
Subject compliance......................................................................................................................53
9
Trial supplies ...........................................................................................................................................54
9.1
Trial products...............................................................................................................................54
9.2
Labelling......................................................................................................................................55
9.3
Storage.........................................................................................................................................55
9.4
Drug accountability and destruction............................................................................................56
9.5
Auxiliary supplies........................................................................................................................56
10 Interactive voice/web response system..................................................................................................57
11 Randomisation procedure and breaking of blinded codes..................................................................58
11.1
Breaking of blinded codes ...........................................................................................................58
12 Adverse events, technical complaints and pregnancies .......................................................................59
12.1
Definitions ...................................................................................................................................59
12.2
Reporting of adverse events.........................................................................................................62
12.3
Follow-up of adverse events........................................................................................................65
12.4
Technical complaints and technical complaint samples ..............................................................66
12.4.1
Reporting of technical complaints .............................................................................66
12.4.2
Collection, storage and shipment of technical complaint samples ............................67
12.5
Pregnancies..................................................................................................................................67
12.6
Precautions and/or overdose ........................................................................................................68
12.7
Committees related to safety........................................................................................................69
12.7.1
Novo Nordisk safety committee ................................................................................69
12.7.2
Event adjudication committee....................................................................................69
12.7.3
Calcitonin monitoring committee ..............................................................................71
13 Case report forms....................................................................................................................................72
13.1
Corrections to case report forms..................................................................................................72
13.2
Case report form flow..................................................................................................................72
13.3
Paper case report forms................................................................................................................73
14 Monitoring procedures...........................................................................................................................74
15 Data management....................................................................................................................................75
16 Computerised systems ............................................................................................................................76
17 Statistical considerations ........................................................................................................................77
17.1
Sample size calculation................................................................................................................77
17.2
Definition of analysis sets............................................................................................................78
17.3
Primary endpoint..........................................................................................................................78
17.4
Supportive secondary endpoints ..................................................................................................79
17.4.1
Efficacy endpoints .....................................................................................................79
17.4.2
Safety endpoints.........................................................................................................80
17.4.3
Pharmacokinetics and/or pharmacodynamics modelling...........................................83
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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18 Ethics........................................................................................................................................................84
18.1
Informed consent .........................................................................................................................84
18.2
Data handling...............................................................................................................................85
18.3
Premature termination of the trial and/or trial site.......................................................................85
19 Protocol compliance................................................................................................................................86
20 Audits and inspections............................................................................................................................87
21 Critical documents ..................................................................................................................................88
22 Responsibilities........................................................................................................................................90
23 Reports and publications........................................................................................................................92
23.1
Communication of results............................................................................................................92
23.1.1
Authorship .................................................................................................................93
23.1.2
Site-specific publication(s) by investigator(s) ...........................................................93
23.2
Investigator access to data and review of results.........................................................................93
24 Retention of clinical trial documentation and human biospecimens..................................................94
24.1
Retention of clinical trial documentation.....................................................................................94
24.2
Retention of human biospecimens...............................................................................................94
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities..............95
26 Indemnity statement ...............................................................................................................................96
27 References................................................................................................................................................97
Appendix A – Monitoring of calcitonin 
Appendix B – PRO questionnaire
Appendix C – Medical Events of Special Interests (MESI)
Attachment I – Global List of key staff and relevant departments
Attachment II – Country List of key staff and relevant departments
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
6 of 98
Table of figures  
Page
Figure 5–1
Trial design of NN9924-3790.................................................................................................28
Figure 5–2
Dosing and fasting conditions for oral treatment (arms 1-8)..................................................30
Figure 12–1
Initial reporting of AEs...........................................................................................................64
Figure 17–1
ADA classification of hypoglycaemia....................................................................................82
Table of tables   
Page
Table 9–1
Trial products (IMP)...............................................................................................................54
Table 9–2
Storage conditions for trial products.......................................................................................55
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
7 of 98
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ANCOVA
analysis of covariance
AUC
area under the curve
BMI
body mass index
CMC
calcitonin monitoring committee
CRF
case report form
CT
computerised axial tomography 
CTR
clinical trial report
CVD
cardiovascular disease
DFU
directions for use
DPP-4
dipeptidyl peptidase-4
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EE
ethinylestradiol
EMA
European Medicines Agency
eSIF
electronic safety information form
FAS
full analysis set
FDA
Food and Drug Administration
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
HbA1c
glycosylated haemoglobin
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
8 of 98
hCG
human chorionic gonadotropin
HDL
high density lipoprotein
HOMA-B
homeostasis model assessment of beta-cell function
HOMA-IR
homeostasis model assessment of insulin resistance
IB
Investigator’s Brochure
ICMJE
International Committee of Medical Journal Editors
IEC
independent ethics committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IV/WRS
interactive voice/web response system
LDL
low density lipoprotein
LN
levonorgestrel
LOCF
last observation carried forward
LSFV 
last subject first visit
MD
multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MEN2
multiple endocrine neoplasia type 2
MESI
medical event of special interest
MMRM
mixed model for repeated measurements 
MRI
magnetic resonance imaging
NOAEL
no observed adverse effect level 
NYHA
New York Heart Association
OAD
oral antidiabetic drug
OD
once-daily
OW
once-weekly
PD
pharmacodynamics
PK
pharmacokinetics
PRO
patient reported outcome
SAE
serious adverse event
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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SAP
statistical analysis plan
s.c.
subcutaneous
SD
standard deviation
SF-36
medical outcomes study 36-item short-form health survey
SIF
safety information form
SNAC
sodium N-[8-(2-hydroxybenzoyl) amino] caprylate / 
salcaprozate sodium
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes
TEAE
treatment emergent adverse events
tmax
time to maximal concentration
TMM
Trial Materials Manual
USP
United States Pharmacopeia
UTN
Universal Trial Number
VLDL
very low density lipoprotein
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
10 of 98
1
Summary
Objectives and endpoints:
Primary objective
!
To compare the efficacy on glycaemic control of oral semaglutide in a SNAC formulation 
against placebo in subjects with T2D
Key secondary objectives
!
To compare the efficacy on glycaemic control of oral semaglutide in a SNAC formulation 
against s.c. semaglutide in subjects with T2D
!
To compare the safety and tolerability of three dose escalation schemes using a single end dose 
level during 26 weeks administration of oral semaglutide and SNAC in a tablet formulation in 
subjects with T2D
Primary endpoint
!
Change in HbA1c from baseline to after 26 weeks of treatment
Key secondary endpoints
!
Subjects who, after 26 weeks of treatment, achieve (yes/no) HbA1c <7% (53 mmol/mol)
!
Change in body weight from baseline to after 26 weeks of treatment
!
Change in waist circumference from baseline to after 26 weeks of treatment
!
Change in body mass index (BMI) from baseline to after 26 weeks of treatment
!
Number of treatment emergent adverse events (TEAEs) recorded from baseline until week 31
!
Number of confirmed hypoglycaemic episodes recorded from baseline until week 31
Trial design:
This is a randomised, partially-blinded, multiple-dose, multicentre trial with a total of nine 
treatment arms; seven oral semaglutide treatment arms, an oral placebo arm and an s.c. semaglutide 
arm in a parallel design. The trial will include subjects with T2D who have failed on diet and 
exercise and/or metformin.
Subjects with T2D will be randomised in an equal manner with 67 subjects planned to be 
randomised per treatment arm. Treatment arms 1-8 will include once-daily dosing of a tablet and 
will be blinded. Treatment arm 9 features once-weekly s.c. injection. All arms include 26 weeks of 
treatment and a 5 week follow-up period.
The trial medication will be add-on to previous metformin therapy or as monotherapy in the case 
where the subject is treated with diet and exercise alone.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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Trial population:
A total of 603 subjects with T2D will be randomised.
Key inclusion criteria: 
!
Male or female, age ≥ 18 years at the time of signing inform consent
!
BMI ≥25 and ∀40 kg/m2
!
Subjects diagnosed with T2D treated with diet and exercise and/or who have been on a stable 
dose of metformin for at least 30 days prior to screening
!
HbA1c 7.0-9.5% (53-80 mmol/mol) (both inclusive)
Key exclusion criteria
!
Subjects on selected oral medication with a narrow therapeutic window, such as warfarin, 
digoxin, tricyclic antidepressants, lithium, aminophylline, theophylline and anticonvulsants
!
History of chronic pancreatitis or idiopathic acute pancreatitis
!
Chronic malabsorption, regardless of aetiology
!
History of Crohn’s disease, ulcerative colitis, or other inflammatory bowel disease
!
Treatment with glucose lowering agent(s) other than metformin as stated in the inclusion criteria 
in a period of 90 days before the screening visit
Assessments:
Efficacy assessment
Measurements of laboratory parameters (HbA1c, glucose metabolism parameters and lipids), BMI
and waist circumference. Patient reported outcomes will be based on the SF-36 questionnaire and 
assessed at baseline and end of treatment.
Safety assessment
Adverse events, laboratory safety variables (haematology, biochemistry, calcitonin and urinalysis), 
vital signs, electrocardiograms, physical examinations and hypoglycaemic episodes recorded from 
the first trial-related activity and until completion of the post treatment follow-up visit of the trial.
PK assessment
Trough and peak plasma concentrations of semaglutide will be assessed throughout the trial.
Trial product(s):
The investigational medicinal products used in the trial will be for once-daily oral administration as 
tablets and once-weekly s.c. administration using a pen injector system. The investigational 
medicinal products are:
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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!
Semaglutide 2.5 mg tablets 
!
Semaglutide 5.0 mg tablets 
!
Semaglutide 10 mg tablets 
!
Semaglutide 20 mg tablets 
!
Semaglutide 40 mg tablets 
!
Placebo tablets
!
Semaglutide 1.34 mg/mL, solution for injection, 1.5 mL pre-filled PDS290 pen-injector
CONFIDENTIAL


Protocol
UTN: U1111-1136-4716
Date:
25 June 2013
Status:
Final
Novo Nordisk
Trial ID: NN9924-3790
EudraCT No.: 2012-004994-16
Version:
1.0
Page:
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2
Flow chart
Trial Periods
Screening1
Randomisation
Treatment
End-of-
treatment2
Follow-
up2
End-of-trial –
premature
discontinuation3
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
11X
Timing of visit
Weeks
-2
0
2
4
6
8
12
16
20
24
26
31
26
Visit window
Days
±3
±3
±3
±3
±5
±5
±5
±3
±3
+5
±3
SUBJECT RELATED
INFO/ASSESSMENTS
Informed consent
x
In- and exclusion criteria
x
x
Concomitant medication
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant illness
x
Demography
x
Diagnosis of diabetes
x
Diabetes treatment history
x
Medical history
x
Smoking habits
x
History of gallbladder 
disease
x
History of cardiovascular 
disease
x
Renal impairment history
x
Randomisation
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
Post-dose fasting routines
x
EFFICACY
Height
x
Body weight
x
x
x
x
x
x
x
x
x
x
x
x
Waist circumference
x
x
x
x
x
x
x
x
x
x
x
HbA1c
x
x
x
x
x
x
x
Glucose metabolism
x
x
x
x
x
Lipids
x
x
x


Protocol
UTN: U1111-1136-4716
Date:
25 June 2013
Status:
Final
Novo Nordisk
Trial ID: NN9924-3790
EudraCT No.: 2012-004994-16
Version:
1.0
Page:
14 of 98
Trial Periods
Screening1
Randomisation
Treatment
End-of-
treatment2
Follow-
up2
End-of-trial –
premature
discontinuation3
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
11X
Timing of visit
Weeks
-2
0
2
4
6
8
12
16
20
24
26
31
26
Visit window
Days
±3
±3
±3
±3
±5
±5
±5
±3
±3
+5
±3
SUBJECT RELATED
INFO/ASSESSMENTS
PRO questionnaire
x
x
SAFETY
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
Hypoglycaemic episodes
x
x
x
x
x
x
x
x
x
x
x
x
ECG, overall interpretation4
x
x
Fundoscopy/fundus 
photography
x
Physical examination
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
Antibodies5
x
x
x
x
Biochemistry
x
x
x
Creatinine
x
x
x
Calcitonin
x
x
x
Haematology
x
x
x
PK sampling
x
x
x
x
x
x
x
x
x
PK sampling (trough + 
peak)6
x
x
x
Blood pregnancy test7
x
x
x
x
x
x
x
x
x
x
x
Urinalysis
x
x
x
TRIAL MATERIAL
IV/IWRS call
x
x
x
x
x
x
x
x
x
x
x
Dispensing visit
x
x
x
x
x
x
x
x
x
Hand out directions for use 
of s.c. trial product
x
x
x
x
x
x
x
x
x
Drug accountability
x
x
x
x
x
x
x
x
x
REMINDERS


Protocol
UTN: U1111-1136-4716
Date:
25 June 2013
Status:
Final
Novo Nordisk
Trial ID: NN9924-3790
EudraCT No.: 2012-004994-16
Version:
1.0
Page:
15 of 98
Trial Periods
Screening1
Randomisation
Treatment
End-of-
treatment2
Follow-
up2
End-of-trial –
premature
discontinuation3
Visit number
1
2
3
4
5
6
7
8
9
10
11
12
11X
Timing of visit
Weeks
-2
0
2
4
6
8
12
16
20
24
26
31
26
Visit window
Days
±3
±3
±3
±3
±5
±5
±5
±3
±3
+5
±3
SUBJECT RELATED
INFO/ASSESSMENTS
Dispense glucose meter
x
Dispense subject identity 
card
x
Dispense diary
x
x
x
x
x
x
x
x
x
x
x
Collect and review diary
x
x
x
x
x
x
x
x
x
x
x
Attend visit fasting8
x
x
x
x
x
x
Affirmation statement or 
Case book signed9
x
x
End of trial9
x
x
Abbreviations in table: ECG = electrocardiogram, HbA1c = glycosylated haemoglobin, IV/WRS = interactive voice/web response system, PK = pharmacokinetics, PRO = 
patient reported outcome


Protocol
UTN: U1111-1136-4716
Date:
25 June 2013
Status:
Final
Novo Nordisk
Trial ID: NN9924-3790
EudraCT No.: 2012-004994-16
Version:
1.0
Page:
16 of 98
2.1
Flow chart foot notes
Footer
Description
x1
Subject can be randomised as soon as all inclusion and exclusion criteria are confirmed. The screening assessments must not exceed 2 weeks prior to randomisation (Visit 2).
x2
The End-of-treatment and Follow-up visits are applicable for all randomised subjects including subjects who have discontinued trial product prematurely.
x3
Subjects discontinuing trial product prematurely will be asked to attend the End-of-treatment (V11) as soon as possible after treatment discontinuation and the Follow-up –
premature discontinuation (V12) five weeks later (+5 days visit window). Furthermore, they are asked to attend the End-of-trial – premature discontinuation visit (V11X) (see 
Section 8.1.9).
x4
An ECG performed for any reason unrelated to the trial within 30 days prior to the randomisation visit is acceptable as Visit 2 data, provided no clinical symptoms suggestive 
of cardiac disease has occurred in the meantime.
x5
At the randomisation visit, the antibody assessment must be done pre-dose.
x6
Trough and peak PK sampling is only applicable for subjects in the oral treatment arms. Subjects must attend the visit without having taken the tablet on the same day (see 
Section 8.4.10)
x7
For women of child bearing potential: Serum pregnancy tests must be performed.
x8
Fasting is defined as having consumed only water since midnight. For the Follow-up visit (V12) attending fasting is defined as having consumed only water for at least the 
preceding 2 hours.
x9
Affirmation statement/case book signing and end of trial are at the Follow-up visit (V12). Only patients who have discontinued treatment prematurely are asked to attend the 
End-of-trial – premature discontinuation visit (V11X) which will then be end of trial.


Protocol
CONFIDENTIAL
Date:
25 June 2013
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Trial ID: NN9924-3790
Version:
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UTN: U1111-1136-4716
Status:
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EudraCT No.: 2012-004994-16
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
Type 2 diabetes mellitus and glucagon-like peptide-1
Type 2 diabetes (T2D) is a major global health problem. The disease aetiology is multi-factorial and 
includes genetic predisposition in combination with sedentary life style factors such as physical 
inactivity and obesity.
T2D is a multi-organ disease characterised by defective insulin sensitivity in liver and skeletal 
muscle and a relative impairment of insulin secretion capacity. Furthermore, a blunted secretion 
and/or action of incretin hormones (glucagon-like peptide-1 (GLP-1) and gastric inhibitory 
polypeptide (GIP)) from the gastrointestinal (GI) tract (L-cells) in response to meals are also 
characteristics of T2D. GLP-1 is an important post-prandial hormone secreted from the L-cells in 
the intestine with a stimulating effect on insulin secretion and an inhibitory role on glucagon 
secretion from the endocrine pancreas in a glucose-dependent manner. In addition, GLP-1 restores 
beta-cell sensitivity to glucose. Animal studies suggest that GLP-1 also increases beta-cell mass. 
Extra-pancreatic effects include delaying of gastric emptying and effects on insulin sensitivity, 
although the latter is less clear. Pharmacological levels of GLP-1 reduce food intake and induce 
weight loss. As the majority (>80%) of T2D patients are overweight, the weight reduction 
properties of GLP-1 analogues are perceived to be advantageous compared to many other therapies 
for T2D. Due to the beneficial effects of GLP-1 on both glycaemic and weight control, treatment of 
T2D patients with GLP-1 analogues is considered favourable. 
3.2
Semaglutide and SNAC
Semaglutide is a long-acting GLP-1 analogue that has achieved clinical proof of concept when 
administered subcutaneously (s.c.). Currently, semaglutide is in clinical development (NN9535) as 
a once-weekly s.c. injection for the treatment of T2D. The NN9535 project is in phase 3 
development, encompassing six major safety and efficacy trials (see Section 3.2.3.2 for clinical data 
on s.c. semaglutide).
Oral administration inherently represents a different absorption route to reach systemic circulation 
compared to s.c. administration.
Native GLP-1 and GLP-1 analogues have in general very low oral bioavailability when 
administered in a formulation without absorption enhancement. Formulation with an absorption 
enhancing excipient is therefore needed to increase the oral bioavailability. However, exposure
CONFIDENTIAL


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exhibits a substantially greater dose-to-dose variation following oral administration compared to s.c. 
administration. An oral drug product with this chemical structure and properties will, because of the 
compound’s PK properties (i.e., very low clearance and long terminal half-life), and by using once-
daily administration, limit the variation in steady state plasma exposure. The initial side effects like 
nausea may therefore be low or absent following gradual dose escalation. Food interaction is 
expected to limit absorption, but a long-acting GLP-1 analogue product will allow dosing in the 
fasting state, without compromising the effective plasma profile. In addition, GLP-1 therapy 
generally does not induce hypoglycaemia on its own, which potentially could have been 
problematic given the large intra-patient plasma exposure variation. 
Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate / salcaprozate sodium (SNAC) has been studied 
in combination with acyclovir, peptide tyrosine tyrosine (PYY), cromolyn, ibandronate and heparin. 
Impact on metformin when co-administering SNAC and metformin was investigated as part of 
another trial involving healthy volunteers. The trial did not show any increase in metformin 
exposure when adding SNAC3. When co-formulated with SNAC, exposure of ibandronate (a 
nitrogen-containing bisphosphonate), is increased by 11- and 17-fold (AUC and Cmax, respectively). 
On the other hand, when co-administered with SNAC (in separate formulations) exposure was not 
affected compared to dosing ibandronate without SNAC, suggesting that the drug-drug interaction 
potential between SNAC and co-administered drugs with comparable physiochemical properties 
(compounds with permeability limited absorption) is low4.
The most extensive safety and PK data are available from the heparin formulated with SNAC 
programme including 32 phase 1 studies (daily SNAC doses ranged from 0.172 g – 10.5 g) of 
which three investigated SNAC alone. The studies covered formulation development, food effect, 
hepatic and renal impairment, age effect and drug-drug interactions. Three phase 2 and 3 studies 
have assessed effects of orally delivered heparin solution (>1.5 g SNAC three times daily). At 
present, no drugs containing SNAC have received regulatory approval.
3.2.1
Nonclinical data
The non-clinical programme for semaglutide was designed according to the International 
Conference on Harmonisation (ICH) M3 guideline to support the clinical development. 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 is generally well tolerated, with expected GLP-1 effects on food intake and body 
weight being the dose limiting effects, when dosed s.c. for up to two years in studies with rats and 
mice. No signs of overt toxicity, including safety concerns related to effects on the GI tract, were 
observed after oral administration of semaglutide for up to 26 weeks in rats and 17 weeks in 
cynomolgus monkeys. Two potential safety issues have been identified. 
CONFIDENTIAL


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CONFIDENTIAL
Date:
25 June 2013
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Trial ID: NN9924-3790
Version:
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UTN: U1111-1136-4716
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3.2.1.1
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. Early C-cell changes were also 
identified in repeated dose toxicity studies with semaglutide in mice. However this was not the case 
in other species including a 52-week repeat dose study in non-human primates at exposure levels up 
to 36-fold above the expected clinical exposure. The observed pattern of effects in mice and rats 
(thyroid C-cell proliferation preceded by increase in serum calcitonin) 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 receptor agonists, 
including liraglutide. The relevance for human subjects is unknown.
3.2.1.2
Teratogenicity in rats
Semaglutide has been concluded teratogenic in rats, with exposure at no observable adverse effect 
level (NOAEL) below expected human exposure. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function 
which is specific to rats. Non-human primates and humans do not depend on a yolk sac with 
placental function to supply nutrients to the embryo early in pregnancy. The effect on rat embryo-
foetal development is therefore not likely to be relevant to humans. Preliminary and main embryo-
foetal development (EFD) and pre- and postnatal development (PPND) studies with doses 
corresponding to 7-fold expected clinical exposure in cynomolgus monkeys have been finalised. In 
the main EFD study sporadic abnormalities were reported across all dose groups and in the PPND 
study a dose dependent increase in early pregnancy losses were observed. The findings observed 
across the three studies in cynomolgus monkeys are not indicative of teratogenic potential of 
semaglutide in this species. The increase in early pregnancy losses is indicative of embryo-toxicity, 
which may be related to the maternal effect of semaglutide (marked body weight loss). A 
developmental toxicity NOAEL was determined at an exposure 0.8-fold the expected clinical 
exposure (1 mg/week). A risk for the developing human embryo or foetus cannot be definitely ruled 
out, but the absence of findings indicative of teratogenicity in the EFD and PPND studies in 
cynomolgus monkey decrease the level of concern. 
A comprehensive review of results from the non-clinical studies can be found in the IB for 
Semaglutide (subcutaneous administration), Edition 85 and the IB for Oral administration of 
semaglutide (NN9924), Edition 56, or any updates of these documents 
3.2.1.3
SNAC toxicology
The nonclinical safety programme for SNAC includes safety pharmacology, metabolism and PK
and toxicology and is in line with the ICH M3 guideline7. SNAC was developed as an absorption
enhancing excipient for the oral route of administration.
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
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SNAC is rapidly absorbed (time to maximal concentration (tmax) within 1 hour) and eliminated (t½ = 
1 and 3 hours across species). SNAC is metabolised mainly via stepwise beta-oxidation and de-
acetylation of the side chain and the parent compound and its metabolites also undergo conjugation 
with glucuronic acid. The main elimination route for SNAC metabolites is via urinary excretion.
SNAC was generally well tolerated in animals at and below oral doses of 500 mg/kg/day (NOAEL) 
for up to nine (Rhesus monkey) and twelve (rat) months. Although no overt specific organ toxicity 
has been observed,
 
. A series of nonclinical studies to explore 
possible cause of death have been initiated. These studies include investigations to expand the 
standard package of nonclinical studies on CV and respiratory function, and systematic 
investigations of histological changes in the GI tract and liver after dosing of high 
concentration/high volumes of SNAC. To support the assessment of exposure margins between rats 
and humans, extensive PK and metabolism studies in rats are carried out. The quantification of 
SNAC metabolites will also be assessed in the on-going multiple dose (MD) clinical trial (NN9924-
3991).
In an on-going two-year carcinogenicity study with rats, one unexplained death occurred at a dose 
of 200 mg/kg/day. Several cases of unexplained death were observed at 900 mg/kg/day in repeat 
dose toxicity studies of 26 weeks and 52-weeks duration. A NOAEL for SNAC has been 
determined to be 90 mg/kg/day (corresponding to ~4 to 6 times a human dose of 300 mg based on 
exposure (area under curve)). Histological changes (perivascular lymphoid aggregates) have been 
observed in the lungs at all SNAC dose levels in the 6-month rat study. SNAC appeared to 
exacerbate these lesions which may be indicative of an immunosuppressant effect. 
3.2.2
Nonclinical pharmacology and pharmacokinetics
The focus of the studies done in relation to oral administration of semaglutide in combination with 
SNAC has been on the following issues: 
Mechanism in vitro
SNAC increases absorption of drug compounds through the GI epithelium, which has been shown 
in humans (e.g., for endogenous GLP-1). In vitro studies have indicated that transport of 
compounds occurs mainly via the trans-cellular route and the effect is dependent on both the 
concentration of SNAC and the duration of incubation. 
Enhancement of absorption in vivo
SNAC enhances absorption of semaglutide from the stomach and small intestine in rats. There is 
considerable variability (coefficient of variation around 100%) with some animals showing no 
absorption. In the dog, there is higher bioavailability after oral dosing of tablets (1-2.5%) than after 
capsules (0.7%) or solution (0.07%). Semaglutide and SNAC have to be formulated in the same 
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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tablet to get increased oral bioavailability of semaglutide, indicating that close interaction between 
the two molecules is necessary for enhancing the absorption. There is a strong reduction of 
bioavailability to practically zero when given concomitantly with food in dogs, and also an 
increasing amount of water dosed with the tablet seems to reduce oral bioavailability of semaglutide 
in this model, mimicking recent results in a human trial. Doses of SNAC of 150, 300 and 600 mg 
have been tested in dogs, and there was a tendency towards an optimum at 300 mg in terms of 
bioavailability. Furthermore, there is a tendency for non-linearity in bioavailability when increasing 
the amount of both SNAC and semaglutide in combination or semaglutide alone with constant 
SNAC content, whereas increasing amounts of SNAC alone (300 (one tablet) to 900 mg (three 
tablets)) with constant amount of semaglutide do not seem to significantly increase bioavailability. 
Pharmacodynamics after oral administration
Semaglutide dosed in combination with SNAC is able to induce the same type of PD effects on 
blood glucose, food intake and body weight as seen after s.c. administration of semaglutide and 
other marketed GLP-1 analogues. Thus, semaglutide in combination with SNAC lowered blood 
glucose and body weight in diabetic db/db mice, and reduced food intake and body weight in 
normal rats.
3.2.3
Clinical data
3.2.3.1
Data from literature
Currently, no orally administered GLP-1 receptor agonist is available for the treatment of T2D. 
There are, however, s.c. administered GLP-1 receptor agonists on the market and experience from 
their development has identified some potential safety issues for this class of compounds. 
Nonclinical thyroid C-cell tumours have been observed in rodents. Acute pancreatitis has been 
associated with chronic administration of GLP-1 receptor agonists in man. Elevated lipase has been 
observed in clinical studies but dose-response relationship and overall clinical significance is 
unclear. Hypoglycaemia, GI adverse events (i.e., nausea and vomiting), increased heart rate and 
renal dysfunction due to volume depletion following GI effects have also been observed.
3.2.3.2
Clinical data of s.c. semaglutide
As of 1 February 2013, 5 clinical pharmacology trials (NN9535- 1820, -3679, -3633, -3616 and -
3819) and 1 phase 2 trial (NN9535-1821) have been completed using s.c. semaglutide. A total of 
519 subjects have been exposed to s.c. semaglutide: 164 healthy subjects (both single and multiple 
dosing), 313 patients with T2D (up to 12 weeks of treatment) and 42 patients (4 subjects had T2D) 
with varying degrees of renal impairment (single dosing).
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
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EudraCT No.: 2012-004994-16
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Pharmacokinetics
Results from 2 phase 1 trials (NN9535-3616 and 3819) show that s.c. semaglutide has 
pharmacokinetics (PK) properties compatible with once-weekly administration, with a median time 
to maximum concentration (tmax) of 36 hours post dosing and an elimination half-life (t½) in the 
range of 165-184 hours (~7 days, harmonic mean). Overall, the PK properties of s.c. semaglutide 
appear similar in Caucasian and Japanese subjects, and also in healthy subjects and subjects with 
T2D. In a trial with subjects with different degrees of renal impairment (NN9535-3616), data 
suggested that severe renal impairment result in a slightly higher exposure compared to subjects 
with normal renal function (AUC0- ∞ increased by approximately 22%), whereas subjects with 
mild or moderate renal impairment and subjects on haemodialysis had exposure similar to subjects 
with normal renal function. No safety signals were identified in either of the renal groups, and 
tolerability profiles appeared similar across renal groups; thus, a dose-reduction in subjects with 
severe renal impairment does not appear to be warranted. 
Interaction with oral contraceptives was assessed at semaglutide 1.0 mg steady-state exposures in 
postmenopausal women with T2D (NN9535-3819). Steady-state exposures (AUC0-24h) of
ethinylestradiol (EE) and levonorgestrel (LN) were slightly increased (by 10% and 21%,
respectively), with bioequivalence established for EE but not for LN; the increase was seen when
oral contraceptives were co-administered with semaglutide compared to oral contraceptives alone.
Bioequivalence was demonstrated for Cmax of both EE and LN. These data indicate that semaglutide
does not decrease the exposure of oral contraceptives, and suggest that no adjustments of oral
contraceptive dose are warranted for women of childbearing potential using a low-dose oral 
contraceptive.
Efficacy
As of 1 February 2013, efficacy of s.c. semaglutide in the target population – subjects with T2D –
has been investigated in one phase 2 dose range finding trial (NN9535-1821). The trial was a 12-
week, randomised, double-blind, placebo- and active-controlled trial in which 411 adults with T2D 
received once-weekly s.c. injection of 1 of 5 semaglutide dose levels (0.1-1.6 mg) once-daily, open-
label liraglutide (1.2 mg or 1.8 mg) or once-weekly placebo. 12 weeks of treatment, equivalent to 5-
7 weeks in steady state on maintenance dose, provided statistically significant and clinically 
relevant improvement in glycaemic control for dose levels of 0.2 mg and above. Changes in HbA1c
from baseline was up to -1.19 % (placebo adjusted estimated treatment difference). Dose-dependent 
improvements in fasting plasma glucose (FPG) and postprandial plasma glucose were also 
observed. The improvement in glycaemic control was accompanied by weight loss for semaglutide 
doses of 0.8 mg and above (placebo adjusted estimated treatment difference up to -3.64 kg).
Safety
From the clinical trials conducted so far the following safety observations have been made.
CONFIDENTIAL


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Consistent with findings with other GLP-1 receptor agonists, common adverse events (AEs)
included nausea and vomiting; most of them were mild to moderate in intensity. Hypoglycaemia 
has occurred in subjects receiving semaglutide and these events have mainly been minor. 
An increase in heart rate has been observed in subjects exposed to semaglutide in line with the
increase seen with other GLP-1 analogous. The implications of this increase are unknown.
As is the case with all protein-based pharmaceuticals, subjects treated with s.c. semaglutide may 
develop immunogenic and allergic reactions. Few allergic reactions have been reported in 
connection with semaglutide. These have mainly been mild and transient. However, more 
generalised reactions may occur.
Injection site reactions have been infrequently reported. These have mainly been mild and transient 
in nature.
Please see appropriate IB5 for further details.
3.2.3.3
Clinical data of oral GLP-1 
Clinical trials with increasing doses of oral semaglutide up to two tablets with 10 mg semaglutide
and 300 mg SNAC have shown this to be safe and well tolerated. The oral semaglutide had 
acceptable bioavailability and a PK profile of two tablets with 10 mg semaglutide was similar to 0.5 
mg s.c. semaglutide. Variability of the day-to-day PK profile was 3-4 times higher than compared to 
0.5 mg s.c. once-weekly semaglutide but acceptable for further development. 
The oral bioavailability of human GLP-1 has been demonstrated to increase several fold when 
formulated with SNAC with a tmax of approximately 15-30 min. In addition, even in healthy 
subjects a glucose-dependent insulinotropic action of GLP-1 upon oral delivery was shown.
Five phase 1 trials with oral semaglutide and SNAC have been completed:
!
Single dose trial (NN9924-3691)
!
Multiple dose trial 1 (NN9924-3692)
!
Dosing condition trial (NN9924-3794)
!
Pharmaco-scintigraphy trial (NN9924-3957)
!
Multiple dose trial 2 (NN9924-3991)
For details on the individual trials, please see the current edition of the IB (Oral Administration of 
Semaglutide (NN9924)) Edition 56 and any updates hereof.
3.2.3.4
Clinical data of SNAC
The largest safety data set exists from the programme of orally administrated SNAC and heparin 
(all sponsored by 
): 29 phase 1 trials (doses up to 10.5 g of SNAC), one phase 2 trial 
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
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(doses 1.5 g and 2.25 g of SNAC three times daily for 5 days) and two phase 3 trials (doses: 1.5 and 
2.25 g of SNAC three times daily for 30 days) have been reported. 
Oral SNAC exposure has most extensively been investigated in the phase 3 trial, named ERP-12. 
The objective of the trial was to investigate prevention of venous thrombotic complications 
following total hip replacement. Enrolled subjects were randomised in three treatments arms:
!
Low dose SNAC (1.5 g) and heparin (60,000 USP units) thrice-daily for 30 days
!
High dose SNAC (2.25 g) and heparin (90,000 USP units) thrice-daily for 30 days
!
Enoxaparin sodium 30 mg s.c. twice-daily for 10 days
Total daily dose of oral SNAC was 4.5 g (low dose), 6.75 g (high dose) or 0 g (heparin s.c.). A total 
of 2,264 patients were enrolled with approximately 750 in each group. 
The most frequently reported AEs were GI disorders with a dose relationship of SNAC and heparin, 
which also reflected the most common AEs reported for discontinuation. The SAEs were evenly 
distributed between the groups for all system organ classes other than GI disorders. Likewise, all 
deaths were evenly distributed between the groups and their nature and diversity did not indicate 
any causal relationship to trial drug. No other clinical significant safety issue was identified in the 
trial8.
For further details please see the current edition of the IB (Oral Administration of Semaglutide 
(NN9924)) Edition 56 and any updates hereof.
3.3
Risks and benefits of the trial
There are s.c. administered GLP-1 receptor agonists on the market and experience from their 
development as well as experience from the s.c. semaglutide development programme have 
identified some potential safety issues for this class of compounds: 1) risk of teratogenicity, 2) risk 
of thyroid C-cell tumours, 3) risk associated to high doses of SNAC, 4) risk of carcinogenicity of 
SNAC, 5) risk of pancreatitis, 6) risk of antibody formation, 7) risk of allergic reactions, 8) risk of 
heart rate increase, 9) risk of severe risk of hypoglycaemia and 10) risk of altered renal function.
For further details please see the current edition of the IB (Oral Administration of Semaglutide 
(NN9924)) Edition 56 and any updates hereof.
In this trial, most subjects will receive a treatment anticipated to be more efficacious than the 
treatment they receive at the time of randomisation into the trial. It is expected that subjects will 
benefit from the trial treatment with respect to optimised glycaemic control, a reduced risk of long-
term diabetic complications and a potential weight loss. The subjects in this trial will receive trial 
drug and auxiliary free of charge. Furthermore it is expected that all subjects participating in the 
trial will benefit from participation through close contact with the study site and close follow-up of 
CONFIDENTIAL


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CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
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Status:
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EudraCT No.: 2012-004994-16
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their T2D. Such careful medical examination will most likely result in an intensified management 
of their diabetes.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once-daily 
doses of 2.5 to 40 mg semaglutide with 300 mg SNAC or once-weekly doses of 1.0 mg semaglutide 
in accordance with the planned clinical trial. The risk to the subjects in this trial is low and 
acceptable in view of the benefits an oral GLP-1 analogue would provide to subjects with T2D.
3.4
Rationale for the trial
The trial will compare efficacy of oral semaglutide formulated with a fixed dose of 300 mg SNAC. 
To facilitate the generation of clinical data in subjects with T2D, the NN9924-3790 trial has been 
designed to investigate a dose range expected to cover relevant therapeutic levels, including
systemic exposure equivalent to 0.5 and 1.0 mg of once-weekly s.c. semaglutide. Additional dose 
levels are examined to elucidate a wider dose-response spectrum below and above the expected 
therapeutic range. In addition, the trial will explore the safety and tolerability of three different dose 
escalation approaches (i.e., slow, standard and fast). Finally, the trial will compare parameters of 
efficacy, safety and tolerability and population PK after 26 weeks of treatment between the 
treatment arms.
Data from the NN9924-3790 trial combined with the results of other trials investigating semaglutide 
will support the decision to continue into phase 3 development.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
26 of 98
4
Objective(s) and endpoint(s)
The objectives of the trial, addressed after 26 weeks of treatment, are as follows:
4.1
Objectives
4.1.1
Primary objective
!
To compare the efficacy on glycaemic control of oral semaglutide in a SNAC formulation 
against placebo in subjects with T2D
4.1.2
Secondary objectives
!
To compare the efficacy on glycaemic control of oral semaglutide in a SNAC formulation 
against s.c. semaglutide in subjects with T2D
!
To compare the safety and tolerability of three dose escalation schemes using a single end dose 
level during 26 weeks administration of oral semaglutide and SNAC in a tablet formulation in 
subjects with T2D
!
To compare parameters of efficacy, safety and tolerability, and population PK as reflected by 
endpoints below after 26 weeks of treatment
4.2
Endpoints
4.2.1
Primary endpoint
!
Change in HbA1c from baseline to after 26 weeks of treatment
4.2.2
Supportive secondary endpoints
Supportive secondary efficacy endpoints
!
Subjects who, after 26 weeks of treatment, achieve (yes/no) HbA1c <7% (53 mmol/mol)*
!
Change in fasting plasma glucose (FPG), C-peptide, fasting insulin and glucagon from baseline 
to after 26 weeks of treatment
!
Change in insulin resistance (homeostatic model assessment index of insulin resistance 
(HOMA-IR)) and beta-cell function (homeostatic model assessment index of beta-cell function 
(HOMA-B)) from baseline to after 26 weeks of treatment
!
Change in fasting lipid profile (total cholesterol, low density lipoprotein (LDL), high density 
lipoprotein (HDL), very low density lipoprotein (VLDL), triglycerides and free fatty acids) from 
baseline to after 26 weeks of treatment
!
Change from baseline to week 26 in the patient reported outcome Medical Outcomes Study 36-
Item Short-Form Health Survey (SF-36) (generic questionnaire)
!
Change in body weight from baseline to after 26 weeks of treatment*
!
Change in waist circumference from baseline to after 26 weeks of treatment*
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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!
Change in body mass index (BMI) from baseline to after 26 weeks of treatment*
Supportive secondary safety endpoints
!
Number of treatment emergent adverse events (TEAEs) recorded from baseline until week 31*
!
Number of confirmed hypoglycaemic episodes recorded from baseline until week 31*
!
Change in vital signs (pulse, systolic- and diastolic blood pressure) from baseline to after 26 
weeks of treatment
!
Change in electrocardiogram (ECG) from baseline to after 26 weeks of treatment
!
Change in physical examination from baseline to after 26 weeks of treatment
!
Change in laboratory safety variables (haematology, biochemistry, hormone and urinalysis) 
from baseline to after 26 weeks of treatment
!
Occurrence of antibodies against semaglutide during 26 weeks of treatment (positive/negative):
!
Anti-semaglutide antibodies
!
Anti-semaglutide antibodies with in vitro neutralising effect
!
Anti-semaglutide antibodies cross reacting with endogenous GLP-1
!
Cross reacting antibodies with in vitro neutralising effect to endogenous GLP-1
!
Antibody level during 26 weeks of treatment
Supportive secondary pharmacokinetic endpoint
!
Semaglutide concentrations to be evaluated in a population PK analysis
* Key supportive secondary endpoint prospectively selected for posting on clinicaltrials.gov
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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5
Trial design
5.1
Type of trial
This is a randomised, partially-blinded, dose range, dose escalation, multicentre trial including nine 
treatment arms in total; seven oral semaglutide treatment arms, an oral placebo arm and an s.c. 
semaglutide arm with a parallel design (see Figure 5–1). All treatment arms include subjects with 
T2D who have failed on diet and exercise and/or metformin. The placebo tablets do not contain 
SNAC.
Figure 5–1
Trial design of NN9924-3790
Subjects with T2D will be randomised in an equal manner with 67 subjects planned to be 
randomised per treatment arm. Treatment arms 1-8 will include once-daily dosing of a tablet and
will be blinded. Treatment arm 9 features open-label once-weekly s.c. injection. All arms include 26 
weeks of treatment and a 5 week follow-up period. Oral dosing will be performed following 
specified fasting conditions (see Figure 5–2).
The nine treatment arms will include:
1. Semaglutide tablets once-daily: 2.5 mg for 26 weeks
2. Semaglutide tablets once-daily: 2.5 mg for 4 weeks, then 5.0 mg for 22 weeks
3. Semaglutide tablets once-daily: 5.0 mg for 4 weeks, then 10 mg for 22 weeks
4. Semaglutide tablets once-daily: 5.0 mg for 4 weeks, then 10 mg for 4 weeks, then 20 mg for 18 
weeks
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
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EudraCT No.: 2012-004994-16
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5. Semaglutide tablets once-daily: 5.0 mg for 4 weeks, then 10 mg for 4 weeks, then 20 mg for 4 
weeks, then 40 mg for 14 weeks
6. Semaglutide tablets once-daily: 5.0 mg for 8 weeks, then 10 mg for 8 weeks, then 20 mg for 8
weeks, then 40 mg for 2 weeks
7. Semaglutide tablets once-daily: 5.0 mg for 2 weeks, then 10 mg for 2 weeks, then 20 mg for 2 
weeks, then 40 mg for 20 weeks
8. Placebo tablets once-daily for 26 weeks
9. Semaglutide injections once-weekly: 0.25 mg for 4 weeks, then 0.50 mg for 4 weeks, then 1.0 
mg for 18 weeks
For all groups the trial medication will be add-on to previous metformin therapy or as monotherapy 
in the case where the subject with T2D is treated with diet and exercise alone. At randomisation, 
subjects will be stratified according to one stratification value with two strata: Treatment with 
metformin at screening (yes/no).
5.2
Rationale for trial design
Parallel treatment groups and a randomised partially-blinded, controlled design have been chosen in 
accordance with the trial objectives. To avoid bias in the assessment of the different doses of oral 
semaglutide, the eight oral treatment arms are double-blind. The doses are escalated in standard four 
week intervals to limit gastrointestinal AEs. Escalation intervals of two weeks and six weeks are 
also being explored to investigate effect on onset of action and overall AEs.
The use of s.c. semaglutide as active comparator was chosen to confirm that oral semaglutide in at 
least one of the selected doses reach the same levels of systemic exposure as for s.c. semaglutide. 
The active comparator is open-label to limit unnecessary injections (e.g., by use of double-dummy)
as the objectives of the trial are to investigate the effects of the oral formulation.
5.3
Treatment of subjects
The subjects will attend a screening visit to determine their eligibility. If found eligible, the subjects
will return for the first treatment visit where they will be randomised and receive treatment. The
total duration of the trial will be 31 weeks for all subjects from randomisation to last visit. The 
highest dose for any trial subject will be 40 mg oral semaglutide once-daily or 1.0 mg s.c. 
semaglutide once-weekly.
Metformin is considered background medication (non-investigational medicinal product) and will 
not be provided by Novo Nordisk. Metformin should be used at the discretion of the investigator. 
Treatment with metformin extended/slow release formulations is allowed.
For the safety of the subjects, medications with a narrow therapeutic window may not be used in the 
trial (see the exclusion criteria, Section 6.3).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
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Subjects will follow a fixed dose escalation regimen, which they have been randomised to, 
following the scheme in Figure 5–1.
5.3.1
Dose levels and escalation regimen for oral dosing
Subjects on the oral dosing (treatment arms 1-8) must administer the dose following specific rules:
!
Fasting for at least six hours (e.g., in the morning following an overnight fast) before tablet
ingestion
!
Water and oral concomitant medication is allowed two hours prior to dosing
!
Intake of maximum 120 mL of water is allowed when swallowing the tablet
!
Subjects are required to abstain from food and fluid intake for at least 30 minutes after ingestion
of oral semaglutide or placebo
!
Oral concomitant medication can be taken two hours post-dosing. If taken with food,
concomitant medication can be administered 30 minutes after ingestion of the semaglutide or
placebo tablet
See illustration of oral dosing and fasting rules in Figure 5–2.
Figure 5–2
Dosing and fasting conditions for oral treatment (arms 1-8)
5.3.2
Dose levels and escalation regimen for s.c. dosing
Subjects randomised to the s.c. treatment arm will follow a fixed dose escalation for semaglutide. 
The maintenance dose of 1.0 mg will be reached after four doses (four weeks) of 0.25 mg, followed 
by four doses (four weeks) of 0.50 mg. The maintenance dose of 1.0 mg, once attained, may not be 
decreased for the duration of the study. Injections may be administered in the thigh, abdomen or 
upper arm, at any time of day irrespective of meals. The injections should be administered on the 
same day of the week during the trial.
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Protocol
CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
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EudraCT No.: 2012-004994-16
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5.4
Treatment after end of trial
The trial products will not be available to subjects after the end of trial.
When discontinuing trial products the subject should be switched to a suitable marketed product at 
the discretion of the investigator.
5.5
Rationale for treatment
The oral route of semaglutide administration investigated has been chosen to increase convenience 
and initiate earlier use of GLP-1 treatment of T2D patients, thus offering true GLP-1 benefits in a 
tablet format. The dose range of the oral treatment (2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg) has
been chosen based on phase 1 data and modelling derived from phase 1 trials with the aim to cover 
the same exposure as observed with s.c. semaglutide. The standard escalation scheme (i.e., dose 
escalation every four weeks to desired dose) has been chosen based on phase 1 data. The slow and 
fast dose escalation arms will investigate if AEs decrease or increase, respectively, compared to the 
standard dose escalation. The 26-week treatment period will provide additional data on safety and
tolerability, investigate the variability at steady state exposure, test for efficacy and suggest which 
doses and escalation scheme to continue into pivotal development.
For further details please see the current edition of the IB (Oral Administration of Semaglutide 
(NN9924)) Edition 56 and any updates hereof.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened:
1,005
Number of subjects planned to be randomised:
603
Number of subjects expected to complete the trial:
482
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 ≥ 18 years at the time of signing inform consent
3. BMI ≥25 and ∀40 kg/m2
4. Subjects diagnosed with T2D treated with diet and exercise and/or who have been on a stable 
dose of metformin for at least 30 days prior to screening
5. HbA1c 7.0-9.5% (53-80 mmol/mol) (both inclusive)
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”.
1. Known or suspected hypersensitivity to trial product(s) or related products
2. Previous participation in this trial. Participation is defined as informed consent
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice) for the duration of the trial and for three months 
following last dose
Germany: Adequate contraceptive measures are implants, injectables, combined oral 
contraceptives, hormonal intrauterine device, sexual abstinence or vasectomised partner. 
Sweden: Adequate contraceptive measures are hormonal intrauterine devices, hormonal oral 
contraceptives, hormonal implants or injections, double barrier (a condom or diaphragm) with 
spermicide, sexual abstinence or vasectomised partner.
United Kingdom: Established use of oral, injected or implanted hormonal methods of 
contraception, intrauterine device or intrauterine system, barrier methods of contraception 
(condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilisation 
or true abstinence when in line with the preferred and usual lifestyle of the subject.
4. Participation in another clinical trial within 30 days before the screening visit
5. Any chronic disorder or severe disease which, in the opinion of the investigator, might 
jeopardise subject’s safety, compliance with the protocol and/or ability to complete the study
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Date:
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Trial ID: NN9924-3790
Version:
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UTN: U1111-1136-4716
Status:
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Page:
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6. Subjects on selected oral medication with a narrow therapeutic window, such as warfarin, 
digoxin, tricyclic antidepressants, lithium, aminophylline, theophylline and anticonvulsants
7. History of chronic pancreatitis or idiopathic acute pancreatitis
8. Screening calcitonin value ≥ 50 ng/L
9. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN2)
10. Chronic malabsorption, regardless of aetiology
11. History of Crohn’s disease, ulcerative colitis, or other inflammatory bowel disease
12. Previous gastrointestinal surgery such as invasive and corrective procedures involving the 
oesophagus, stomach, duodenum, gallbladder, pancreas or intestinal resections. Exempt are 
subjects that underwent uncomplicated surgical and diagnostic procedures such as 
appendectomy, hernia surgery, polypectomy, biopsies, as wells as colonic- and gastric 
endoscopy
13. Surgery scheduled for the trial duration period (excluding minor surgical procedures performed 
in local anaesthesia, according to the opinion of the investigator)
14. Treatment with glucose lowering agent(s) other than metformin as stated in the inclusion criteria 
in a period of 90 days before the screening visit
15. Mental inability, unwillingness or language barrier precluding adequate understanding of or 
compliance with study procedures
16. Impaired renal function defined as estimated glomerular filtration rate (eGFR) < 60 
mL/min/1.73 m2 per Modification of Diet in Renal Disease (MDRD) formula
17. Heart failure, New York Heart Association (NYHA) class IV
18. Within the past 6 months before the screening visit, any of the following: Episode of unstable 
angina, acute coronary event, cerebral stroke/transient ischemic attack or other significant 
cardiovascular event as judged by the investigator
19. Uncontrolled hypertension (defined as systolic blood pressure ≥ 180 mmHg or diastolic blood 
pressure ≥100 mmHg)
20. Known proliferative retinopathy or maculopathy requiring acute treatment according to the 
opinion of the investigator
21. Diagnosis of malignant neoplasm in the previous five years from the screening visit (except 
basal cell skin cancer or squamous cell skin cancer)
6.4
Rescue criteria
Subjects with unacceptable hyperglycaemia should be offered treatment intensification (rescue 
medication) according to local label at the discretion of the investigator as add-on to randomised 
treatment and should continue to follow the protocol-specified visit schedule. Rescue medication 
should exclude other incretin-based therapies such as other GLP-1 receptor agonists, DPP-4
inhibitors and amylin analogues.
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CONFIDENTIAL
Date:
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Trial ID: NN9924-3790
Version:
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UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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Unacceptable hyperglycaemia in this trial is defined as:
!
FPG >15 mmol/L (270 mg/dL) from baseline to week 6
!
FPG >13.3 mmol/L (240 mg/dL) from week 6 to week 12
!
FPG >11.1 mmol/L (200 mg/dL) or HbA1c > 8.0% (64 mmol/mol) from week 12 to end of trial
6.5
Withdrawal criteria and discontinuation of trial product
6.5.1
Withdrawal from trial
The subject may withdraw at will at any time. The subject may be withdrawn from the trial at the 
discretion of the investigator due to a safety concern. Please see Section 8.1.10 for procedure to be 
performed in case of subject withdrawal.
A subject must be withdrawn from the trial if the following applies:
1. Included in the trial in violation of the inclusion and/or exclusion criteria
2. Pregnancy
3. Intention of becoming pregnant
Subjects should stay in the trial irrespective of lack of adherence to randomised treatment, lack of 
adherence to visit schedule, missing assessments, trial product discontinuation due to AE (see 
Section 6.5.2), unwillingness to cope with injection regimen, development of co-morbidities or 
clinical outcomes, hence this should not be considered as a valid reason for withdrawal from the 
trial.
Subjects considering withdrawing from the trial should be encouraged to have the procedures
performed according to the End-of-treatment visit and the Follow-up visit, please see Section 8.1.8.
Subjects who are withdrawn will not be replaced.
6.5.2
Discontinuation of trial product
The trial treatment must be discontinued if the subject meets one of the following criteria:
1. The investigator suspects acute pancreatitis. All drugs suspected to relate to this condition 
should be discontinued until confirmatory tests have been conducted and appropriate treatment 
should be initiated. Subjects who are diagnosed with acute pancreatitis must be discontinued 
from trial treatment. Diagnosis is based on at least 2 of the following 3 criteria:
a.
characteristic abdominal pain
b. amylase and/or lipase > 3x upper normal range, or 
c.
characteristic findings on ultrasound / computerised axial tomography (CT) /
magnetic resonance imaging (MRI)
2. Calcitonin level ≥50 ng/L. The subject should be referred to a specialist in thyroid disease. All 
drugs suspected to relate to this condition should be discontinued
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3. Other safety concerns as evaluated by the investigator
A treatment discontinuation session must be performed in the interactive voice/web response 
system (IV/WRS). The primary reason for discontinuation of the IMP must be specified in the 
electronic case report form (eCRF).
Subjects discontinuing the IMP should be called in for the End-of-treatment visit as soon as 
possible after discontinuation of the IMP and for the Follow-up visit five weeks later. Furthermore, 
the subjects should attend the End-of-trial – premature discontinuation visit (see Section 8.1.9).
If the IMP is discontinued, the subject can be prescribed alternative therapy at the investigator’s 
discretion.
6.6
Rationale for trial population
This trial will include adult subjects with T2D and insufficient glycaemic control following 
treatment with diet/exercise or metformin. The T2D subjects will have an HbA1c of 7.0-9.5% and a 
BMI of 25-40 kg/m2. The trial will be carried out in Europe, North America and single countries in 
Africa, Asia and the Middle East as the first global, multicentre trial and will include both genders.
This population is expected to mimic the target population in both a future phase 3 programme and 
once marketed.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
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EudraCT No.: 2012-004994-16
Page:
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7
Milestones
Planned duration of recruitment period (i.e., first subject first visit (FSFV) on 2 Dec 2013 – last 
subject first visit on 21 Apr 2014): 20 weeks
End of trial is defined as last subject last visit: 8 Dec 2014
Recruitment
The clinical sites participating in the trial will recruit subjects according to a recruitment plan.
The screening and randomisation rate will be followed closely via the interactive voice/web 
response system (IV/WRS) 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 IV/WRS will be closed for further screening. All subjects included in the 
screening period and eligible for randomisation will be randomised.
Trial registration
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. According 
to the Novo Nordisk Code of Conduct for Clinical Trial Disclosure, it will also be disclosed 
according to other requirements such as those of the International Committee of Medical Journal 
Editors (ICMJE)9, the Food and Drug Administration Amendment Act (FDAAA)10, European 
Commission Regulation for EudraCT11 and other relevant recommendations or regulations. 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.
CONFIDENTIAL


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CONFIDENTIAL
Date:
25 June 2013
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Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
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8
Methods and assessments
8.1
Visit procedures
8.1.1
Introduction
Throughout the trial the investigator must ensure working in accordance with ICH GCP1 and local 
regulations. The investigator must ensure that trial procedures are performed as described in the 
protocol. Any discrepancies will result in protocol and/or GCP deviations and the investigator must 
take appropriate actions to avoid recurrence of the detected discrepancies.
8.1.2
Visit 1 (Screening)
For procedures and assessments performed at screening, please see flow chart Section 2.
Investigators must obtain informed consent for each subject no later than at Visit 1 prior to any 
protocol-related procedures. For information on informed consent procedure please see Section 
18.1.
All subjects will be provided with a copy of their own signed and dated informed consent form.
The IV/WRS must be contacted to register the subject as screened (see Section 10) at the screening 
visit. Subject will be assigned a unique number (lowest available number allocated to site) which is 
maintained throughout the trial.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. The subject screening log and subject enrolment log may be combined in one list 
and may be generated from IV/WRS. 
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.
For screening failures the screening failure form must be completed with the reason for not 
continuing in the trial. Serious and non-serious adverse events from screening failures must be 
transcribed by the investigator into the electronic case report form (eCRF). Follow-up of serious 
adverse events (SAEs) must be carried out according to Section 12.3. A screening failure session 
must be made in the IV/WRS. The case book must be signed.
Re-screening of subjects having signed the informed consent is not allowed.
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Once all data relating to Visit 1 have been obtained, these must be reviewed by the investigator to 
ensure that the subject is eligible to continue the trial. 
8.1.3
Fasting visits
The subjects should attend several visits in a fasting state (see Section 2). Fasting is defined as 
having consumed only water since midnight. An exception from this is the Follow-up visit where 
fasting is defined as having consumed only water for the last two hours.
Subjects are allowed to take the IMP and oral concomitant medication during fasting if following 
the conditions outlined in Section 5.3. An exception is at three visits in the oral treatment arms 
where peak and trough PK will be measured and the oral IMP will be administered at the site (see 
Section 8.4.10).
If a subject attends a fasting visit in a non-fasting condition or a peak and trough PK meeting having 
taken the oral dose the same day, then blood sampling and body weight must be re-scheduled within 
the visit window. The date for each fasting assessment or PK assessment at the specific visit must 
be updated accordingly in the eCRF. All other assessments can be performed. Re-scheduling of 
fasting visits or peak and trough PK visits are not considered unscheduled visits.
8.1.4
Unscheduled visits
An unscheduled visit can be scheduled at any time at the discretion of the investigator. An 
unscheduled visit form must be completed in the eCRF indicating the reason for the visit. Coming 
to the site for any of the following reasons should not be considered as unscheduled visits:
!
dispense additional trial products 
!
dispense additional auxiliary supplies
!
re-test of blood- or urine sampling (not allowed if results are available)
In case of additional trial products being dispensed, a dispensing session should be made in the 
IV/WRS selecting additional medication.
8.1.5
Visit 2 (Randomisation)
For procedures and assessments performed at randomisation, see Section 2.
Visit 2 will take place within two weeks after Visit 1.
The randomisation session must be performed in the IV/WRS which will allocate the Dispensing 
Unit Number (DUN) of the IMP to be dispensed to the subject. Eligible subjects will be randomised 
into one of nine treatment arms.
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Version:
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The IMP will be dispensed to the subject by the trial site staff, hospital pharmacy staff or equivalent 
at each visit during the trial from randomisation to last visit before the End-of-treatment visit (see 
Section 2). The investigator must document that subjects are instructed in oral IMP administration 
at every dispensing visit.
For subjects randomised to the s.c. injection, the investigator must document that a direction for use 
(DFU) is handed out at each dispensing visit. Ability and willingness to self-inject can be tested by 
administration of injections with a test pen for subjects who do not have prior experience with self-
injection. Novo Nordisk will provide the test pens.
Please see Section 9 for further information about the IMPs.
8.1.6
Visit numbers
For visit numbers, timing of site visits and visit windows during the trial period, please refer to the 
flow chart, Section 2. Planned visits can be re-scheduled within the allowed visit window.
It is the responsibility of the investigator to ensure that all site visits occur according to the flow 
chart (see Section 2).
8.1.7
Visits 3-10 (Treatment)
For procedures and assessments performed at visits 3, 4, 5, 6, 7, 8, 9, and 10, see the flow chart in 
Section 2.
8.1.8
Visits 11-12 (End-of-treatment and Follow-up)
All subjects must attend the End-of-treatment visit (Visit 11) which should be scheduled when the 
subject has completed the treatment with the IMP and a Follow-up visit (Visit 12) should be 
performed at least 5 weeks after (+5 days visit window). A completion session must be performed 
in the IV/WRS. Please see the flow chart for details (Section 2).
The Follow-up visit serves to collect AEs, technical complaints, hyperglycaemic episodes and blood 
samples for anti-semaglutide antibodies.
8.1.9
Visit 11X (End-of-Trial – premature discontinuation)
For subjects who discontinue the IMP prematurely the End-of-treatment visit (Visit 11) should be 
scheduled shortly after the subject has discontinued the IMP. The Follow-Up visit (Visit 12) should 
be scheduled at least 5 weeks (+5 days visit window) after treatment discontinuation. Treatment 
discontinuation and drug accountability sessions must be done in the IV/WRS. Please see the flow 
chart for details (Section 2).
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Subjects who discontinue their IMP prematurely must also be requested to attend the visit End-of-
trial – premature discontinuation (Visit 11X) at the time of the scheduled end of treatment (i.e., 26 
weeks after randomisation). Data on AEs and the primary endpoint from this final visit are 
important for the data quality of the trial.
8.1.10
Withdrawals
If a subject is withdrawn from the trial, the investigator must aim to undertake procedures similar to 
those for visit 11 (End-of-treatment) as soon as possible, and the Follow-up visit at least 5 weeks 
after. The end-of-trial form must be completed and the subject should return all trial products to the 
site to have final drug accountability performed. Drug accountability must be performed even if the 
subject is not able to come to the trial site. A treatment discontinuation session must be performed
in the IV/WRS (see Section 10). The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing from a trial, 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 discontinuation must be 
specified on the end-of-trial form in the eCRF (see Section 6.5.1):
8.1.11
Investigator’s assessment
Review of diaries, laboratory reports, ECGs, eye examination (fundoscopy/fundus photography), 
physical examination and patient reported outcome (PRO) questionnaires must be documented with 
the investigator’s or delegated site staff’s dated signature either on the front page of the documents 
or in the subject’s medical record. The documents should be signed prior to the following visit and 
must be retained at the investigator site as source documentation.
For ECGs and eye examinations the evaluations must be in the following categories:
!
Normal
!
Abnormal
!
Was the finding clinically significant? (yes/no)
For laboratory report values outside the reference range, the investigator must specify whether the 
value is non-clinically or clinically significant. All laboratory printouts must be signed and dated by 
the investigator on the day of evaluation.
In case of abnormal clinically significant findings (e.g., in laboratory reports, ECGs, eye 
examination or physical examination), the investigator must state a comment in the subject’s 
medical record and record this on the concomitant illness form in the eCRF at the screening or 
randomisation visits. At subsequent visits any clinically significant changes or new clinically 
significant findings must be reported as an AE according to Section 12.2.
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If clarification of entries or discrepancies in the diary or PROs 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.
8.2
Subject related information
8.2.1
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e., at the screening visit
or found as a result of screening procedure). The concomitant illness should be recorded in the 
eCRF.
Medical history is a medical event that the subject has experienced in the past. Only medical 
history considered relevant 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.
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.
Smoking habit: Details of smoking habit must be recorded at the first visit. Smoking is defined as 
smoking at least one cigarette, cigar or pipe daily. The collected information should include whether 
or not the subject smokes or has smoked. If the subject smokes or has smoked, record 
approximately when the subject started smoking and, if applicable, when the subject stopped 
smoking.
Diabetes complications should be captured in the medical history or concomitant illness form and 
should include: 
!
diabetic retinopathy
!
diabetic neuropathy
!
diabetic nephropathy
!
macroangiopathy including peripheral vascular disease
!
other complications where relevant
8.2.2
Concomitant medication
A concomitant medication is any medication, other than the trial products, which is taken during 
the trial, including the screening 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.
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The information collected for each concomitant medication includes:
!
trade name or generic name
!
indication
!
start and stop date or continuation
!
total daily dose (only applicable for antidiabetic medication)
If a change is due to an AE, then this must be recorded and reported according to Section 12.2. If 
the change influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.3
Demography
Demography will be recorded in the eCRF at screening and consists of:
!
date of birth or age (according to local regulation)
!
sex
!
race (according to local regulation)
!
ethnicity (according to local regulation)
8.2.4
Diagnosis of diabetes
The date of diagnosis of T2D will be recorded in the eCRF at screening.
8.2.5
Diabetes treatment history
The dose and the date of initiating treatment with metformin will be recorded in the eCRF at 
screening if the subject is currently treated with metformin.
8.2.6
History of gallbladder disease
Information related to history of gallbladder disease (i.e., pancreatitis, gallstone disease, 
cholecystis) will be recorded in the eCRF at screening visit.
8.2.7
History of cardiovascular disease
Information related to history of cardiovascular disease (CVD) (i.e., heart failure including NYHA 
class, hypertension or ischaemic stroke) or other risk factors for CVD will be recorded in the eCRF 
at screening visit.
8.2.8
Renal impairment history
Information related to history of renal impairment will be recorded in the eCRF at screening visit.
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8.2.9
Post-dose fasting routines
The fasting routines following oral trial product administration should be recorded in the subject’s 
diary handed out at Visit 10 and transcribed to the eCRF by the investigator at the End-of-treatment 
visit to determine the usual fasting time after tablet ingestion during the trial.
The post-dose fasting routines are recorded as time in minutes from IMP administration until the 
usual time of:
!
food consumption (i.e., meal or snack)
!
drinking (i.e., any beverage including water)
8.3
Assessments for efficacy
8.3.1
Blood samples
Blood samples will be drawn according to flow chart (see Section 2) and analysed at the central 
laboratory to determine levels of the following efficacy laboratory parameters:
Glucose metabolism:
!
HbA1c
!
Fasting plasma glucose (FPG)
!
Fasting insulin
!
Fasting C-peptide
!
Fasting glucagon
Lipids (all fasting):
!
Total cholesterol
!
LDL-cholesterol
!
VLDL-cholesterol
!
HDL-cholesterol
!
Triglycerides
!
Free fatty acids
8.3.2
Body measurements
Body weight
Body weight should be measured without shoes and only wearing light clothing. It should be 
recorded with one decimal and using the same set of scales throughout the trial (i.e., kg or lb)
Height
Height is measured without shoes in centimetres or inches and recorded to nearest ½ cm or ¼ inch.
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Waist circumference
The waist circumference is defined as the minimal abdominal circumferences located midway 
between the lower rib margin and the iliac crest.
Three consecutive measurements of waist circumference should be performed and recorded in the 
eCRF. The waist circumferences will be measured using a non-stretchable measuring tape. It should 
be recorded to the nearest ½ cm or ¼ inch using the same measuring tape throughout the trial.
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing with accessible waist. The subject should be standing with arms down their side and feet 
together. The 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.
BMI
BMI will be captured in the eCRF using the equation:
BMI = Body weight (kg)/(Height (m) x Height (m)) [kg/m2 = lb/in2 x 703]
8.3.3
Patient reported outcomes
The PRO questionnaire used in this trial is SF-36v2TM.
The questionnaire should be completed by the subject as specified in the flow chart, see Section 2, 
preferably before any other trial-related activities. It takes approximately ten minutes to complete 
the questionnaire.
The questionnaire is checked by the investigator for completion and unreported AEs (see Section 
8.1.11). The investigator or site staff must date and sign the document and enter the results in the 
eCRF.
The SF-36v2™ questionnaire will be used to assess subjects overall Health related Quality of Life 
and can also be used to estimate Quality-Adjusted Life Year which is used in cost effectiveness 
calculations. This instrument contains 36 items and measures the individual overall health related 
quality of life on eight domains: physical functioning, role functioning, bodily pain, general health, 
vitality, social functioning, role emotional and mental health. 
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8.4
Assessments for safety
8.4.1
Hypoglycaemic episodes
Plasma glucose should always be measured and recorded when a hypoglycaemic episode is 
suspected.
All plasma glucose values:
!
≤ 3.9 mmol/L (70 mg/dL) or
!
> 3.9 mmol/L (70 mg/dL) when they occur in conjunction with hypoglycaemic symptoms,
should be recorded by the subject in the diary. These must be transcribed into the eCRF 
(hypoglycaemic episode form) throughout the trial from Visit 1-12.
The record should include the following information:
!
Date and time of hypoglycaemic episode
!
The plasma glucose level before treating the episode (if available)
!
Whether the episode was symptomatic
!
Whether the subject was able to treat him/herself
!
Date and time of last trial product administration prior to episode
!
Type of last trial product prior to episode
!
Date and time of last main meal prior to episode
!
Whether the episode occurred in relation to increased physical activity
The answer to the question: “Was subject able to treat him/herself?” must be answered “No” if oral 
carbohydrates, glucagon or IV glucose had to be administered to the subject by another person. Oral 
carbohydrates should not be given if the subject is unconscious.
A hypoglycaemic episode form must be filled in for each hypoglycaemic episode. If the 
hypoglycaemic episode fulfils the criteria for an SAE then an AE form and an electronic safety 
information form (eSIF) must also be filled in (see Section 12.2)
For all FPG values measured by central laboratory that meet the definition of a hypoglycaemic 
episode, a hypoglycaemic episode form must be completed in the eCRF.
8.4.2
Blood samples
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:
!
Differential count (basophils, eosinophils, lymphocytes, monocytes and neutrophils)
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!
Erythrocytes
!
Haematocrit
!
Haemoglobin
!
Leucocytes
!
Thrombocytes
Biochemistry:
!
Alanine aminotransferase
!
Albumin
!
Alkaline phosphatase
!
Amylase
!
Aspartate aminotransferase
!
Bilirubin, total
!
Calcium, total
!
Calcium, albumin corrected (ionized)
!
Creatine kinase
!
Creatinine
!
Lipase
!
Potassium
!
Sodium
!
Urea
Hormone:
!
Calcitonin (see Section 8.4.11)
Pregnancy test:
!
Serum or plasma human chorionic gonadotropin (hCG)
8.4.3
Pregnancy test
Females of childbearing potential will have a serum pregnancy test (i.e., beta-hCG) performed as 
specified in Section 2 or as required by local law. 
Pregnancy testing will not be required (unless required by local law) for subjects who are post-
menopausal (defined as women who have undergone a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation or for women above the age of 50, who have been without menstrual period 
for at least 1 year).
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8.4.4
Urinalysis
Subjects will be asked to bring first morning urine during the trial (see Section 2). The urine 
samples will be analysed at the central laboratory to determine levels of the following safety 
laboratory parameters:
!
Urinary albumin to creatinine ratio
!
Urinalysis by urine dip-stick: erythrocytes, protein, glucose and ketones, pH
8.4.5
Antibodies
Blood samples will be drawn during the trial and analysed at specialised laboratory for 
determination of serum antibodies to semaglutide, including cross reactivity to endogenous GLP-1 
(see flow chart, section 2). Samples positive for antibodies against semaglutide will be further 
characterised for in vitro neutralising effect towards semaglutide. In addition, samples positive for 
antibodies cross-reacting with endogenous GLP-1 will be analysed for in vitro neutralising effect 
towards endogenous GLP-1. Furthermore, samples drawn at randomisation may be used for 
calculations of the neutralising effect in the in vitro neutralising antibody assays. The in vitro 
neutralising assays will be performed by Novo Nordisk.
At randomisation, the antibody assessment must be done pre-dose.
8.4.6
Vital signs
The method for measuring systolic and diastolic blood pressure needs to follow the standard clinical 
practice at site but as a minimum; the following guideline must be adhered to: Avoid caffeine, 
smoking and exercise at least 30 minutes prior to measuring the blood pressure. The blood pressure 
should be measured in a sitting position, with the legs uncrossed, the back and arms supported and 
positioned at heart level. Subjects should be sitting for at least five minutes before the first 
measurement is taken. The subject should not talk during the measurement. Pulse (beats per minute) 
should be measured after resting for five minutes in a sitting position. Results are recorded in the 
eCRF.
In case of an “abnormal, clinically significant finding”, the investigator must record the finding on 
the medical history or concomitant illness form if present at screening.
Any new abnormal, clinically significant finding during the trial and any clinically significant 
worsening from baseline must be reported as an AE.
8.4.7
Electrocardiogram – 12-lead
12-lead ECG will be performed during the trial (see Section 2). All ECGs will undergo central 
assessment.
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Sites will be informed of the central ECG evaluation in case this evaluation reveals an abnormal 
ECG reading. If the abnormality represents an unreported AE, SAE or MESI, such findings must be 
reported if the investigator finds the abnormality clinically significant (see Section 8.1.11).
Additional ECG recordings can be performed at the investigators site at the investigator’s discretion 
at other visits than the planned ECG visits. All such ECGs will undergo central assessment.
An ECG performed for any reason unrelated to the trial within 30 days prior to the randomisation 
visit is acceptable as Visit 2 data, provided no clinical symptoms suggestive of cardiac disease has 
occurred in the meantime.
If the ECG is performed before the subject has signed the informed consent form, it must be 
documented in the medical records that the reason for performing the procedure was not related to 
this trial.
For electronic central ECG evaluation vendor details, see Attachment I.
8.4.8
Fundoscopy/fundus photography
Fundoscopy/fundus photography will be performed at randomisation by the investigator or 
according to local practice. Results of the fundoscopy/fundus photography will be reviewed, signed 
and dated by the investigator (see Section 8.1.11). Dilation is not a requirement.
If fundoscopy/fundus photography has been performed within 90 days before the screening visit, 
the procedure does not need to be repeated unless worsening of visual function since the last 
examination. A subject cannot be randomised without results confirming there is not retinopathy or 
maculopathy requiring acute treatment.
If the fundoscopy/fundus photography is performed before the subject has signed the informed 
consent form, it must be documented in the medical records that the reason for performing the 
procedure was not related to this trial.
8.4.9
Physical examination
A physical examination will be performed by the investigator according to local procedures, see 
Section 2). 
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A physical examination must include:
!
General appearance
!
Central and peripheral nervous system
!
Head, ears, eyes, nose, throat, neck
!
Thyroid gland
!
Respiratory system
!
Cardiovascular system
!
Gastrointestinal system including mouth
!
Musculoskeletal system
!
Skin
!
Lymph node palpation
The results are recorded as described in Section 8.1.11.
8.4.10
Pharmacokinetics
Blood samples for the population PK will be drawn from all subjects for bioanalysis of the plasma 
concentrations of semaglutide at Visits 3-11 (see flow chart, Section 2). The investigator must 
record the exact time for drawing the blood samples in the laboratory requisition form and 
transcribe the data to the eCRF.
Subjects on oral treatment will also have PK measured pre-dose and post-dose (trough and peak) at 
three visits (see Section 2). At the visits for trough and peak PK measurements, the investigator 
needs to ensure that the subjects on oral treatment follow these procedures:
!
Attend the visit fasting
!
Have the IMP administered at the visit (i.e., subjects must not self-administrate the tablet on the 
day of the visit)
!
Ingest tablet at site
!
Eat a meal 30-60 minutes after IMP administration
!
Have an extra blood sample drawn 60-90 minutes after IMP administration
The exact time points of trial drug administration, start of meal and blood sampling must be 
recorded in the eCRF by the investigator.
For the oral treatments, the date and time of the latest trial drug administration must be recorded by 
the subject in the subject diary and transcribed to the eCRF by the investigator.
For the s.c. semaglutide arm, the date, time, dose and injection site of the two latest trial drug 
administrations must be transcribed to the eCRF by the investigator based on the subject’s diary.
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8.4.11
Calcitonin
Blood samples for the measurement of calcitonin concentration will be drawn as per flow chart (see 
Section 2). Calcitonin values ≥20 ng/L will be submitted to an independent committee of thyroid 
experts. The Calcitonin Monitoring Committee (CMC) will provide guidance to the investigator 
with regards to treatment and further investigations. It is recommended that screening failure 
subjects with a calcitonin value ≥10 ng/L are referred to a thyroid expert for further evaluation. For 
details please refer to Appendix A.
8.5
Laboratory assessments
The laboratory analyses will mainly be performed by a central laboratory. For analyses of anti-
semaglutide antibodies (see Section 8.4.5) and semaglutide plasma concentrations (see Section 
8.4.10) a special laboratory will be used. Also, in the situation described in Section 8.6.2.1 a special
laboratory will be used. Laboratory samples comprise both urine and blood samples. Descriptions 
of assay methods, laboratory supplies and procedures for collecting, handling, storing and shipping 
samples and information regarding who will perform the assessments will be described in the 
laboratory manual provided by the central laboratory (for central and special laboratory details, see 
Attachment I).
Samples will be coded in order to keep subject identity anonymous.
Laboratory samples not collected on the day of the actual visit should preferably be collected on 
another day within the visit window as 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 collected during the trial, subjects must attend the relevant site visits 
fasting (fasting is defined in Section 8.1.3).
At three visits (see Section 2), the subjects on oral treatment must attend the relevant site without 
having taken the trial product the same day to have PK measured pre-dose and post-dose (trough 
and peak), see Section 8.4.10.
The central laboratory will provide laboratory results to the investigator on an on-going basis and 
the investigator must review all laboratory results for concomitant illnesses and AEs and report 
these according to Section 12.2.
An exception to this is that anti-semaglutide antibody and semaglutide plasma concentration results 
will not be available to the investigator during the trial. These results will be provided to the 
investigator upon request after the completion of the clinical trial report (CTR).
All laboratory samples will be destroyed at the latest at the completion of the CTR, except samples 
obtained for anti-semaglutide antibody analysis which may be kept up to ten years or stored until 
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approval by health authorities. Antibody samples will only be analysed if requested by the health 
authorities or for safety.
The laboratory equipment may provide analyses not requested in the protocol but produced 
automatically in connection with the requested analyses according to specifications in the laboratory 
standard operating procedures. Such data will not be transferred to the trial database, but abnormal 
values must be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to this protocol.
8.6
Other assessments
8.6.1
Subject diary
The subject must be provided with diaries at all visits until the End-of-treatment visit. Entries in the 
diary are only to be made by the subject.
The investigator/delegate should instruct the subject in recording the following data in the diary:
!
For all subjects:
!
date and time of first IMP administration
!
hypoglycaemic episodes
!
concomitant medication
!
AEs
!
For subjects treated with oral semaglutide: 
!
date and time of last IMP administration prior to each visit
!
post-dose fasting routines during the trial and recorded at the End-of-treatment visit
!
For subjects treated with s.c. semaglutide:
!
date, time, dose and injection site of the last two IMP administrations before each visit
The diaries should be collected at the following visit. The recordings must be reviewed as described 
in Section 8.1.11.
8.6.2
Additional safety assessments
8.6.2.1
Thyroidectomy, tissue sample and genetic testing
Thyroidectomy pathology slides
In case a subject undergoes a thyroidectomy (partial or total) for any reason during the trial the 
subject will be asked to inform the investigator prior to the operation.
In addition to the review of the thyroid tissue routinely made by the hospital pathology laboratory, 
the pathology slides of the thyroid tissue will be sent centrally for a second review by a pathologist 
with expertise in thyroid and C-cell pathology. The central pathologist will be blinded to both 
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randomised treatment and the diagnosis from the hospital pathology laboratory. Both the hospital 
pathology report and the central pathology report will be reviewed by an independent Event 
Adjudication Committee (EAC) (see Section 12.7.2). Once the samples are re-examined they will 
be sent back to the hospital pathology laboratory.
The investigator will be informed of the results of central pathology report and if C-cell pathology 
is confirmed by the EAC, the CMC will provide guidance to the investigator with regards to 
treatment and further investigations.
Thyroid tissue sample collection in case of thyroidectomy (not applicable for Israel)
If C-cell pathology is confirmed (i.e., hyperplastic or neoplastic thyroid C-cells) the subject will be 
asked to consent to have a sample of the removed thyroid tissue tested for RET Y1062 
phosphorylation in the thyroid C-cells, if allowed by local law. The tissue sample will be destroyed 
after examination.
Blood sample for genetic testing in case of confirmed C-cell pathology (not applicable for 
Israel)
In addition, the subject will also be asked to consent to be tested (blood sample) to identify germline 
RET gene mutations associated with MEN2 syndrome. This RET gene mutation detection will only 
be conducted if the EAC has confirmed C-cell abnormality (medullary carcinoma or C-cell 
hyperplasia). The genetic testing will only be performed if allowed by local law.
The blood sample should be collected at the first visit to the clinic after the confirmation of C-cell 
pathology. The extraction of DNA will be performed by the central laboratory whereas the 
identification of gene mutations will be performed by a specialised laboratory. The blood sample 
will be destroyed as soon as the genetic analysis is complete.
8.6.2.2
Assessments in case of suspicion of acute pancreatitis
In case of acute, severe persistent abdominal pain characteristic of acute pancreatitis, the IMP must
promptly be interrupted until pancreatitis is excluded (see Section 6.5.2). Appropriate additional 
examinations should be performed according to local practice. If acute pancreatitis is not confirmed 
trial product should be re-initiated.
If pancreatitis is confirmed (as a minimum 2 of 3): 
!
characteristic abdominal pain 
!
blood amylase and/or lipase >3x upper normal range (UNR) 
!
characteristic findings on ultrasound/CT/MRI
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appropriate treatment and careful monitoring of the subject should be initiated. Trial product should 
not be re-initiated but subject should remain in the trial. The event should be reported as a MESI 
and will undergo assessment by the EAC (see Section 12.7.2).
8.6.2.3
Assessments in case of suspicion of severe hypersensitivity
If a severe immediate hypersensitivity reaction to the IMP is suspected, blood sampling for 
assessment of anti-semaglutide IgE antibodies and anti-semaglutide binding antibodies should be 
collected after a suitable washout period (minimum 5 weeks). In these cases, it is also
recommended to test for tryptase (total and/or mature tryptase) within three hours of the reaction.
Furthermore, a tryptase sample should be taken at the same time as the IgE sample is obtained. 
Tryptase concentrations (if measured) as well as results of anti-semaglutide antibody and IgE-
isotype anti-semaglutide antibodies should be sent to Novo Nordisk.
8.7
Subject compliance
Subject compliance will be assessed by monitoring of drug accountability. Prior to visits where 
drug accountability is performed the subject will be asked to return all used, partly used and unused 
IMPs. The investigator must assess the amount of IMPs returned compared to what was dispensed 
at the last dispensing visit and, in case of discrepancies, question the subject.
Throughout the trial the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. 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.
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9
Trial supplies
Trial supplies comprise trial products and auxiliary supplies. Additional details regarding trial 
supplies can be found in the Trial Materials Manual (TMM).
Trial products must not be dispensed to any person not included in the trial.
For injectable products, the trial product must not be used if:
!
it does not appear clear and colourless
!
it has been frozen
!
it has been exposed to excessive heat or direct sunlight
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products (IMP)
Active substance
Strength
Dosage form
Semaglutide
2.5 mg
tablet
Semaglutide
5.0 mg
tablet
Semaglutide
10 mg
tablet
Semaglutide
20 mg
tablet
Semaglutide
40 mg
tablet
Placebo
N/A
tablet
Semaglutide
1.34 mg/mL
solution for injection, 
1.5 mL pre-filled PDS290 pen-injector
N/A: not applicable
The IMPs for oral use will be packed in 15 mL Duma containers (lid with desiccant). Each
container will include ten tablets. Subjects in the oral treatment arms will be instructed in how to 
ingest the tablets following the condition rules. All tablets containing semaglutide or placebo are 
identical with regards to visual appearance, taste and smell.
The semaglutide, solution for injection will be delivered open-label with the pre-filled PDS290 pen-
injector. The direction for use of the pen-injector will be given to each subject in the s.c. treatment 
arm at each dispensing visit.
For further details, please see the current edition of the IB (Oral Administration of Semaglutide
(NN9924) Edition 56 and any updates hereof.
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Version:
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Metformin may be used at the discretion of the investigator. Metformin will not be supplied by 
Novo Nordisk. However, metformin will be reimbursed if required by the country’s Health 
Authority or independent ethics committee/Institutional Review Board (IEC/IRB).
9.2
Labelling
Labelling of the trial products will be in accordance with Annex 1312, local regulations and trial 
requirements.
Each investigator site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IV/WRS. Dispensing unit numbers (DUNs) will be distributed to the sites 
according to enrolment and randomisation. 
The investigator or delegate must document that direction for use of the device is handed out at 
each dispensing visit. This could be by signature in the subject’s medical record.
9.3
Storage
Tablets containing the SNAC enhancer are susceptible to degradation in humid environment. It is 
important to protect the tablets by following the storage conditions in Table 9–2. Before opening the 
Duma container for the first time, the container must acclimatise for 1 hour at room temperature due 
to risk of condensation.
Table 9–2
Storage conditions for trial products
Trial product
Storage conditions (not-in-use)
In-use conditions
In-use time*
Semaglutide and 
placebo tablets
!
Must be stored in a refrigerator 
(2ºC to 8ºC) / (36ºF to 46ºF)
!
Do not freeze
!
Protect from light and 
humidity
!
Store below 30°C / 86ºF
!
Do not refrigerate
!
Do not freeze
!
Protect from light and humidity
!
Container must be stored with 
lid tightly closed at all times
Use within 4 weeks
Semaglutide, 
solution for injection
!
Must be stored in a refrigerator 
(2°C to 8°C) / (36ºF to 46ºF)
!
Do not freeze
!
Protect from light
!
Store below 30°C / 86ºF
!
Do not refrigerate
!
Do not freeze
!
Protect from light
Use within 1 month 
Semaglutide placebo, 
solution for injection 
(test pen)
!
Must be stored in a refrigerator 
(2°C to 8°C) / (36ºF to 46ºF)
!
Do not freeze
!
Protect from light
!
For single use only
For single use only
* In-use time starts when first dose is taken.
The investigator must ensure the availability of proper storage conditions, record and evaluate the 
temperature. The investigator must inform Novo Nordisk immediately if any trial product has been 
stored outside defined conditions (e.g., outside temperature range).
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Version:
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Status:
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Trial products that have been stored improperly must not be dispensed to any subject before it has 
been re-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 is the responsibility of the investigator.
Returned trial product (used/partly used or unused including empty packaging material) can be 
stored at room temperature and must be stored separately from non-allocated trial product.
The trial products will be dispensed to each subject as required according to treatment group. The 
IV/WRS will allocate trial product to the subject at each dispensing visit. The correct dispensing 
unit number(s) (DUN(s)) must be dispensed to the subject.
The investigator or delegated person is responsible for ensuring that:
!
Trial products are not dispensed to any person not included in the trial
!
Drug accountability is performed using the IV/WRS drug accountability module
!
Subjects are instructed to return all used, partly used and unused trial product including empty 
packaging material at every visit
!
Returned trial product(s) (used, partially used or unused including empty packaging material) is 
kept and stored separately from non-allocated trial products
Destruction will be done according to local procedures after accountability is finalised and verified 
by the monitor. Destruction of products must be documented.
9.5
Auxiliary supplies
Auxiliary supplies provided by Novo Nordisk:
!
Blood glucose meters, including lancets, plasma-calibrated test strips and control solutions.
!
Direction for use for devices (only subjects on s.c. semaglutide)
!
Needles for pre-filled pen systems (only subjects on s.c. semaglutide)
!
Test pens containing semaglutide placebo (only subjects on s.c. semaglutide)
Test pens containing semaglutide placebo, solution for injection, 1.5 mL pre-filled PDS290 pen-
injector will be supplied at the randomisation visit to subjects randomised to injection treatment. 
Training with the test pen is optional and recommended for subjects without prior injection 
experience to ensure the subject’s willingness and ability to self-inject. The test pen should be 
administered once and the training be performed at the clinical site. The subjects must not take the 
test pens home.
Details of the auxiliary supplies are provided in the TMM.
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Date:
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Trial ID: NN9924-3790
Version:
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10 Interactive voice/web response system
A trial-specific IV/WRS will be set up which can be accessed at any time via the internet or 
telephone. Access to the IV/WRS must be restricted to and controlled by authorised persons. 
IV/WRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
IV/WRS user manuals will be provided to each trial site.
During the trial, only DUNs allocated by the IV/WRS are allowed to be dispensed to a subject. This 
will ensure that:
!
needed stock is available at a site for the subjects
!
no allocation of IMP that will expire before the next dispensing contact
!
drug accountability can be made in IV/WRS
If a subject needs IMP between dispensing visits, the investigator must make an additional 
dispensing session in the IV/WRS.
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Date:
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Version:
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11 Randomisation procedure and breaking of blinded codes
The trial is partially blinded. The oral semaglutide arms and the oral placebo arm are double-blind 
whereas the s.c. semaglutide active comparator arm is open-label.
The randomisation is stratified according to one stratification factor with two strata: Treatment with 
metformin at screening (yes/no).
11.1
Breaking of blinded codes 
If the trial site needs to break the code, Novo Nordisk should, if possible, be contacted before the 
code is broken. The IV/WRS 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 IV/WRS, 
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 IV/WRS is not accessible at the time of code break the
monitor should be contacted and if monitor cannot get access the IV/WRS vendor helpdesk should 
be contacted. Contact details are listed in Attachment I.
If the code has been broken, the subject should be discontinued from trial product but be asked to 
continue in the trial (see Section 8.1.9).
If the subject is withdrawn after the code has been broken, a treatment discontinuation session 
should be completed in IV/WRS.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
Adverse event
An adverse event is any untoward medical occurrence in a subject administered a 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 procedures (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 8.4.1)
The following definitions are used when assessing an AE:
!
Severity assessment:
!
Mild – no or transient symptoms, no interference with the subject’s daily activities, 
acceptable
!
Moderate – marked symptoms, moderate interference with the subject’s daily activities, 
but still acceptable
!
Severe – considerable interference with the subject’s daily activities; unacceptable
!
Causality assessment
The following terms and definitions are used when assessing the relationship between an AE 
and the relevant trial product(s):
!
Probable – Good reason and sufficient documentation to assume a causal relationship
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!
Possible – A causal relationship is conceivable and cannot be dismissed
!
Unlikely – The event is most likely related to aetiology other than the trial product
!
Final outcome of an AE
!
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 – This term is only applicable if the subject has completed the trial 
or has died from another AE. The condition is improving and the subject is expected to 
recover from the event.
!
Recovered/resolved with sequelae – The subject has recovered/resolved 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 at the time of reporting.
!
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.
Serious adverse event
A serious adverse event is an experience that at any dose results in any of the following:
!
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 this definition of SAEd. Suspicion of transmission of infectious agents 
via trial product must always be considered an SAE
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 severe.
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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 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 dyscrasiasis or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a 
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below 
defined MESI criteria.
1. Fatal Events (All events with fatal outcome) (A) 
2. Acute Coronary Syndrome (Myocardial Infarction, Hospitalization for Unstable Angina) (A) 
3. Cerebrovascular Events (Stroke, Transient Ischemic Attack) (A) 
4. Coronary Revascularization Procedure (A) 
5. Heart Failure requiring Hospital Admission (A) 
6. Pancreatitis or clinical suspicion of pancreatitis (A) 
7. Neoplasms (A)
8. Thyroid Disease ((A) if thyroidectomy is required)
9. Medication errors concerning trial products:
!
Administration of wrong drug
!
Wrong route of administration
!
Administration of a high dose with the intention to cause harm (e.g., suicide attempt)
!
Administration of a lower or higher dose than intended (e.g., taking more than the planned 
number of tablets); however, the administered dose must deviate from the intended dose to 
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Version:
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Status:
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an extent where clinical consequences for the trial subject were likely to happen as judged 
by the investigator, although not necessarily did happen
MESIs marked with an ‘(A)’ in the list above will undergo adjudication by an independent EAC 
(see Section 12.7.2).
Any event confirmed or suspected to be a MESI must be reported. In case the sponsor identifies 
potentially missed MESIs through predefined review of available data, the investigator will be 
asked to reconsider if this is a MESI. However, MESIs should not be reported for screening 
failures.
For further information regarding definitions of MESIs and an overview of which events that should 
undergo adjudication, please refer to Appendix C.
When reporting a MESI the following forms must be completed: AE form, eSIF, specific MESI 
follow-up questions (MESI form) and if applicable, the Event Adjudication Document Collection 
Form (only events for adjudication) in the eCRF.
Technical complaint
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g., discoloration, particles or 
contamination)
!
The packaging material (e.g., leakage, cracks, rubber membrane issues or errors in labelling 
text)
!
Problems related to devices (e.g., to the injection mechanism, dose setting mechanism, glucose 
measurement, push button or interface between the pen and the needle)
12.2
Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events 
from the first trial-related activity after the subject has signed the informed consent until the end of 
the post-treatment follow-up period. The events must be recorded in the applicable eCRF forms in a 
timely manner (see timelines below and 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?”
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All AEs, either observed by the investigator or reported by the subject, must be reported by the 
investigator and evaluated. Novo Nordisk assessment of expectedness is performed according to the 
following reference document: IB (Oral Administration of Semaglutide (NN9924)), Edition 56 and 
any updates hereof.
All AEs must be recorded by the investigator on an 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.
For SAEs, an eSIF must be completed in addition to the AE form. 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.
MESIs, regardless of seriousness, must be reported using both the AE form, the safety information 
form and a MESI form. The MESI form is an electronic form tailored to collect specific information 
related to the individual MESIs. For MESIs qualifying for event adjudication, an Event 
Adjudication Document Collection Form will also have to be completed in the eCRF. The Event 
Adjudication Document Collection Form is a check list of clinical data to be provided from the site.
The AE form for a non-serious AE should be signed when the event is resolved or at the end of the 
trial.
Timelines for initial reporting of AEs:
The investigator must complete the following forms in the CRF/eCRF within the specified 
timelines:
!
SAEs: The AE form within 24 hours and the safety information form 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. 
!
SAEs fulfilling the MESI criteria: In addition to above, the MESI form within 14 calendar 
days of the investigator’s first knowledge of the AE
!
Non-serious AE fulfilling the MESI criteria: The AE form, and safety information form and 
MESI form within 14 calendar days of the investigator’s first knowledge of the event.
If a MESI fulfils the Event Adjudication criteria the investigator must complete the Event 
Adjudication Document Collection Form within 14 calendar days of the investigator’s first 
knowledge of the adverse event.
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If the eCRF is unavailable, the concerned AE information must be reported on paper forms 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 re-enter the information on the appropriate 
forms in the eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator’s trial file.
Figure 12–1
Initial reporting of AEs
Reporting of trial product-related SUSARs by the sponsor:
Novo Nordisk will notify the investigator of trial product-related suspected unexpected serious 
adverse reactions (SUSARs) in accordance with local requirements and GCP1. In addition, the 
investigator will be informed of any trial-related SAEs that may warrant a change to any trial 
procedure.
In accordance with regulatory requirements, Novo Nordisk will inform the regulatory authorities, 
including EMA, of trial product-related SUSARs. In addition, Novo Nordisk will inform the 
IRBs/IECs of trial product-related SUSARs in accordance with local requirement and GCP1, unless 
locally this is an obligation of the investigator.
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12.3
Follow-up of adverse events
During and following a subject’s participation in the trial, the investigator should ensure that 
adequate medical care is provided to the subject for any AE, including significant laboratory values 
related to the trial. The investigator should inform the subject when medical care is needed for 
AE(s) of which the investigator becomes aware. 
The investigator must record follow-up information by updating the forms in the eCRF.
Follow up information must be reported to Novo Nordisk according to the following:
!
SAEs: All SAEs must be followed up 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. The applicable forms must be signed within 7 calendar days from the date the new 
information was entered in the eCRF.
!
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.
!
Non-serious AE fulfilling the MESI criteria: Follow-up information on MESIs should only 
include new (e.g., corrections or additional) information and must be reported within 14 
calendar days of the investigator’s first knowledge of the information. This is also the case for 
previously non-serious AEs which subsequently fulfil the MESI criteria.
The investigator must record follow-up information on non-serious AEs by updating the AE form in 
the eCRF.
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The investigator must ensure that 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.
Queries or follow-up requests from Novo Nordisk must be responded to within 14 calendar days 
from the date of receipt of the request, unless otherwise specified in the follow-up request.
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 tablets
!
Placebo tablets
!
Semaglutide for s.c. injection, solution for injection, 1.5 mL pre-filled PDS290 pen injector
!
Semaglutide placebo for s.c. injection, solution for injection, 1.5 mL pre-filled PDS290 pen-
injector (test pen)
!
Novo Nordisk needles
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 the investigator’s trial file.
The investigator must assess whether the technical complaint is related to any AEs, SAEs and/or 
MESI.
Technical complaints must be reported on a separate technical complaint form for each product 
listed. If the technical complaint involves more than one code number, lot number or DUN, a 
technical complaint form for each code number, lot number or DUN 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.
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12.4.2
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample 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 the investigator’s trial file) 
and ensure that the sample is sent as soon as possible. A print of the technical complaint form must 
be sent with the sample.
The investigator must ensure that the technical complaint sample contains the code number and, if 
available, the DUN.
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. The shipment of the technical complaint sample should be done in 
accordance with the same conditions as for storage (see Section 9).
12.5
Pregnancies
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, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner.
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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: 
!
Paper AE form* within 14 calendar days of the investigator's first knowledge of the initial or 
follow-up information to the non-serious AE
SAEs: 
!
Paper AE form* within 24 hours of the investigator's first knowledge of the SAE
!
Paper safety information form 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
* 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.
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 confirmed hypoglycaemia include: hunger, slight headache, nausea, light-headedness, 
palpitations and sweating. Major hypoglycaemia (severe) may produce loss of consciousness. 
Symptoms of confirmed and not major hypoglycaemia should be treated by ingestion of 
carbohydrates.
Major hypoglycaemia resulting in loss of consciousness should be treated at the investigator’s 
discretion according to best available medical practise.
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One case of accidental overdose of oral semaglutide with SNAC was reported in the NN9924-3692 
trial in a subject treated with 20 mg semaglutide with 300 mg SNAC. The subject accidentally took 
the trial product 
 on Day 
 of the trial. No AEs were reported at the time. The medication 
error was discovered at the next scheduled visit. The subject did not report any symptoms and 
treatment was continued without any change.
One case of accidental overdose has been reported in s.c. semaglutide treated subjects. The case 
classified as moderate in severity and considered to be probably related to semaglutide was reported 
by a subject enrolled in trial NN9535-1821. No hospitalisation was needed. The subject 
inadvertently injected  mg of semaglutide instead of 0.4 mg, which corresponds to a 
-fold 
higher dose than the maximum dose included in that trial. After 
 hours 
 felt nauseated, 
vomited and had a headache. The subject was instructed to drink copious amounts of fluids. 
and the subject wished to continue in the trial. 
Blood glucose levels, blood pressure and pulse were monitored during the following five days, and 
no symptoms of hypoglycaemia or any other symptoms or signs were noted. The subject was 
withdrawn from the trial after 
 days of treatment due to an AE (diarrhoea).
For further details please see the current edition of the IB (Oral Administration of Semaglutide 
(NN9924) Edition 56 and any updates hereof.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal Oral GLP-1 safety committee to perform on-going safety 
surveillance. The Oral GLP-1 safety committee may recommend un-blinding of any data for further 
analysis, and in this case an independent ad hoc safety group will be established in order to maintain 
the blinding of the trial personnel.
12.7.2
Event adjudication committee
An external event adjudication committee (EAC) is established to perform qualitative or 
quantitative 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.
The events are reviewed by the EAC in an independent and blinded manner.
The EAC is composed of permanent members covering required medical specialities. EAC 
members must disclose potential conflicts of interest and must be independent of Novo Nordisk. 
The role of the EAC is solely to adjudicate events in a blinded manner. The EAC will have no 
authorisations to impact on trial conduct, trial protocol or amendments.
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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.
The events will be adjudicated according to FDA requirements and the adjudication vendor will 
ensure that the EAC gets access to all the documents provided by the investigator. The EAC will 
initiate the review and may ask for additional information that the investigator needs to provide if it 
is available.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g., X-ray images, ECGs, ultrasound images, discharge summaries, 
pathology reports and death certificates). The investigator must provide medical documentation 
within 4 weeks of event identification.
The assessments made by the EAC will be included in the CTR as well as assessments made by the 
investigator. However, the adjudication made by an EAC, given its independence and in-depth 
analysis of each event, will be attributed with greater importance of the two. The outcomes of 
adjudication will be kept in the clinical trial database.
The following AEs will be adjudicated in this trial:
!
Fatal Events (All events with fatal outcome)
!
Acute Coronary Syndrome (Myocardial Infarction, Hospitalization for Unstable Angina)
!
Cerebrovascular Events (Stroke, Transient Ischemic Attack)
!
Coronary Revascularization Procedure
!
Heart Failure requiring Hospital Admission
!
Pancreatitis or clinical suspicion of pancreatitis
!
Neoplasms
!
Thyroid Disease (if thyroidectomy is required)
Event adjudication will not be performed for AEs in screening failures.
There are two processes for capturing AEs for adjudication: Direct reporting of MESIs by the 
investigator and by potential missed MESI process.
Direct reporting of MESI by investigator: For each AE reported in the eCRF, the investigator must 
complete whether the event in his/her opinion is a MESI (yes/no).
By ticking YES:
!
The investigator must specify the type of MESI event being reported
!
The investigator must complete the event adjudication document collection form (‘adjudication
form’) in the eCRF according to the timeline specified in Section 12.2. This form indicates the
data/documents required for adjudication
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!
For each required document the investigator should specify/indicate when/if the data/document 
will be available. If a document is unobtainable this needs to be specified. The investigator must 
provide medical documentation within 4 weeks of event identification
By ticking NO:
All NOs within the relevant MESI category are screened for being potential missed MESI.
!
If needed, the investigator will be asked to provide an explanation of why the event is not 
reported as a MESI (alternative etiology)
!
The vendor or EAC can evaluate an event not initially reported as a MESI for adjudication to be 
adjudicated. In this case the investigator must provide data/documents required for adjudication 
as soon as possible when receiving a request from Novo Nordisk or the vendor
A site manual will be provided to each site detailing the specifics surrounding the medical 
documentation that must be provided by site to the adjudication vendor including how this 
documentation should be provided.
12.7.3
Calcitonin monitoring committee
The CMC will provide recommendations to the investigators with regards to further investigation 
and treatment of the individual subject (see Appendix A).
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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 supplied by a vendor.
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 CRFs:
!
Pregnancy forms
In addition paper AE forms, SIF and technical complaint forms will be provided. These must be 
used when access to the eCRF is revoked (i.e., EDC system not available).
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 case book 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 authorised 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 authorised staff after the date the investigator has 
signed the case book, the case book must be signed and dated again by the investigator.
13.2
Case report form flow
The investigator must ensure that data are recorded in the eCRF as soon as possible after the visit, 
preferably within 5 days. Once data have been entered, they will be available to Novo Nordisk for 
data verification and validation purposes.
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At the end of the trial the investigator must ensure that all remaining data have been entered into the 
eCRF, preferably within 3 days after the last subject’s 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.
13.3
Paper case report forms
The pregnancy forms are paper based CRFs. Also, the SIF, technical complaint form and AE form 
will be provided in paper but are only to be used if for any reason the eCRF is unavailable.
The investigator must ensure that data are recorded in these forms as soon as possible after the visit 
and ensure that Novo Nordisk receives these forms within the required timelines (see Sections 12.2, 
12.4.1 and 12.5).
Corrections to the data in the CRFs may only be made by drawing a straight line through the 
incorrect data and then writing the correct entry next to the data that were crossed out. Each 
correction must be initialled, dated and explained (if necessary) by the investigator or the 
investigator’s authorised staff.
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14 Monitoring procedures 
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 FSFV and 
no later than 4 weeks after. The monitoring visit intervals will depend on the outcome of the remote 
monitoring of the eCRFs, the trial site's recruitment rate and the compliance of the trial site to the 
protocol and GCP, but will not exceed 4 weeks during the recruitment period (i.e., from FSFV to 
last subject first visit (LSFV)). After LSFV the monitoring visit intervals will not exceed 8 weeks.
The monitor must be given direct access to 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 (except for BMI).
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.
For screening failures the monitor will ensure that relevant eCRF pages and other trial-related forms 
containing data from screening failures are completed. For screening failures the following data 
should be source verified: informed consent, reason for screening failure and AEs, if any.
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 completed diaries will be collected from the subject at each site visit and must be kept as source 
data at the site. The investigator/delegate must transcribe the data into the eCRF.
The monitor will ensure that the eCRFs are completed on an ongoing basis and within agreed 
timelines.
Monitors must 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 addressing any action to be taken.
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15 Data management
Data management is always the responsibility of Novo Nordisk. Data management may be 
delegated under an agreement of transfer of responsibilities to an external 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 from the laboratory performing the 
analyses. In cases where laboratory data are 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 identification number. 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. 
Results from the statistical analysis will generally be presented by two-sided confidence intervals 
with a confidence level of 95% including a p-value for test of no difference between treatments.
The stratification variable referred to in the following is defined as the two level factor of treatment 
with metformin (yes/no).
The “planned comparisons between treatment arms” referred to in this section covers the following 
comparisons: a) between each of the oral semaglutide treatment arms and placebo, b) between the 
s.c. semaglutide arm and placebo, c) between each of the oral semaglutide treatment arms and s.c. 
semaglutide, and d) between the three treatment arms with an end dose of 40 mg.
A standard mixed model for repeated measurements (MMRM) will be used in the analysis of the 
primary and continuous secondary endpoints. The model will include treatment, country and the 
stratification variable as fixed factors, and the corresponding baseline value as covariate. All factors 
and the covariate will be nested within visit. Unless otherwise stated, the estimated differences with 
corresponding two sided p-values and 95% confidence intervals at 26 weeks will be presented for 
the planned comparisons between treatment arms.
In order to describe the dose-response relation of oral semaglutide and estimate the relative potency 
vs. s.c. semaglutide with regards to selected key endpoints, an explorative analysis will be 
conducted. In this model data from oral semaglutide arms using the standard titration scheme will 
be included. One or both of the treatment arms with an end dose of 40 mg using an alternative 
titration scheme may be included and pooled with the oral semaglutide arm with an end dose of 40 
mg and using the standard titration scheme, if deemed appropriate based on the planned pairwise 
comparisons between the arms. Data from the placebo arm (corresponding to a dose of zero mg) 
could be included if deemed appropriate. The model will developed ad hoc after unblinding and aim 
for a suitable fit of the dose-response relation using e.g. a linear or a four-parameter logistic relation
of the endpoint of interest vs. the logarithm of the dose.
17.1
Sample size calculation
The primary endpoint, change from baseline to end of treatment (i.e., after 26 weeks of treatment) 
in HbA1c, will be analysed by the standard MMRM.
In order to demonstrate efficacy of oral semaglutide the sample size is based on an initial 
comparison of change from baseline to end of treatment (i.e., after 26 weeks of treatment) in HbA1c
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between a) the pool of the two treatment arms using standard and fast escalation regimens, 
respectively, to an end dose of 40 mg and b) placebo.
A standard deviation (SD) of 1.2% for change from baseline in HbA1c is chosen as assumption for 
the sample size calculation. The SD observed in several phase 3 trials of 26 weeks duration with s.c. 
liraglutide suggests a standard deviation less than 1.1%. However, as it is uncertain if the added 
variation in exposure compared to s.c. liraglutide will transfer to an added variation in the 
therapeutic response, a SD of 1.2% is assumed.
In trial NN9535-1821 the withdrawal rate for the doses 0.2 mg-0.8 mg was 16%-24%. In the 
present trial, GI events are mitigated by dose escalation and based on this the drop-out rate is 
expected to be 20%, equally distributed among treatment arms. For completers the treatment 
difference between the pooled 40 mg arm and placebo is expected to be at least 0.64% whereas for 
dropouts the treatment difference is set conservatively to 0.32%, thus leading to a detectable mean 
difference of 0.58%. With these assumptions, and using a two-sided t-test with a significance level 
of 5%, 134 subjects should be randomised to the pooled 40 mg treatment arm and 67 to placebo in 
order to have 90% power to demonstrate superiority of the pooled 40 mg treatment arm versus 
placebo. For similarity between the treatment arms, 67 subjects should be randomised in each of the 
nine treatment arms.
In total, 603 subjects are to be randomised.
17.2
Definition of analysis sets
Full Analysis Set (FAS): includes all randomised subjects who have received at least one dose and 
have any post randomisation data. The statistical evaluation of the FAS will follow the intention-to-
treat (ITT) principle and subjects will contribute to the evaluation “as randomised”.
Safety Analysis Set (SAS): includes all subjects exposed to at least one dose of randomised 
liraglutide or liraglutide placebo. Subjects in the SAS will contribute to the evaluation “as treated”.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to 
exclude a subject or single observations from the statistical analysis is the joint responsibility of the 
members of the study group. Exclusion of data from analyses will 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.
17.3
Primary endpoint
The primary endpoint, change from baseline to end of treatment (i.e., after 26 weeks of treatment) 
in HbA1c, will be analysed by the standard MMRM.
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In order to confirm efficacy of oral semaglutide without risk of inflation of the type 1 error an initial 
comparison of the primary endpoint between a) the pool of the two treatment arms using standard 
and fast escalation regimens to an end dose of 40 mg and b) placebo. The comparison will be made 
using the MMRM by estimating the difference between the mean of means in the two 40 mg arms 
and the mean in placebo. The estimated difference with corresponding two sided p-value and 95% 
confidence interval at 26 weeks will be presented, and efficacy of oral semaglutide will be 
considered confirmed if the upper limit of the confidence interval is strictly less than zero.
If efficacy of oral semaglutide is confirmed the planned comparisons between the nine original 
treatment arms will be evaluated.
Subjects in the FAS and only measurements taken before treatment discontinuation or initiation of 
rescue therapy will be included in the analysis.
Due to the uncertainty in relation to if the added variation in the exposure in the oral semaglutide 
arms compared to s.c. liraglutide will transfer to an added variation in the therapeutic response, a 
sensitivity analysis allowing the within subject unstructured covariance matrix to be fitted 
separately for each treatment arm will be conducted.
Furthermore, the following sensitivity analyses will be conducted in order to investigate the 
sensitivity of the results due to the impact of missing values:
!
An MMRM similar to the primary analysis but including all data recorded after randomisation 
regardless of the data being obtained when the subjects have received rescue therapy or have 
discontinued randomised treatment.
!
An analysis of covariance (ANCOVA) model including subjects in the FAS and using 
imputation of missing values according to the last observation carried forward (LOCF) method. 
The model will include fixed factors for treatment, country and the stratification variable and 
the baseline value as covariate. In accordance with the LOCF method, the dependent variable 
will be the last available value obtained within the 26 weeks period of the study.
!
A completer analysis, i.e. an ANCOVA similar to the one above including only data obtained at 
26 weeks from subjects who: 
!
did not discontinue treatment prematurely
!
did not receive rescue therapy
!
had a valid HbA1c assessment at baseline and after 26 weeks of treatment 
17.4
Supportive secondary endpoints
17.4.1
Efficacy endpoints
The FAS will be used in all analyses of the supportive secondary efficacy endpoints.
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Subjects who, after 26 weeks of treatment, achieve (yes/no) HbA1c <7% (53 mmol/mol)
The binary endpoint will be analysed by a logistic regression model which will include fixed factors 
for treatment and the stratification variable and baseline HbA1c as a covariate. Estimated odds 
ratios with corresponding two sided p-values and 95% confidence intervals at 26 weeks will be 
presented for the planned comparisons between treatment arms. Missing response data at 26 weeks 
will be imputed from the MMRM used for the primary analysis of HbA1c.
Change from baseline to week 26 in body weight, waist circumference and fasting plasma 
glucose. 
These endpoints will be analysed by the standard MMRM.
Change from baseline to week 26 in C-peptide, fasting insulin, glucagon, HOMA-IR, HOMA-
B, total cholesterol, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, triglycerides and 
free fatty acids. 
For each endpoint, the assessments at every week will be log-transformed and subsequently 
analysed by the standard MMRM. The estimated differences and corresponding 95% confidence 
intervals at 26 weeks will be back transformed and presented as ratios together with the two sided 
p-values.
The fasting HOMA endpoints (i.e., fasting HOMA-B and HOMA-IR) will be calculated based on 
fasting insulin and FPG as follows:
1. Fasting HOMA-B (%) = 20 x fasting insulin [μU/ml]/(FPG[mmol/L]-3.5)
2. Fasting HOMA-IR (%) = fasting insulin [μU/ml] x FPG [mmol/L]/22.5
PRO outcomes
The outcomes from the SF-36 in terms of total scores overall and within each domain will be 
calculated and each of these scores will be analysed by the standard MMRM.
17.4.2
Safety endpoints
All safety endpoints will be summarised and analysed using the safety analysis set. Unless 
otherwise specified safety endpoints will be analysed by descriptive statistics only. 
Adverse events
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 event that has onset date (or increase in 
severity) on or after the first day of exposure to randomised treatment and no later than the follow-
up visit. TEAEs are summarised descriptively, whereas non-treatment emergent AEs are presented 
in listings.
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Number of confirmed treatment emergent hypoglycaemic episodes
A hypoglycaemic episode will be defined as treatment emergent if the onset of the episode occurs 
on or after the first day of trial product administration and no later than the follow-up visit.
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of confirmed 
hypoglycaemia and the ADA classification of hypoglycaemia (see Figure 17–1).
Confirmed hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)13. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of confirmed hypoglycaemia.
Confirmed hypoglycaemic episodes are defined as episodes that are: 
!
severe (i.e., an episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions) and/or
!
biochemically confirmed by a plasma glucose value of <3.1 mmol/L (56  mg/dL), with or 
without symptoms consistent with hypoglycaemia 
ADA classification of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 mg/dL)
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL).
!
Relative hypoglycaemia: An episode during which the person with diabetes reports any of the 
typical symptoms of hypoglycaemia, and interprets those as indicative of hypoglycaemia, but 
with a measured plasma glucose concentration > 3.9 mmol/L (70 mg/dL).
!
Probable symptomatic hypoglycaemia: An episode during which symptoms of hypoglycaemia 
are not accompanied by a plasma glucose determination (but that was presumably caused by a 
plasma glucose concentration ≤ 3.9 mmol/L [70 mg/dL]).
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Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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Figure 17–1
ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes will be summarised descriptively using the 
above definitions.
The number of confirmed treatment emergent hypoglycaemic episodes during 26 weeks treatment 
will be analysed using a negative binomial regression model with a log-link function and the 
logarithm of the time period in which an occurrence of a hypoglycaemic episode is considered 
treatment emergent as offset. The model will include treatment, country and stratification variable
as fixed factors and baseline HbA1c as covariate. Estimated rate ratios with corresponding two sided 
p-values and 95% confidence intervals at 26 weeks will be presented for the planned comparisons 
between treatment arms.
Change in pulse, systolic- and diastolic blood pressure from baseline to after 26 weeks of 
treatment
These endpoints will be analysed by the standard MMRM.
Change in amylase and lipase from baseline to after 26 weeks of treatment
For each endpoint, the assessments at every week will be log-transformed and subsequently 
analysed by the standard MMRM. The estimated differences and corresponding 95% confidence 
intervals at 26 weeks will be back transformed and presented as ratios together with the two sided 
p-values.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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Change from baseline to after 26 weeks of treatment in electrocardiogram (ECG), physical 
examination, laboratory safety variables (haematology, biochemistry, hormone and
urinalysis) other than amylase and lipase
These endpoints will be summarised by descriptive statistics.
Endpoints related to occurrence of anti-semaglutide antibodies during 26 weeks of treatment: 
Antibody level during 26 weeks of treatment, anti-semaglutide antibodies (positive/negative), 
anti-semaglutide antibodies with in vitro neutralising effect (positive/negative), anti-
semaglutide antibodies cross reacting with endogenous GLP-1 (positive/negative), cross 
reacting antibodies with in vitro neutralising effect to endogenous GLP-1 (positive/negative) 
These endpoints will be summarised by descriptive statistics and correlated to PK and PD.
17.4.3
Pharmacokinetics and/or pharmacodynamics modelling
If relevant, population PK and PK/PD modelling will be used to evaluate semaglutide exposure and 
exposure-response relationship after oral and subcutaneous administration in subjects with T2D to 
inform dose selection in future trials.
The objectives of these exploratory analyses are to:
!
assess the dose-dependence of semaglutide exposure in plasma
!
explore the effects of covariates on semaglutide exposure
!
explore the relationship between semaglutide exposure and response variables of interest
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk A/S and 
will be reported separately from the CTR.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
84 of 98
18 Ethics
The trial will be conducted in compliance with ICH GCP1 and applicable regulatory requirements, 
and in accordance with the Declaration of Helsinki2.
All subjects will be included after a thorough evaluation in regards to in- and exclusion criteria
defined in order to ensure that subjects are eligible for trial treatment. Subjects will be treated
within a regimen anticipated to be better than or equal to the treatment they receive at the time of 
entry into the trial. However, they will have to spend some extra time, as additional assessments and
visits to the clinic are required. It is the responsibility of the investigator to ensure the best possible 
care according to the principles outlined in Diabetes Care 2013, Standards of Medical Care in 
Diabetes14, or any updates thereof.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks. 
The safety profile of semaglutide generated from the clinical and nonclinical development 
programme has not revealed any safety issues that would prohibit administration of once-daily oral 
doses of 2.5-40 mg semaglutide or once-weekly doses of 1.0 mg semaglutide in accordance with the 
planned clinical trial. Furthermore, a rescue strategy is implemented in this trial to ensure the safety 
of subjects experiencing deterioration of glycaemic control during the course of the trial to address 
the concern regarding the placebo arm and the inclusion of patients with an HbA1c up to 9.5%. It is 
concluded that the risk to the subjects in this trial is low and acceptable in view of the benefits a 
GLP-1 analogue in a tablet formulation would provide to people with T2D.
The trial products may be associated with AEs, but relevant precautions have been implemented in 
the design and planned conduct of the trial in order to minimise the risks and inconveniences of 
participation in the trial. These precautions include thorough information regarding the correct 
administration of the trial products and gradual dose adjustment. Furthermore, subjects are fully 
informed about possible AEs and inconveniences and will be instructed to contact the investigator
in case of any concerns regarding the trial participation. 
18.1
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH GCP1 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 subject is allowed to bring a companion when the oral information is provided.
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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent form will be obtained from the subject 
before any trial-related activity.
The responsibility for seeking informed consent must remain with the investigator, but the task may 
be delegated by the investigator 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.
18.2
Data handling
If the subject is withdrawn from the trial or lost to follow-up, then the subject’s data will be handled 
as follows:
!
Data already collected will be retained by Novo Nordisk, entered into the database and used for 
the trial report
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to local and 
national requirements
If data are used, it will always be in accordance with local law and IRBs/IECs.
18.3
Premature termination of the trial and/or trial site
Novo Nordisk, the investigator, 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 a 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 should also 
promptly inform the IRBs/IECs and provide a detailed written explanation. The relevant regulatory 
authorities should be informed.
If, after the termination of the trial, the risk/benefit analysis changes, the new evaluation should 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 does have an impact, the actions needed to inform and protect the 
subjects should be described.
An interim analysis to allow for premature discontinuation of the trial has not been planned.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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19 Protocol compliance
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 clinical database.
Documentation on all protocol deviations must be kept in the investigator’s trial file and Novo 
Nordisk trial master file.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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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.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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21 Critical documents
Before a site is allowed to start screening subjects, 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 substantial 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
!
Curricula vitae of the investigator and sub-investigator(s) (current, dated and signed – must
include documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
Signed and dated agreement on the final protocol
!
Signed and dated agreement on any substantial protocol amendment, if applicable
!
Financial agreement(s)
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Signed and dated Investigator Agreement
!
Financial disclosure form for all investigators
!
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of
Financial Conflict of Interest
!
For US trial sites: FDA Form 1572 must be completed and signed by each investigator
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA form 1572
FDA form 1572 (for sites outside the US):
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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By signing the protocol, each investigator agrees to comply fully with ICH GCP1, applicable 
regulatory requirements and the Declaration of Helsinki2.
By signing the protocol, each investigator also agrees to allow Novo Nordisk making investigator’s 
name and information about site name and address publically available if this is required by 
national or international regulations.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site. If any tasks are delegated, 
the investigator should maintain a list of appropriately qualified persons to whom he/she has 
delegated specified significant trial-related duties. The investigator should ensure that there is 
adequate 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 must ensure adequate supervision of the conduct of the trial at the trial site. 
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’s trial file. The documents should be kept in a secure locked facility, 
so no unauthorized persons can get access to the data. The subject ID list should be kept securely 
and separate from the personal 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.
The investigator must keep a log of staff and delegation of task(s) at site. The investigator must sign 
the log of staff and delegation of task(s) at site at the time of delegation of tasks. 
If the investigator is no longer able to fulfil the role of investigator (e.g., if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and site personnel must have sufficient English skills according to their assigned 
task(s).
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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Novo Nordisk will be responsible for the preparation of the protocol, eCRF, supply of trial products 
and stated equipment, monitoring, data management, statistics and the CTR as documented by 
Novo Nordisk procedures and internal specific agreements as well as the current GCP guidelines1.
Novo Nordisk will provide a system for EDC. This system and support services to the system will 
be supplied by a vendor. The activities of the vendor will be under the direction and supervision of 
Novo Nordisk. Furthermore, Novo Nordisk will be responsible for the IV/WRS.
A central laboratory will be responsible for providing all lab supplies for the analysis of all blood 
and urine samples taken during the trial. All results are received as paper copies at the sites as well 
as electronic transfer to Novo Nordisk clinical database.
The name of the central laboratories is listed in protocol attachment I.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
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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 Novo Nordisk for regulatory purposes and 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.
The CTR will be reviewed and signed by one or more investigator(s) (signatory investigator) 
appointed by Novo Nordisk based on their experience in clinical research and input during the 
analysis phase.
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.
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 invalidate the results of the entire trial.
At the end of the trial, one or more public disclosures 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.
The results of this trial will be subject to public disclosure on external web sites according to 
international regulations, as reflected in the Novo Nordisk Code of Conduct for Clinical Trial 
Disclosure.
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 
statistical tables, figures and reports needed to support 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 principal investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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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 
the Novo Nordisk trial manager 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 Editors (sometimes referred to as the Vancouver 
Criteria15).
At the end of the trial, one or more publications (abstracts, posters, manuscripts) will be prepared 
for submission to scientific congresses and peer-reviewed journals in collaboration between Novo 
Nordisk and investigator(s) appointed by Novo Nordisk. These investigator(s) must meet the
ICMJE authorship criteria to be named authors on publications.
23.1.2
Site-specific publication(s) by investigator(s)
For a multi-centre 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 for publication of such primary 
policy 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 participants' data and will be provided with the 
randomisation code after results are available.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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24 Retention of clinical trial documentation and human biospecimens
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 site. If the Novo 
Nordisk provided data (e.g., the CD-ROM) is not readable during the entire storage period, the 
investigator can request a new copy, as a copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for as long as the 
product is on the market plus 20 years. 
The files from the investigator site/institution must be retained for 15 years after the completion of 
the trial, or longer if required by national regulations. The deletion process must ensure 
confidentiality of data and must be done in accordance with local regulatory requirements.
24.2
Retention of human biospecimens
Serum samples (3-4 mL) of antibodies to semaglutide will be stored at the CRO after finalisation of 
the CTR (see Section 8.5). The retained antibody samples will only be used for further 
characterisation of antibodies against semaglutide if required by health authorities or for safety. The 
samples will remain anonymous (no personal data will be received). 
Samples will be stored for up to ten years or until approval by health authorities. They may be 
transferred from the CRO to Novo Nordisk. Only Novo Nordisk and the CRO/laboratory will have 
access to the samples.
There are no potential consequences for the subjects or their relatives on the potential use of the 
antibody samples stored.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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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 sponsor, 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, substantial protocol amendments, non-substantial 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 risk/benefit 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.
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 should be filed in the investigator’s trial file and copies must be sent to Novo 
Nordisk.
Regulatory Authorities
Regulatory authorities will receive the clinical trial application (CTA) or clinical trial notification, 
protocol amendments, reports on SAEs and the CTR according to national requirements.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability is 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 by the clinics or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with:
!
For Germany: Drug Law dated August 24, 1976 last amended by Second Law for Changes in 
Regulations on Drugs and Other Issues dated October 19, 2012.
!
For Spain: Royal decree 223/2004, of 6th February, establishing the requisites concerning 
clinical trials.
CONFIDENTIAL


Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
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27 References
1 International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good 
Clinical Practice. 01-May-1996.  
2 World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research 
Involving Human Subjects. 59th WMA General Assembly, Seoul. 1-Oct-2008.
3 Bittner B, McIntyre C, Jordan P, Schmidt J. Drug-drug interaction study between a novel oral 
ibandronate formulation and metformin. Arzneimittelforschung 2011; 61(12):707-713.
4 McIntyre C, Schmidt J, Castelli M, Bittner B. Study on the impact of SNAC (sodium N-[8-(2-
hydroxybenzoyl) amino] caprylate) on the bioavailability of ibandronate (IBN) in 
postmenopausal women. J.Drug Del.Sci.Tech. 2011, 21 (6) 521-525.
5 Investigator's Brochure Semaglutide (subcutaneous administration), Edition 8. June 2013. 
6 Investigator's Brochure Oral administration of semaglutide (NN9924), Edition 5. June 2013. 
7 International Conference on Harmonisation; Guidance on M3(R2) Nonclinical Safety Studies 
for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals; 
availability. Notice. Fed Regist 2010; 75(13):3471-3472.
8 
 I. ERP-12/7, clinical trial report: A Randomized, Double-Blind, 
Multicenter Study Comparing the Safety and Efficacy of Two Dosing Regimens of Oral 
 SNAC/Heparin with Subcutaneous Enoxaparin Sodium for the Prevention of 
Venous Thromboembolic Events Following Elective Total Hip Replacement Surgery. Nov. 
2002. 
9 De Angelis C., Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N Engl 
J Med 2004; 351(12):1250-1251.
10 Food and Drug Administration Amendments Act (FDAAA), VIII-CLINICAL TRIAL 
DATABASES, SEC. 801. EXPANDED CLINICAL TRIAL REGISTRY DATA BANK, 27-
Sep-2007.  
11 European Commission. Detailed guidance on the European clinical trials database 
(EUDRACT Database) April 2003 and successor documents CT 5.1 Amendment describing 
the Development of EurdaCT- Lot 1 for 1 May 2004 and CT 5.2 EudraCT core dataset.  
12 European Union. The rules governing medicinal products in the European Union, Volume 4, 
EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and 
Veterinary Use; Annex 13, Investigational Medicinal Products - Brussels, February 2010.
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Protocol
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
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13 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):777-781.
14 Standards of medical care in diabetes--2013. Diabetes Care 2013; 36 Suppl 1:S11-S66.
15 International Committee of Medicinal Journal Editors. Uniform Requirements for Manuscripts 
submitted to Biomedical Journals. N Engl J Med 1997; 336:309-315.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 6
Appendix A
Semaglutide, NN9924-3790
Monitoring of calcitonin
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
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.


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 6
Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin and C-cell abnormalities – evaluation and follow-up..........................................................4
2.1
CT ≥ 100 ng/L................................................................................................................................4
2.2
CT ≥ 50 and < 100 ng/L.................................................................................................................4
2.3
CT ≥ 20 and <50 ng/L....................................................................................................................5
2.4
CT ≥ 10 and < 20 ng/L...................................................................................................................5
3
References..................................................................................................................................................6
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 6
1
Background
Semaglutide treatment is associated with thyroid C-cell changes in rodents but not in the non-
human primate. The proliferative C-cell changes in rodents are a known effect following GLP-1 
receptor activation by GLP-1 receptor agonists and 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 can 
become challenging. 
There are several known confounding factors affecting calcitonin levels, namely renal dysfunction, 
smoking, autoimmune thyroiditis and 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.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 6
2
Calcitonin and C-cell abnormalities – evaluation and follow-up
Subjects with a personal or family history of medullar thyroid cancer (MTC) or multiple endocrine 
neoplasia syndrome type 2 (MEN2) or with a screening calcitonin ≥ 50 ng/L will be excluded from 
the trial. 
A blood sample will be drawn at pre-specified trial visits for measurement of calcitonin. In case a 
subject has an increased calcitonin value ≥ 10 ng/L the algorithm outlined below should be 
followed. The algorithm applies for all calcitonin values including screening values.
All calcitonin values ≥20 ng/L will be submitted to an independent Calcitonin Monitoring 
Committee (CMC) of thyroid experts, together with relevant supplementary data, i.e. subject’s 
demographics, diabetes history, concomitant medical history, concomitant medications, smoking 
status as well as information about relevant adverse events reported during the trial.
The CMC will provide recommendations to the investigators with regards to further investigation 
and treatment of the individual subject. The CMC will be blinded to trial treatment. 
The summary for the rationale for the use of specific calcitonin values to trigger medical evaluation 
and an overview of the algorithm is provided below:
2.1
CT ≥ 100 ng/L  
The value will be submitted to the CMC and the subject should be discontinued from trial product. 
If the value is a screening value the subject can not be randomised and the subject must be referred 
to a thyroid specialist. 
These values were found in 0.15% of the population published by Constante et al1 and in one 
subject (on active comparator) in the liraglutide development program. For a calcitonin value of 
≥100 ng/L, the subject should be assumed to have significant C-cell disease and a high likelihood of 
having medullary carcinoma of the thyroid. Diagnostic evaluation should consist of thyroid 
ultrasound, fine needle aspiration of any nodules >1 cm and potentially surgery with neck 
dissection. Family history of MTC or MEN2 should be evoked and a RET proto-oncogene analysis 
should be performed. 
2.2
CT ≥ 50 and < 100 ng/L
The value will be submitted to the CMC and the investigator will receive guidance from the CMC 
with regards to continuation of trial product. If the value is a screening value the subject can not be 
randomised and the subject should be referred to a thyroid specialist.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
5 of 6
These values were found in 0.18% of a population with thyroid nodular disease published by 
Constante et al1 Diagnostic evaluation will likely include ultrasound examination and if available 
and if there is no contraindication, subjects should undergo a pentagastrin stimulation test (Europe). 
Subjects with positive pentagastrin stimulation tests will be considered to undergo surgery. In the 
US where pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may 
add important clinical information informing the need for surgery. 
2.3
CT ≥ 20 and <50 ng/L
The value will be submitted to the CMC. If the subject is a screen failure the subject should be 
referred to a thyroid specialist for further evaluation.
These values are expected to be found in up to 1% of subjects. Based on data from Constante et al1,
the predictive value of calcitonin levels ≥ 20 and < 50 ng/L clinically significant C-cell disease 
begins to fall. However, up to 25% of these subjects had a positive pentagastrin stimulation test.  
The likelihood of having a medullary carcinoma >1 cm with calcitonin in this range is extremely 
low. 
2.4
CT ≥ 10 and < 20 ng/L
Confounding factors should be evaluated. If drugs potentially affecting calcitonin can be 
discontinued safely, calcitonin can be repeated after a washout period. Gastrin levels return to the 
normal range by ~10 days after stopping proton pump inhibitors (PPIs). No further actions are 
needed during the trial if the next calcitonin values remain below 20 ng/L.
If the subject is a screening failure or if the value is the last one taken in the trial, the subject should 
preferably be referred to a thyroid specialist for further evaluation.
These values may be found in ~2.5 to 4% of the trial population. Costante et al1 had 216 patients in 
this category. 1/216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell 
hyperplasia at surgery, a lesion of unknown clinical significance. Two other studies used a cutoff of 
CT > 10 ng/L to screen for C-cell disease, but they do not provide sufficient information on patients 
with basal CT >10 and <20 ng/L to allow conclusions2, 3.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
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, Vierhapper H, Bieglmayer C et al. Sporadic 
hypercalcitoninemia: clinical and therapeutic consequences. Endocr Relat 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.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
NN9924-3790
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 6
Appendix B
Questionnaires SF36v2™
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
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.


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
NN9924-3790
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 6
Your Health and Well-Being
This survey asks for your views about your health.  This information will help 
keep track of how you feel and how well you are able to do your usual 
activities. Thank you for completing this survey!
For each of the following questions, please mark an 
in the one box that best 
describes your answer.
1.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
 
 

 
 
  
1
  
2
  
3
  
4
  
5
2.
Compared to one year ago, how would you rate your health in general 
now?
Much better 
now than one 
year ago
Somewhat 
better 
now than one 
year ago
About the 
same as 
one year ago
Somewhat 
worse 
now than one 
year ago
Much worse 
now than one 
year ago
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
NN9924-3790
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 6
The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities?  If so, how much? 
4.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
     
a
Cut down on the amount of 
time you spent on work or 
other activities.................................
1 .............
2 .............
3 .............
4.............
5
b
Accomplished less than you 
would like........................................
1 .............
2 .............
3 .............
4.............
5
c
Were limited in the kind of 
work or other activities ...................
1 .............
2 .............
3 .............
4.............
5
d
Had difficulty performing the 
work or other activities (for 
example, it took extra effort)...........
1 .............
2 .............
3 .............
4.............
5
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
NN9924-3790
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 6
5.
During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or anxious)?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
     
a
Cut down on the amount of 
time you spent on work or 
other activities.................................
1 .............
2 .............
3 .............
4.............
5
b
Accomplished less than you 
would like........................................
1 .............
2 .............
3 .............
4.............
5
c
Did work or other activities 
less carefully than usual..................
1 .............
2 .............
3 .............
4.............
5
6.
During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with family, 
friends, neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
7.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very severe
      
  
1
  
2
  
3
  
4
  
5
  
6
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
NN9924-3790
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2012-004994-16
Page:
5 of 6
8.
During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
9.
These questions are about how you feel and how things have been with you 
during the past 4 weeks.  For each question, please give the one answer that 
comes closest to the way you have been feeling.  How much of the time 
during the past 4 weeks…
All of 
the time
Most of 
the time
Some of 
the time
A little of the 
time
None of 
the time
     
a Did you feel full of life?..................
1 .............
2 .............
3 .............
4 .............
5
b Have you been very nervous? .........
1 .............
2 .............
3 .............
4 .............
5
c Have you felt so down in the 
dumps that nothing could 
cheer you up? ..................................
1 .............
2 .............
3 .............
4 .............
5
d Have you felt calm and  
peaceful? .........................................
1 .............
2 .............
3 .............
4 .............
5
e Did you have a lot of energy? .........
1 .............
2 .............
3 .............
4 .............
5
f Have you felt downhearted 
and depressed? ................................
1 .............
2 .............
3 .............
4 .............
5
g Did you feel worn out?....................
1 .............
2 .............
3 .............
4 .............
5
h Have you been happy? ....................
1 .............
2 .............
3 .............
4 .............
5
i Did you feel tired?...........................
1 .............
2 .............
3 .............
4 .............
5
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
NN9924-3790
Version:
3.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2012-004994-16
Page:
6 of 6
10.
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)?
All of 
the time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
 
 
 
 
 
  
1
  
2
  
3
  
4
  
5
11.
How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly 
true
Don’t 
know
Mostly 
false
Definitely 
false

 


a
I seem to get sick a little
easier than other people...................
1 .............
2 .............
3..............
4 .............
5
b
I am as healthy as 
anybody I know...............................
1 .............
2 .............
3..............
4 .............
5
c
I expect my health to 
get worse .........................................
1 .............
2 .............
3..............
4 .............
5
d
My health is excellent .....................
1 .............
2 .............
3..............
4 .............
5
Thank you for completing these questions!
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 5
Appendix C
NN9924-3790
Multiple dose trial examining dose range, escalation and 
efficacy of oral semaglutide in subjects with type 2 diabetes
Medical events of special interest (MESI)
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
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.


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 5
Event Title
Definition
Rationale
1
Fatal events
All cause mortality: 
1. Cardiovascular death,
2. Non-cardiovascular death,
3. Undetermined cause of death
An FDA guidance 
document requests that 
sponsors demonstrate 
the cardiovascular 
safety profile of any 
new therapy for type 2 
diabetes, in order to 
ensure that the new 
therapy does not 
increase the 
cardiovascular risk to 
an unacceptable extend.
2
Acute coronary 
syndrome:
!
Myocardial
Infarction
!
Hospitalisation for
unstable angina
All types of myocardial 
infarction (MI) must be reported:
!
Spontaneous MI (including
re-infraction and MI
associated with stent
thrombosis)
!
Percutaneous coronary
intervention (PCI) related MI
!
Coronary artery bypass graft
surgery (CABG) related MI
!
Silent MI
All events with symptoms of 
myocardial ischemia requiring 
hospitalisation must be reported.
An FDA guidance 
document requests that 
sponsors demonstrate 
the cardiovascular 
safety profile of any 
new therapy for type 2 
diabetes, in order to 
ensure that the new 
therapy does not 
increase the 
cardiovascular risk to 
an unacceptable extend.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 5
Event Title
Definition
Rationale
3
Cerebrovascular event 
(stroke or transient 
ischemic attack)
Transient ischemic attack:
Transient ischemic attack (TIA) 
is defined as a transient (<24 
hours) episode of neurological 
dysfunction caused by focal 
brain, spinal cord, or retinal 
ischemia, without acute 
infarction.
Stroke (ischemic, haemorrhagic, 
undetermined):
Stroke is defined as an acute 
episode of neurological 
dysfunction caused by focal or 
global brain, spinal cord, or 
retinal vascular injury.
An FDA guidance 
document requests that 
sponsors demonstrate 
the cardiovascular 
safety profile of any 
new therapy for type 2 
diabetes, in order to 
ensure that the new 
therapy does not 
increase the 
cardiovascular risk to 
an unacceptable extend.
4
Coronary 
Revascularisation 
Procedure
Coronary Revascularization 
Procedure:
!
Coronary Artery Bypass
Graft Surgery
!
Percutaneous Coronary
Intervention
A coronary revascularization 
procedure is a catheter-based or 
open surgical procedure designed 
to improve myocardial blood 
flow.
An FDA guidance 
document requests that 
sponsors demonstrate 
the cardiovascular 
safety profile of any 
new therapy for type 2 
diabetes, in order to 
ensure that the new 
therapy does not 
increase the 
cardiovascular risk to 
an unacceptable extend.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 5
Event Title
Definition
Rationale
5
Heart failure requiring 
hospital admission3
Clinical manifestations of a new 
episode or worsening of an 
existing heart failure.
An FDA guidance 
document requests that 
sponsors demonstrate 
the cardiovascular 
safety profile of any 
new therapy for type 2 
diabetes, in order to 
ensure that the new 
therapy does not 
increase the 
cardiovascular risk to 
an unacceptable extend.
6
Pancreatitis or clinical 
symptoms leading to 
suspicion of 
pancreatitis
Two of the following diagnostic 
criteria fulfilling the diagnosis of 
acute pancreatitis: 
1. severe acute abdominal pain
2. elevated blood levels of
pancreatic enzymes (lipase,
amylase) > 3xUNR
3. characteristic imaging finding
(ultrasound, computerised
axial tomography (CT),
magnetic resonance imaging
(MRI))
Chronic pancreatitis will be 
defined by characteristic imaging 
finding (ultrasound, CT, MRI) 
with abnormal pancreatic 
function tests or characteristic 
histological findings.
Treatment with GLP-1 
agonists has been 
associated with acute 
pancreatitis and Novo 
Nordisk therefore 
monitors these events 
closely.
CONFIDENTIAL


Semaglutide
CONFIDENTIAL
Date:
21 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
3.0
Protocol - Appendix C
Status:
Final
EudraCT No.: 2012-004994-16
Page:
5 of 5
Event Title
Definition
Rationale
7
Neoplasm
(excluding thyroid 
neoplasms) 
All types of neoplasms must be 
reported including:
!
Malign neoplasm
!
In situ neoplasm
!
Benign neoplasm
!
Neoplasms of uncertain or 
unknown behaviour
Neoplasm is an event 
Novo Nordisk follows
closely for GLP-1 
analogues due to non-
clinical findings in rats 
and mice treated with 
GLP-1 agonists.
8
Thyroid disease 
(including thyroid 
neoplasms) 
All disorders of thyroid gland 
must be reported 
Thyroid C-cells 
carcinogenicity has 
been reported in rats 
and mice treated with 
GLP-1 agonists in non-
clinical studies
9
Medication errors 
concerning trial 
products
1. Administration of wrong 
drug or use of wrong device
2. Wrong route of 
administration, such as 
intramuscular instead of 
subcutaneous
3. Administration of a high dose 
with the intention to cause 
harm, e.g. suicide attempt
4. Administration of an 
accidental overdose, i.e.
a) a pre-defined threshold is 
exceeded OR 
b) a dose which may lead to 
significant health 
consequences, as judged by 
the investigator, irrespective 
of whether the SAE criteria 
are fulfilled or not.
Standard MESI in all 
Novo Nordisk clinical 
trials. 
Medication errors are 
captured to collect 
information which may 
be used to improve the 
design, name or 
packaging of the 
product and/or 
information which may 
have an impact on 
product labelling (for 
example information 
about substantial 
overdoses).
CONFIDENTIAL


Attachment I
CONFIDENTIAL
Date:
18 April 2013
Novo Nordisk
Trial ID:
Version:
0.1
UTN:
Status:
Draft
EudraCT No.:
Page:
1 of 3
Attachment I 
Global list of key staff and relevant departments and 
vendors of clinical relevance
Attachment versioning is independent of the protocol.
For CDP trials: To be completed and maintained by the International Trial Manager or 
Clinical Pharmacologist.
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.
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.


Attachment I
CONFIDENTIAL
Date:
18 April 2013
Novo Nordisk
Trial ID:
Version:
0.1
UTN:
Status:
Draft
EudraCT No.:
Page:
2 of 3
Mandatory for Japan: The responsibilities for each person/ vendors of clinical relevance must be 
described.
Sponsor:
Name:
Novo Nordisk
Address:
Sponsor’s global medical 
expert:
Name:
Title:
Address:
Tel:
Email
If multinational trial or clinical pharmacology CDP trial:
International Trial 
Manager(s):
Name:
Address:
Tel:
Fax:
Tel:
E-mail:
Customer Complaint Center,
Recipient of technical 
complaint samples:
Name:
Novo Nordisk A/S
Att: Customer Complaint Center
Address:
CONFIDENTIAL


Attachment I
CONFIDENTIAL
Date:
18 April 2013
Novo Nordisk
Trial ID:
Version:
0.1
UTN:
Status:
Draft
EudraCT No.:
Page:
3 of 3
List laboratory(ies), and other medical and/or technical department(s), and/or institutions involved 
in the trial that are of clinical relevance. If multiple labs are used, describe what each lab analyses 
and/or responsibility. Also include which lab provides the lab kit.
Laboratory(ies):
Name:
Address:
Tel:
Fax:
Mobile:
E-mail:
For eCRF, IV/WRS etc include each vendor:
eCRF vendor:
Name:
Address:
Tel:
Fax:
Mobile:
E-mail:
IV/WRS vendor:
Name:
Address:
Tel:
Fax:
Mobile:
E-mail:
CONFIDENTIAL


Attachment II
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 5
Attachment II
Insert name of country 
Consider to include country code in header
It is mandatory to obtain the information listed in attachment II, but the information can 
be captured and updated elsewhere (eg in local regulatory documents). Attachments I and 
II may be integrated into one document if convenient (eg for single centre trials). 
List of key staff and relevant departments
To be completed and maintained for each country
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.
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.


Attachment II
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 5
If monitored by a CRO:
Monitor:
Name:
Address:
Tel of the 
CRO:
CONFIDENTIAL


Attachment II
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 5
List for each trial site:
For countries in EU/EEA, state the National Coordinating Investigator
National Coordinating 
Investigator:
Name:
Title 
/qualification:
(Medical qualification [eg MD, DMD] of the 
investigator must be stated)
Address:
Tel:
Fax:
E-mail:
Investigator:
Name:
Title:
Address:
Tel:
CONFIDENTIAL


Attachment II
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 5
If the investigator is not a qualified physician, state responsible physician:
Responsible physician:
Name:
Title/qualifications:
Address:
(If different from above)
Tel:
Fax:
Mobile:
E-mail:
Mandatory if name(s) and address(es) of the laboratory(ies) and other medical and/or technical 
department(s) and/or institutions involved in the trial are not included in the protocol:
Local laboratory(ies):
Name:
Address:
Tel:
CONFIDENTIAL


Attachment II
CONFIDENTIAL
Date:
25 June 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
5 of 5
Other medical and/or
technical department(s)
and/or institution(s):
Name:
Address:
Tel:
CONFIDENTIAL


Protocol Amendment 
CONFIDENTIAL
Date:
05 September 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 4
Protocol Amendment
no 1
to Protocol, Final Version 1.0
dated 25 June 2013 
Trial ID:NN9924-3790
Multiple dose trial examining dose range, escalation and
efficacy of oral semaglutide in subjects with type 2 diabetes
Trial phase: 2
Applicable to Sweden
Amendment originator:
  
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.
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 Amendment 
CONFIDENTIAL
Date:
05 September 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 4
Table of contents
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
CONFIDENTIAL


Protocol Amendment 
CONFIDENTIAL
Date:
05 September 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
This local substantial amendment for Sweden implements the requirement for a changed definition 
on adequate contraceptive measures for patients participating in the trial in Sweden as requested by 
the Medical Products Agency (MPA).
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment 
CONFIDENTIAL
Date:
05 September 2013
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 4
2
Changes
2.1.
Section
6.3 Exclusion criteria
The following text will be changed under exclusion criteria No 3:
Sweden: Adequate contraceptive measures are hormonal intrauterine devices, hormonal oral 
contraceptives, hormonal implants or injections, double barrier (a condom or diaphragm) with 
spermicide, sexual abstinence or vasectomised partner.
is re-written according to the explicit request by the MPA to:
Sweden: Oral (except low-dose gestagen (lynestrenol and norestisteron)), injectable, or implanted 
hormonal contraceptives, intrauterine device, intrauterine system (for example, progestin-releasing 
coil), vasectomized male (with appropriate postvasectomy documentation of the absence of sperm 
in the ejaculate).
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 8
Protocol Amendment
no 2
to Protocol, final version 1.0
dated 25 June 2013
including all amendments
Trial ID: NN9924-3790
Multiple dose trial examining dose range, escalation and
efficacy of oral semaglutide in subjects with type 2 diabetes
Trial phase: 2
Applicable to all countries 
Amendment originator:
 
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.
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 Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 8
Table of contents
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 2.1 Flow chart foot notes ..................................................................................................4
2.2
Section 5.2 Rationale for trial design.............................................................................................4
2.3
Section 6.4 Rescue criteria.............................................................................................................4
2.4
Section 8.4.7 Electrocardiogram – 12-lead....................................................................................5
2.5
Section 8.4.10 Pharmacokinetics...................................................................................................5
2.6
Section 12.1 Definitions ................................................................................................................5
2.7
Section 12.2 Reporting of adverse events......................................................................................5
2.8
Section 12.7.2 Event adjudication committee................................................................................6
2.9
Section 17.1 Sample size calculation.............................................................................................6
2.10
Section 17.2 Definition of analysis sets.........................................................................................6
2.11
Section 17.3 Primary endpoint.......................................................................................................6
2.12
Section 17.4.2 Safety endpoints.....................................................................................................6
2.13
Section 25 Institutional Review Boards/Independent Ethics Committees and regulatory 
authorities.......................................................................................................................................7
2.14
Section 27 References....................................................................................................................8
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 8
1
Introduction including rationale for the protocol amendment
The HbA1c criterion will be removed as part of the rescue criteria during the treatment period. It has 
been judged that there is a risk of having an inappropriately high proportion of the subjects 
requiring rescue due to high HbA1c levels during the trial. Hence it has been decided to only assess 
the need for rescue medication based on confirmed fasting plasma glucose levels. As described in 
the statistical section, subjects on rescue medication will not be included in the primary analysis 
(only data up to the point of rescue) meaning that a high number of subjects on rescue medication 
could potentially invalidate the data and trial results. The investigator can at anytime during the trial 
decide to discontinue trial product and initiate other treatment if any safety issues are seen, 
consequently this change is not assessed to have any safety risks for the subjects.
The process of reporting central ECG evaluation back to investigator has been changed. Only 
clinically significant abnormal findings as evaluated by the central reader will be sent to the 
investigator. The investigators will do their own assessment at site, hence it is not relevant to inform 
the investigator of all findings as this would increase the workload significantly at the site without 
adding value with regards to the safety of the subject.
The ADA classification of hypoglycaemia has recently been updated. The protocol has been 
updated to be aligned with the new definition. Furthermore, the section on IRB and IEC has been 
updated to comply with the recent update of the Declaration of Helsinki.
The definition of thyroid events for adjudication has been updated to add clarity and to be aligned 
with the Event Adjudication Charter. Thyroid events must be reported for adjudication both in case 
of thyroid neoplasm AND in case of thyroidectomies regardless of indication.
In addition, minor inconsistencies and errors have been corrected.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 8
2
Changes
2.1
Section 2.1 Flow chart foot notes
x6: Trough and peak PK sampling is only applicable for subjects in the oral treatment arms and 
replaces the regular PK sampling for these subjects at visits 4, 8 and 11. Subjects must attend the 
visit without having taken the tablet on the same day (see Section 8.4.10)
x8: Fasting for lab sampling is defined as having consumed only water since midnight. For the 
Follow-up visit (V12) attending fasting is defined as having consumed only water for at least the 
preceding 2 hours. For the trough and peak PK sampling visits (V4, 8, 11) the fasting is outlined in 
section 5.3.1.
2.2
Section 5.2 Rationale for trial design
Parallel treatment groups and a randomised partially-blinded, controlled design have been chosen in 
accordance with the trial objectives. To avoid bias in the assessment of the different doses of oral 
semaglutide, the eight oral treatment arms are double-blind. The doses are escalated in standard four 
week intervals to limit gastrointestinal AEs. Escalation intervals of two weeks and six eight weeks 
are also being explored to investigate effect on onset of action and overall AEs.
2.3
Section 6.4 Rescue criteria
Subjects with unacceptable hyperglycaemia should be offered treatment intensification (rescue 
medication) according to local label at the discretion of the investigator as add-on to randomised 
treatment and should continue to follow the protocol-specified visit schedule. Rescue medication 
should exclude other incretin-based therapies such as other GLP-1 receptor agonists, DPP-4 
inhibitors and amylin analogues.
Unacceptable hyperglycaemia in this trial is defined as:
!
FPG >15 mmol/L (270 mg/dL) from baseline to week 6
!
FPG >13.3 mmol/L (240 mg/dL) from week 6 to week 12
!
FPG >11.1 mmol/L (200 mg/dL) or HbA1c > 8.0% (64 mmol/mol) from week 12 to end of trial
If any of the FPG values exceed the limits outlined below and no intercurrent cause of the 
hyperglycaemia can be identified the subject should be offered treatment intensification (rescue 
medication):
!
15.0 mmol/L (270 mg/dL) from randomisation to end of Week 5
!
13.3 mmol/L (240 mg/dL) from Week 6 to end of Week 11
!
11.1 mmol/L (200 mg/dL) from Week 12 to end of trial
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
5 of 8
A confirmatory FPG should be obtained by central laboratory if related to a scheduled visit or by
local laboratory if not related to scheduled visits. If the confirmatory FPG exceeds the values 
described above the subject should be offered treatment intensification (rescue medication) at the 
discretion of the investigator and in accordance with ADA/European Association for the Study of 
Diabetesa (preferably excluding GLP-receptor agonists, DPP-4 inhibitors and amylin analogues). 
Rescue medication (intensification of existing background medication and/or initiation of new 
medication) and any changes to this should be captured on the concomitant medication form in the 
eCRF. Rescue medication should be prescribed as add-on to randomised treatment and subjects 
should continue to follow the protocol-specified visit schedule.
Reference a added see section 2.14
2.4
Section 8.4.7 Electrocardiogram – 12-lead
Sites will be informed of the central ECG evaluation in case this evaluation reveals an abnormal,
clinically significant ECG reading. If the abnormality represents an unreported AE, SAE or MESI, 
such findings must be reported if the investigator finds the abnormality clinically significant (see 
Section 8.1.11).
2.5
Section 8.4.10 Pharmacokinetics
For subjects on oral treatment, three of the PK sampling assessments will be pre-dose and post-
dose (trough and peak) only Subjects on oral treatment will also have PK measured pre-dose and 
post-dose (trough and peak) at three visits (see Section 2). At the visits for trough and peak PK 
measurements, the investigator needs to ensure that the subjects on oral treatment follow these 
procedures:
2.6
Section 12.1 Definitions
Medical event of special interest
A medical event of special interest (MESI) is an event which, in the evaluation of safety, has a
special focus. A MESI is an AE (SAE or non-serious AE) which fulfils one or more of the below
defined MESI criteria.
8. Thyroid Disease ((A) if thyroidectomy is required)((A) if thyroid neoplasm or resulting in 
thyroidectomy)
2.7
Section 12.2 Reporting of adverse events
All events meeting the definition of an AE must be collected and reported. This includes events
from when the first trial-related activity after the subject has signed the informed consent until the 
end of the post-treatment follow-up period. The events must be recorded in the applicable eCRF 
forms in a timely manner (see timelines below and Figure 12–1).
All AEs, either observed by the investigator or reported by the subject, must be reported by the
investigator and evaluated. Novo Nordisk assessment of expectedness is performed according to the
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
6 of 8
following reference document: IB (Oral Administration of Semaglutide (NN9924)) section 6.2.6.1 
Reference safety information, Edition 56 and any updates hereof.
2.8
Section 12.7.2 Event adjudication committee
!
Thyroid Disease (if thyroidectomy is requiredif thyroid neoplasm or resulting in 
thyroidectomy))
2.9
Section 17.1 Sample size calculation
A standard deviation (SD) of 1.2% for change from baseline in HbA1c is chosen as assumption for 
the sample size calculation. The SD observed in several phase 3 trials of 26 weeks duration with s.c. 
liraglutide suggests a standard deviation less than 1.1%. However, as it is uncertain if the added 
variation in exposure compared to s.c. liraglutidesemaglutide will transfer to an added variation in 
the therapeutic response, a SD of 1.2% is assumed.
2.10
Section 17.2 Definition of analysis sets
Safety Analysis Set (SAS): includes all subjects exposed to at least one dose of randomised
liraglutidesemaglutide or liraglutidesemaglutide placebo. Subjects in the SAS will contribute to the 
evaluation “as treated”.
2.11
Section 17.3 Primary endpoint
Due to the uncertainty in relation to if the added variation in the exposure in the oral semaglutide 
arms compared to s.c. liraglutide semaglutide will transfer to an added variation in the therapeutic 
response, a sensitivity analysis allowing the within subject unstructured covariance matrix to be 
fitted separately for each treatment arm will be conducted.
2.12
Section 17.4.2 Safety endpoints
Confirmed hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 
3.1mmol/L (56 mg/dL)13. Therefore, Novo Nordisk has included hypoglycaemia with plasma 
glucose levels below this cut-off point in the definition of confirmed hypoglycaemia.
Confirmed hypoglycaemic episodes are defined as episodes that are:
!
severe (i.e., an episode requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions)according to the ADA classification 
below and/or
!
biochemically confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with or 
without symptoms consistent with hypoglycaemia
ADA classificationb of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. other resuscitative 
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
7 of 8
actions. Plasma glucose concentrations may not be available during an event, but 
neurological recovery following the return of plasma glucose back to normal is considered 
sufficient evidence that the event was induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of 
hypoglycaemia, but with a measured plasma glucose concentration ≤ 3.9 mmol/L (70 
mg/dL)
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of 
hypoglycaemia are accompanied by a measured plasma glucose concentration ≤ 3.9 mmol/L 
(70 mg/dL).
!
RelativePseudo-hypoglycaemia: An episode during which the person with diabetes reports 
any of the typical symptoms of hypoglycaemia, and interprets those as indicative of 
hypoglycaemia, but with a measured plasma glucose 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 plasma glucose determination (but that was 
presumably caused by a plasma glucose concentration ≤ 3.9 mmol/L ([70 mg/dL]).
Figure 17–1 ADA classification of hypoglycaemia
Reference b added see section 2.14
2.13
Section 25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
16 January 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
8 of 8
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or sponsor, 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, substantial protocol amendments, non-substantial 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 risk/benefit 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 clinical trial report synopsis to the IRB/IEC.
2.14
Section 27 References
2     World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research
Involving Human Subjects. 59th WMA General Assembly, Seoul. 1-Oct-2008. Last amended by the 
64th WMA General Assembly, Fortaleza, Brazil, October 2013
a    Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management 
of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the 
American Diabetes Association (ADA) and the European Association for the Study of Diabetes 
(EASD). Diabetes Care 2012 Jun;35(6):1364-79.
b     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 36: 1384-1395, 2013
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 April 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 4
Protocol Amendment
no 3
to Protocol, final version 1.0
dated 25 June 2013
including all amendments
Trial ID: NN9924-3790
Multiple dose trial examining dose range, escalation and
efficacy of oral semaglutide in subjects with type 2 diabetes
Trial phase: 2
Applicable to Germany
Amendment originator:
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.
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 Amendment
CONFIDENTIAL
Date:
28 April 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 4
Table of contents   
Page
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................4
2.1
Section 6.4 Rescue criteria.............................................................................................................4
CONFIDENTIAL


Protocol Amendment
CONFIDENTIAL
Date:
28 April 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
3 of 4
1
Introduction including rationale for the protocol amendment
According to the deficiency letter from 
from 28-Feb-
2014, the global substantial Amendment no 2 to Protocol, final version 1.0 dated 25 June 2013, 
final version 1.0, dated 16 January 2014 will be amended by this document for 
.
The HbA1c criterion will be removed as part of the rescue criteria during the treatment period. It 
has been judged that there is a risk of having an inappropriately high proportion of the subjects 
requiring rescue due to high HbA1c levels during the trial. Hence it has been decided to only assess 
the need for rescue medication based on confirmed fasting plasma glucose levels. As described in 
the statistical section, subjects on rescue medication will not be included in the primary analysis 
(only data up to the point of rescue) meaning that a high number of subjects on rescue medication 
could potentially invalidate the data and trial results. The investigator can at any time during the 
trial decide to discontinue trial product and initiate other treatment if any safety issues are seen, 
consequently this change is not assessed to have any safety risks for the subjects.
To ensure proper treatment respectively treatment intensification of subjects, the rescue FPG 
criteria will be lowered from 200 mg/dl to 180 mg/dl from week 12 and onwards. 
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
CONFIDENTIAL
PPI


Protocol Amendment
CONFIDENTIAL
Date:
28 April 2014
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U1111-1136-4716
Status:
Final
EudraCT No.: 2012-004994-16
Page:
4 of 4
2
Changes
2.1
Section 6.4 Rescue criteria
Subjects with unacceptable hyperglycaemia should be offered treatment intensification (rescue 
medication) according to local label at the discretion of the investigator as add-on to randomised 
treatment and should continue to follow the protocol-specified visit schedule. Rescue medication 
should exclude other incretin-based therapies such as other GLP-1 receptor agonists, DPP-4 
inhibitors and amylin analogues.
Unacceptable hyperglycaemia in this trial is defined as:
!
FPG >15 mmol/L (270 mg/dL) from baseline to week 6
!
FPG >13.3 mmol/L (240 mg/dL) from week 6 to week 12
!
FPG >11.1 mmol/L (200 mg/dL) or HbA1c > 8.0% (64 mmol/mol) from week 12 to end of trial
If any of the FPG values exceed the limits outlined below and no intercurrent cause of the 
hyperglycaemia can be identified the subject should be offered treatment intensification (rescue 
medication):
!
15.0 mmol/L (270 mg/dL) from randomisation to end of Week 5
!
13.3 mmol/L (240 mg/dL) from Week 6 to end of Week 11
!
11.1 mmol/L (200 mg/dL) 10.0 mmol/L (180 mg/dL) from Week 12 to end of trial
A confirmatory FPG should be obtained by central laboratory if related to a scheduled visit or by 
local laboratory if not related to scheduled visits. If the confirmatory FPG exceeds the values 
described above the subject should be offered treatment intensification (rescue medication) at the 
discretion of the investigator and in accordance with ADA/European Association for the Study of 
Diabetesa (preferably excluding GLP-receptor agonists, DPP-4 inhibitors and amylin analogues). 
Rescue medication (intensification of existing background medication and/or initiation of new 
medication) and any changes to this should be captured on the concomitant medication form in the 
eCRF. Rescue medication should be prescribed as add-on to randomised treatment and subjects 
should continue to follow the protocol-specified visit schedule.
CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT01923181 
Sponsor trial ID: 
NN9924-3790 
Official title of study: 
Multiple dose trial examining dose range, escalation and 
efficacy of oral semaglutide in subjects with type 2 diabetes 
Document date: 
01 July 2015 
 


Link
Link
List of contents
Statistical analysis plan.....................................................................................................................
DBL stat memo..................................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Oral GLP-1
Trial ID: NN9924-3790
Clinical Trial Report
Appendix 16.1.9
01 July 2015
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL
CONFIDENTIAL


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
1 of 551
Statistical Analysis Plan
Trial ID: NN9924-3790
Multiple dose trial examining dose range, escalation and
efficacy of oral semaglutide in subjects with type 2 diabetes
Author:
Click here to enter text.
Click here to enter text.
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.
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 VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
2 of 551
Table of contents
Page
Table of contents...............................................................................................................................................2
List of abbreviations.........................................................................................................................................4
1
Introduction...............................................................................................................................................5
1.1
Trial information............................................................................................................................5
1.2
Scope of the statistical analysis plan..............................................................................................5
2
Statistical considerations ..........................................................................................................................5
2.1
Sample size calculation..................................................................................................................6
2.2
Definition of analysis sets..............................................................................................................6
2.3
Definition of baseline.....................................................................................................................6
2.4
Definition of observation periods ..................................................................................................6
In-trial observation period..............................................................................................................7
On-treatment observation period ...................................................................................................7
On-treatment without rescue:.........................................................................................................8
2.5
Imputation of missing observations...............................................................................................8
2.6
Primary endpoint............................................................................................................................9
2.7
Supportive secondary endpoints ..................................................................................................10
2.7.1
Efficacy endpoints .....................................................................................................10
2.7.2
Safety endpoints.........................................................................................................11
2.7.3
Pharmacokinetics and/or pharmacodynamics modelling...........................................15
2.8
End of text outputs for subject disposition and demographics ....................................................16
2.9
End of text outputs for efficacy endpoints...................................................................................16
2.10
End of text outputs for safety endpoints ......................................................................................18
2.11
Listings.........................................................................................................................................22
3
Changes to the statistical analyses planned in the protocol.................................................................22
4
Pre-defined groups of adverse events....................................................................................................24
4.1
Gastrointestinal adverse events....................................................................................................24
4.2
Allergic reactions.........................................................................................................................63
4.3
Antibody adverse events..............................................................................................................72
4.4
Calcitonin adverse events ............................................................................................................74
4.5
Cardiovascular adverse events.....................................................................................................74
4.6
Gallbladder disease adverse events............................................................................................124
4.7
Immune complex adverse events...............................................................................................129
4.8
Injection site reactions ...............................................................................................................138
4.9
Elevated lipase and/or amylase adverse events..........................................................................152
4.10
Medication error adverse events................................................................................................153
4.11
Neoplasm adverse events...........................................................................................................168
4.12
Overdose adverse events............................................................................................................343
4.13
Pancreatic carcinoma adverse events.........................................................................................344
4.14
Pancreatitis adverse events ........................................................................................................346
4.15
Thyroid adverse events ..............................................................................................................348
4.16
Transmission adverse events......................................................................................................356
4.17
Rare adverse events ...................................................................................................................358
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4.18
Renal failure adverse events ......................................................................................................449
4.19
Malignant tumour adverse events..............................................................................................452
5
References..............................................................................................................................................551
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List of abbreviations
AE
Adverse event
ANCOVA
Analysis of covariance
BMI
Body mass index
CI
Confidence interval
CRF
Case report form
CTR
Clinical trial report
EoT
End-of-text
LOCF
Last observation carried forward
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamics
PK
Pharmacokinetics
PP
Per protocol
SAE
Serious adverse event
SAP
Statistical analysis plan
SD
Standard deviation
SE
Standard error
TEAE
Treatment emergent adverse event
MMRM
Mixed model for repeated measures
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1
Introduction
1.1
Trial information
This is a randomised, partially-blinded, multiple-dose, multicentre trial with a total of nine 
treatment arms; seven oral semaglutide treatment arms, one oral placebo arm and one open-label 
subcutaneous (s.c.) semaglutide arm in a parallel design. The trial will include subjects with T2D 
who have failed on diet and exercise and/or metformin.
The primary objective of the trial is to compare the efficacy on glycaemic control of oral 
semaglutide in a SNAC formulation against placebo in subjects with T2D.
1.2
Scope of the statistical analysis plan
This statistical analysis plan (SAP) is based on the protocol “3790-consolidated-protocol-file-
protocol-version-3 0”, that is, the consolidated version 3 which includes protocol amendments one 
and two. 
This SAP contains a more technical and detailed elaboration of the statistical analyses specified in 
the statistical section of the protocol. . 
2
Statistical considerations
Results from the statistical analysis will generally be presented by two-sided confidence intervals
with a confidence level of 95% including a p-value for test of no difference between treatments.
The stratification variable referred to in the following is defined as the two level factor of treatment
with metformin (yes/no).
The “planned comparisons between treatment arms” referred to in this section covers the following
comparisons: a) between each of the oral semaglutide treatment arms and placebo, b) between the
s.c. semaglutide arm and placebo, c) between each of the oral semaglutide treatment arms and s.c.
semaglutide, and d) between the three oral semaglutide treatment arms with an end dose of 40 mg.
A standard mixed model for repeated measurements (from now on referred to as “the standard 
MMRM”) will be used in the analysis of the primary and continuous secondary endpoints. The 
model will include treatment, country and the stratification variable as fixed factors, and the 
corresponding baseline value as covariate. All factors and the covariate will be nested within visit. 
The model will assume an unstructured covariance matrix within subject. 
Unless otherwise stated, the estimated differences with corresponding two sided p-values and 95% 
confidence intervals at 26 weeks will be presented for the planned comparisons between treatment 
arms.
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The patient years observation time (PYO) used in e.g. the calculation of AE rates will for an 
observation period be calculated as the difference between start-date and end-date, both inclusive. 
Values of laboratory parameters below the blower limit of quantification (LLOQ) will be set to
LLOQ/2.
The stratification variable “Treatment with metformin at screening (yes/no)” will based on the 
actual information on concomitant medication recorded through the eCRF. 
2.1
Sample size calculation
Please refer to section 17.1 of the protocol. 
2.2
Definition of analysis sets
Full Analysis Set (FAS): includes all randomised subjects who have received at least one dose of 
randomised semaglutide (oral or s.c.) or semaglutide placebo. Subjects in the FAS will contribute to 
the evaluation based on their randomised treatment.
Safety Analysis Set (SAS): includes all randomised subjects who have received at least one dose of 
randomised semaglutide (oral or s.c.) or semaglutide placebo. Subjects in the SAS will contribute to 
the evaluation based on their actual treatment.
Before data are locked for statistical analysis, a review of all data will take place. Any decision to
exclude a subject or single observations from the statistical analysis is the joint responsibility of the
members of the study group. Exclusion of data from analyses will 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 clinical trial report (CTR).
2.3
Definition of baseline
For each lab parameter and each vital sign, the baseline assessment is defined as the last valid 
measurement at or before the randomisation visit (visit 2). This specifically implies that if a visit 2 
assessment is missing (whether it’s planned or not planned) then the screening assessment (from 
visit 1) will be used as the baseline assessment, if available.
2.4
Definition of observation periods
Unless subjects withdraw their informed consent, data collection will continue for the full duration 
of the trial. 
The data for all tables, listings and figures developed for this trial will be selected in a two-step 
fashion.
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In the first step, the population of subjects for the specific analysis is selected based on the specified 
analysis set (either the full analysis set or the safety analysis set). 
In the second step, observations for the subjects in the analysis set are selected according to whether
or not they belong to a specified observation period. Observations that do not belong to the 
specified observation period will be treated as missing for the specific output. 
In this trial, three observation periods will be defined, as described below. One observation period
will be primary when selecting data related to efficacy and another will be primary when selecting 
data related to safety. The last observation period is considered supportive. Notice that for 
adjudicated events, onset date will be the EAC adjudicated onset date.
The three observation periods are:
In-trial observation period
In-trial: This observation period represents the time period in which a subject is considered a
participant and where data are collected systematically. This observation period will be used for 
supportive analyses of both efficacy and safety. The in-trial observation period includes 
observations recorded at or after randomisation and not after the last subject-investigator contact, 
which is scheduled to take place 5 weeks after planned last dose of trial treatment at a follow-up 
visit (visit 12). 
For subjects that prematurely discontinue treatment, their in-trial observation period will end with 
visit 11X if this comes after their follow-up visit. 
For subjects that withdraw their informed consent and do not attend visit 11, nor visit 12, their in-
trial observation period ends at their date of withdrawal. 
If a subject is lost to follow-up, the end of the in-trial observation period is defined as the date of the 
last subject-investigator contact (site or phone visit).
On-treatment observation period
On-treatment: This observation period is a subset of the in-trial observation period, namely the part 
where the subject is considered to be exposed to trial treatment. 
For adverse events and hypoglycaemic episodes, this period includes those observations from the 
in-trial observation period that are recorded on or after the date of first dose of trial treatment and 
not after the end of the 5 week washout period that follows the date of last dose of trial treatment. 
The follow-up visit is scheduled to take place 5 weeks after the date of last dose of trial product 
with a visit window of +5 days. For adverse events and hypoglycaemic episodes, the end-date for 
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the on-treatment observation period is therefore defined as the first date encountered after 
randomisation of the following dates [date of visit 12, date of last dose + 40 days, end-date for the 
in-trial observation period], using the convention that a missing date is set to infinity.
For other endpoints than adverse events and hypoglycaemic episodes, including both safety and 
efficacy, but with the exception of anti-semaglutide antibodies, the end-date for the on-treatment 
observation period will be defined as [date of visit 12, date of last dose + 7 days, end-date for the 
in-trial observation period], that is, similarly to above, but adding the s.c. dosing interval of 1 week 
to the date of last dose instead of 40 days. The on-treatment observation period will not be used to 
analyse anti-semaglutide antibodies.
The on-treatment observation period is the primary observation period for examination of safety 
endpoints including adverse events and hypoglycaemic episodes. 
The definition of the on-treatment period for adverse events and hypoglycaemic episodes 
corresponds to the protocol definition of the treatment emergent period. 
On-treatment without rescue: 
On-treatment without rescue: This observation period is a subset of the on-treatment observation 
period. To avoid potential confounding of initiation of anti-diabetic rescue therapies on efficacy 
endpoints, information that is collected after initiation of anti-diabetic rescue therapies are excluded 
from this observation period. Specifically, it includes observations recorded at or after date of first 
dose of trial treatment and not after the first occurrence of the following 
-
the end-date of the on-treatment observation period
-
initiation of rescue medication
This observation period is the primary observation period for examination of efficacy endpoints. 
We will use the convention that all baseline assessments belong to each of the observation periods.
2.5
Imputation of missing observations
Missing observations for laboratory parameters and vital signs will be imputed with two methods: 
last observation carried forward (LOCF), where missing observations are imputed as the last post-
baseline available value obtained prior to the missing assessment, and by prediction from the 
standard MMRM for the specific endpoint, where missing observations are imputed as the value 
that is predicted by the MMRM model. The MMRM imputations will be based on the randomised 
treatment and carried out for those endpoints where the standard MMRM analysis is part of the 
examination. 
For subjects that have no post-baseline assessment of a given endpoint, no imputation will be done
for this endpoint. 
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Note that the LOCF and MMRM imputations depend on the considered observation period, and 
separate imputation for the three observation periods will be carried out. 
2.6
Primary endpoint
The primary endpoint, change from baseline to end of treatment (i.e., after 26 weeks of treatment)
in HbA1c, will be analysed by the standard MMRM.
In order to confirm efficacy of oral semaglutide without risk of inflation of the type 1 error an initial
comparison of the primary endpoint will be made between a) the pool of the two treatment arms 
using standard and fast escalation regimens to an end dose of 40 mg and b) placebo. The 
comparison will be made by pooling the standard 40 mg arm and the fast 40 mg arm and then 
estimating the treatment difference between this pooled group and the placebo group by the 
standard MMRM. The estimated treatment difference with corresponding two sided p-value and 
95% confidence interval at 26 weeks will be presented, and efficacy of oral semaglutide will be
considered confirmed if the upper limit of the confidence interval is strictly less than zero.
If efficacy of oral semaglutide is confirmed, the planned comparisons between the nine original
treatment arms will be evaluated.
Subjects in the FAS and only measurements belonging to the on-treatment without rescue 
observation period will be included in the analysis.
Due to the uncertainty in relation to if the added variation in the exposure in the oral semaglutide
arms compared to s.c. semaglutide will transfer to an added variation in the therapeutic response, a
sensitivity analysis allowing the within subject unstructured covariance matrix to be fitted
separately for each treatment arm will be conducted.
Furthermore, the following sensitivity analyses will be conducted in order to investigate the
sensitivity of the results due to the impact of missing values:
!
An MMRM similar to the primary analysis but for the in-trial observation period.
!
An analysis of covariance (ANCOVA) model including subjects in the FAS and using
imputation of missing values according to the last observation carried forward (LOCF) 
method. The model will include fixed factors for treatment, country and the stratification 
variable and the baseline value as covariate and will be based on the on-treatment period. 
!
A complete case analysis, i.e. an ANCOVA similar to the one above including only data 
obtained at 26 weeks from subjects who:
o
did not discontinue treatment prematurely
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o
did not receive rescue therapy
o
had a valid HbA1c assessment at baseline and after 26 weeks of treatment
2.7
Supportive secondary endpoints
2.7.1
Efficacy endpoints
The FAS will be used in all analyses of the supportive secondary efficacy endpoints. The on-
treatment without rescue observation period will be the primary observation period for examination 
of efficacy endpoints. The specific outputs developed for efficacy endpoints will be detailed in 
section 2.7.3.
Subjects who, after 26 weeks of treatment, achieve (yes/no) HbA1c <7% (53 mmol/mol)
The binary endpoint will be analysed by a logistic regression model which will include fixed factors
for treatment and the stratification variable and baseline HbA1c as a covariate. Estimated odds
ratios with corresponding two sided p-values and 95% confidence intervals at 26 weeks will be
presented for the planned comparisons between treatment arms. Missing response data at 26 weeks 
will be imputed from the MMRM used for the primary analysis of HbA1c.
Change from baseline to week 26 in body weight, waist circumference and fasting plasma
glucose
These endpoints will be analysed by the standard MMRM. Both absolute (kg) and relative change 
from baseline (%) in body weight will be analysed. 
Subjects with at least 5 % weight loss after 26 weeks of treatment (yes/no) and subjects with 
more than 10 % weight loss added after 26 weeks of treatment (yes/no)
These binary endpoints will be analysed by separate logistic regression models which will include 
fixed factors for treatment and the stratification variable and baseline body weight as a covariate. 
Estimated odds ratios with corresponding two sided p-values and 95% confidence intervals at 26 
weeks will be presented for the planned comparisons between treatment arms. Missing response 
data at 26 weeks will be imputed from the MMRM used for the analysis of body weight.
Change from baseline to week 26 in C-peptide, fasting insulin, glucagon, HOMA-IR, HOMA-
B, total cholesterol, LDL-cholesterol, HDL-cholesterol, VLDL-cholesterol, triglycerides and
free fatty acids
For each endpoint, the assessments at every week will be log-transformed and subsequently
analysed by the standard MMRM. The estimated differences and corresponding 95% confidence
intervals at 26 weeks will be back transformed and presented as ratios together with the two sided
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p-values. Standard errors of the back transformed estimated means will be calculated using the 
Delta-methodi. 
The fasting HOMA endpoints (i.e., fasting HOMA-B and HOMA-IR) will be calculated based on
fasting insulin and FPG as follows:
1. Fasting HOMA-B (%) = 20 x fasting insulin [PU/ml]/(FPG[mmol/L]-3.5)
2. Fasting HOMA-IR (%) = fasting insulin [PU/ml] x FPG [mmol/L]/22.5
PRO outcomes
The outcomes from the SF-36 questionnaire in terms of total scores overall and within each domain 
will be calculated. Each of these scores will be analysed by the standard MMRM.
2.7.2
Safety endpoints
All safety endpoints will be summarised and analysed using the safety analysis set. The on-
treatment observation period will be the primary observation period for examination of all safety 
endpoints. 
Adverse events
All AEs will be coded using the most recent version of the Medical Dictionary for regulatory
Activities (MedDRA) coding. This is version 17.1. A TEAE is an event that has onset date (or 
increase in severity) during the on-treatment observation period. On-treatment AEs are summarised 
descriptively. These are supported by outputs including all in-trial adverse events, i.e. AEs with 
onset date (or increase in severity) during the in-trial observation period. Adverse events with onset 
after the end of the in-trial observation period will be reported in a listing. 
Most frequent adverse events will be defined as preferred terms that are experienced by at least 5% 
of the subjects in any of the treatment arms. 
Based on MedDRA searches, 19 pre-defined groups of adverse events will be evaluated. These are 
defined by Global Safety and consist of pre-specified preferred terms. The groups are the following: 
-
Gastrointestinal adverse events
-
Allergic reactions
-
Antibody adverse events
-
Calcitonin adverse events
-
Cardiovascular adverse events
-
Gallbladder disease adverse events
-
Immune complex adverse events
-
Injection site reactions
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-
Elevated lipase and/or amylase adverse events
-
Medication error adverse events
-
Neoplasm adverse events
-
Overdose adverse events
-
Pancreatic carcinoma adverse events
-
Pancreatitis adverse events
-
Thyroid adverse events
-
Transmission adverse events
-
Rare adverse events
-
Renal failure adverse events
-
Malignant tumour adverse events
The definition of rare adverse events is based on a publication by Shakir from 2005 
(Pharmacoepidemiology, Fourth Edition), called "Prescription-Event Monitoring". For complete 
listings of preferred terms included in the pre-defined groups of adverse events see section 4.
Number of confirmed treatment emergent hypoglycaemic episodes
A hypoglycaemic episode will be defined as treatment emergent if the onset of the episode occurs
during the on-treatment period. Hypoglycaemic episodes are classified according to the Novo 
Nordisk classification of confirmed hypoglycaemia and the ADA classification of hypoglycaemia 
(see Figure 1: ADA classification of hypoglycaemia).
Confirmed hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1
mmol/L (56 mg/dL)ii. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose
levels below this cut-off point in the definition of confirmed hypoglycaemia.
Confirmed hypoglycaemic episodes are defined as episodes that are:
!
severe according to the ADA classification below and/or
!
biochemically confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with or 
without symptoms consistent with hypoglycaemia
Severe or BG confirmed symptomatic hypoglycaemia
!
severe according to the ADA classification below and/or
!
biochemically confirmed by a plasma glucose value of <3.1 mmol/L (56 mg/dL), with 
symptoms consistent with hypoglycaemia
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ADA classificationiii of hypoglycaemia
!
Severe hypoglycaemia: An episode requiring assistance of another person to actively 
administer carbohydrate, glucagon, or take other corrective actions. Plasma glucose 
concentrations may not be available during an event, but neurological recovery following 
the return of plasma glucose back to normal is considered sufficient evidence that the event 
was induced by a low plasma glucose concentration.
!
Asymptomatic hypoglycaemia: An episode not accompanied by typical symptoms of
hypoglycaemia, but with a measured plasma glucose concentration S 3.9 mmol/L (70 
mg/dL)
!
Documented symptomatic hypoglycaemia: An episode during which typical symptoms of
hypoglycaemia are accompanied by a measured plasma glucose concentration S 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 plasma glucose 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 plasma glucose determination (but that was 
presumably caused by a plasma glucose concentration S 3.9 mmol/L (70 mg/dL).
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Figure 1: ADA classification of hypoglycaemia
Data on treatment emergent hypoglycaemic episodes will be summarised descriptively using the
above definitions.
The number of confirmed treatment emergent hypoglycaemic episodes during 26 weeks treatment
will be analysed using a negative binomial regression model with a log-link function and the
logarithm of the time period in which an occurrence of a hypoglycaemic episode is considered
treatment emergent as offset. The model will include treatment, country and stratification variable
as fixed factors and baseline HbA1c as covariate. Estimated rate ratios with corresponding two 
sided p-values and 95% confidence intervals at 26 weeks will be presented for the planned 
comparisons between treatment arms.
The number of subjects experiencing one or more confirmed treatment emergent hypoglycaemic 
episode will be analysed using a logistic regression model with fixed factors for treatment and the 
stratification variable and baseline HbA1c as a covariate. Estimated odds ratios with corresponding 
two sided p-values and 95% confidence intervals at 26 weeks will be presented for the planned 
comparisons between treatment arms.
Similar analyses for severe or BG confirmed symptomatic hypoglycaemic episodes will be 
conducted.
Change in pulse, systolic- and diastolic blood pressure from baseline to after 26 weeks of
treatment
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These endpoints will be analysed by the standard MMRM.
Change in amylase and lipase from baseline to after 26 weeks of treatment
For each endpoint, the assessments at every week will be log-transformed and subsequently 
analysed by the standard MMRM. The estimated differences and corresponding 95% confidence 
intervals at 26 weeks will be back transformed and presented as ratios together with the two sided 
p-values. Standard errors of the means will be calculated using the Delta-method. 
Change from baseline to after 26 weeks of treatment in electrocardiogram (ECG), physical
examination, laboratory safety variables (haematology, biochemistry, hormone and
urinalysis) other than amylase and lipase
These endpoints will be summarised by descriptive statistics. 
Endpoints related to occurrence of anti-semaglutide antibodies during 26 weeks of treatment:
Antibody level during 26 weeks of treatment, anti-semaglutide antibodies (positive/negative),
antisemaglutide antibodies with in vitro neutralising effect (positive/negative), 
antisemaglutide antibodies cross reacting with endogenous GLP-1 (positive/negative), cross
reacting antibodies with in vitro neutralising effect to endogenous GLP-1 (positive/negative)
These endpoints will be summarised by descriptive statistics and correlated to PK and PD.
Categorical summary tables for the occurrence of antibodies by treatment week as well as for 
occurrence of antibodies versus mean HbA1c and versus mean trough PK value will be produced. 
In addition, scatter plots of antibody level (%B/T) vs. HbA1c and vs. trough PK value will be 
developed. 
2.7.3
Pharmacokinetics and/or pharmacodynamics modelling
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk A/S and 
will be reported separately from the CTR. 
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2.8
End of text outputs for subject disposition and demographics
To describe the trial population, descriptive tables for the disposition of subjects amongst the two 
analysis sets and treatment/trial completion statuses will be developed. 
The time from randomisation to withdrawal, premature treatment discontinuation and initiation of 
rescue medication, and the duration of the three observation periods will be examined with 
descriptive figures. 
Baseline characteristics for continuous and categorical variables will be summarised in descriptive 
tables. 
Descriptive tables for general medical history, history of cardiovascular and gall bladder disease
and concomitant medication will be developed. 
2.9
End of text outputs for efficacy endpoints 
As mentioned above, the primary observation period used for examination of efficacy endpoints 
will be the on-treatment without rescue observation period. For safety endpoints the primary 
observation period will be the on-treatment observation period. Outputs will be based on data in SI 
units, and where applicable they will be repeated for conventional units. This will among other 
endpoints apply to HbA1c, where data is collected in both “%” and “mmol/mol”. The analysis of 
HbA1c in “%” is considered primary. 
The specific outputs developed for the different endpoints are detailed here below. 
Continuous efficacy endpoints
For continuous efficacy endpoints the end of text outputs will constitute of: 
-
Tables with descriptive statistics for observed values as well as change from baseline
-
Tables with results of statistical analyses including estimated means (LS means) for week 26 
values as well as for change from baseline to week 26, and in addition estimated treatment 
differences/ratios for the planned comparisons of treatment arms
-
Panel plots with mean of observed as well as change from baseline values over time grouped by 
the time of last observation. There will be a panel for each treatment arm in these plots and they 
serve to illustrate the observed means over time for different time-patterns of missing data. 
-
Plots with estimated mean values over time. These plots present the estimated means from the 
statistical analyses. 
-
Bar plots with estimated means at week 26 from the statistical analyses.
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-
Forest plots with the estimated treatment differences/ratios from the statistical analyses for the 
planned comparisons, where deemed relevant
-
Cumulative distribution functions presenting the distribution of the endpoints at week 26, 
including MMRM imputed values
Categorical efficacy endpoints
For HbA1c and body weight, binary responder endpoints have been defined. The outputs for 
assessment of these include: 
-
Categorical summary tables with counts and percentages of the response categories. 
-
Tables with results of statistical analyses including estimated odds at week 26 values as well as 
odds ratios for the planned comparisons of treatment arms
-
Bar plots with observed proportions of subjects achieving the responses
-
Forest plots with estimated odds ratios at week 26 based on the statistical analyses
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2.10
End of text outputs for safety endpoints
Adverse events
Adverse events will be evaluated with
-
Overview tables that summarise the events across treatment arms in relation to seriousness, 
severity, relationship to trial product, outcome and whether they led to premature treatment 
discontinuation
o
These will be developed for all adverse events and serious adverse events based on both 
the on-treatment and the in-trial observation period. For most frequent adverse events, 
adverse events leading to premature treatment discontinuation and pre-defined MedDRA 
searches they will be developed for the on-treatment observation period. 
-
Summary tables describing the distribution of adverse events across treatment arms by system 
organ classes and preferred terms
o
These will be developed for all adverse events, serious adverse events, adverse events 
with fatal outcome and pre-defined MedDRA searches based on both the on-treatment 
and the in-trial observation period. For adverse events leading to premature treatment 
discontinuation and adverse events by severity they will be developed for the on-
treatment observation period alone. 
-
Figures presenting the time to first event as well as the average number of events over time
o
These will be developed based on the on-treatment observation period for all adverse 
events, serious adverse events, most frequent adverse events and pre-defined MedDRA 
searches. 
-
Plots summarising the incidence by preferred term
o
These will be developed for most frequent adverse events, adverse events leading to 
premature treatment discontinuation and pre-defined MedDRA searches. 
-
Plots of the incidence over time by treatment and incidence over time by severity. 
o
These will be developed for all gastro-intestinal adverse events, nausea, vomiting and 
diarrhoea. These plots will both serve for comparison between treatment arms of 
incidences over time as well as assessment of the distribution over time of the severity of 
the adverse events.
Number of confirmed treatment emergent hypoglycaemic episodes
CONFIDENTIAL
CONFIDENTIAL


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
19 of 551
Hypoglycaemic episodes will be summarized based on ADA-classification and the combined 
categories “Confirmed” and “Severe or BG confirmed symptomatic hypoglycaemia”.
The number of events and the number subjects experiencing an event will be evaluated for the two 
combined categories using statistical analyses as described above and using plots for time to first 
episode and average number of episodes over time. 
Continuous safety lab parameters
Safety lab parameters that are treated as continuous variables will be reported in groups defined 
below. Except for eosinophils and basophils, all examinations of continuous safety lab parameters 
will be done on logarithmic scale. Where applicable, outputs will be repeated for conventional 
units.  
1. Pancreatic enzymes and hepatic laboratory parameters 
a.
Lipase
b. Amylase
c.
Bilirubin, total
d. Aspartate aminotransferase (AST)
e.
Alanine aminotransferase (ALT)
f.
Alkaline phosphatase
2. Renal laboratory parameters
a.
Creatinine
b. Urea
c.
Urinary albumin/creatinine ratio
3. Electrolytes
a.
Potassium
b. Sodium
c.
Calcium (total)
CONFIDENTIAL
CONFIDENTIAL


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
20 of 551
d. Calcium, albumin corrected (calcium, ionized)
4. Hormones
a.
Calcitonin
5. Other
a.
Creatinine kinase
b. Albumin
6. Haematology
a.
Haemoglobin
b. Haematocrit
c.
Erythrocytes
d. Thrombocytes
e.
Leucocytes
f.
Differential count (eosinophils, neutrophils, basophils, lymphocytes and monocytes)
7. Urinalysis: 
a.
Albumin, urine
Descriptive outputs for these will be similar to those produced for continuous efficacy endpoints but 
based on the on-treatment observation period. The descriptive outputs are: 
-
Tables with descriptive statistics for observed values as well as change from baseline and ratio 
to baseline
-
Categorical summary tables and shift tables for assessments outside of normal ranges. 
-
Tables with descriptive tables of the maximum post-baseline value
-
Panel plots with mean of observed as well as change from baseline values over time grouped by 
the time of last observation. There will be a panel for each treatment arm in these plots and the 
serve to illustrate the observed means over time for different time-patterns of missing data. 
CONFIDENTIAL
CONFIDENTIAL


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
21 of 551
-
Cumulative distribution functions presenting the distribution of the maximum value observed 
post-baseline.
Amylase and lipase will in addition to descriptive examinations also be subject to statistical 
analyses. These will be done on log-scale and reported with the following statistical outputs: 
-
Tables with results of statistical analyses including estimated means (LS means) for week 26 
values as well as for the ratio to baseline at week 26, and in addition estimated treatment ratios 
for the planned comparisons of treatment arms
-
Plots with estimated mean values over time. These plots present the estimated means from the 
statistical analyses. 
Categorical safety lab parameters
Pregnancy test based on hCG serum assessments and results of the urinalysis will be evaluated as 
categorical parameters. For pregnancy test, a categorical summary table by treatment week will be 
produced. The parameters included in the urinalysis are: 
a.
Blood (erythrocytes) 
b. Protein
c.
Glucose
d. ketones
e.
pH
For these parameters, categorical summary tables and shift tables will be produced. 
Vital signs 
Pulse, diastolic blood pressure and systolic blood pressure will be evaluated with outputs similar to 
the continuous safety lab parameters but on observed scale. The evaluation will be based on the on-
treatment observation period. 
Electrocardiograms (ECGs) will be evaluated based on the on-treatment observation period with 
categorical summary tables and shift tables by treatment week based on the investigator’s 
assessment. 
Physical examination will be evaluated similarly to ECG. For eye examination a categorical 
summary table of the baseline assessment will be developed. 
CONFIDENTIAL
CONFIDENTIAL


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
22 of 551
2.11
Listings
Subject disposition and demographics
Continuous and categorical subject characteristics will be listed. Separate listings for medical 
history, concomitant illnesses, concomitant medication and diabetes medication will be prepared.
Efficacy endpoints
Listings with individual response data will be produced for HbA1c, body weight, waist 
circumference, BMI, fasting plasma glucose, Fasting C-peptide, fasting insulin, glucagon and lipids. 
In addition, a listing with data points excluded from the efficacy analyses will be prepared. 
Safety endpoints
Listings based on the on-treatment period for serious adverse events, adverse events with fatal 
outcome, adverse events leading to premature treatment discontinuation and adverse events leading 
to dose reduction. 
These will be supplemented by a listing of adverse events occurring before randomisation, a listing 
of all adverse events during the in-trial observation period as well as a listing for those occurring 
after the end of the in-trial observation period. 
Finally adverse events related to a technical complaint will be listed. 
Separate listings for all hypoglycaemic episodes and severe hypoglycaemic episodes will be 
prepared. 
Listings with observations outside the reference ranges will be produced for continuous safety lab 
parameters. 
For amylase, lipase and calcitonin, listings with individual response data will be produced. 
Listings for vital signs, overall ECG interpretation and anti-semaglutide antibodies will also be 
developed. 
3
Changes to the statistical analyses planned in the protocol
The definition of the FAS is changed to exclude the requirement that a subject must have post-
baseline data. Effectively, the FAS and the SAS will be identical, but subjects will contribute to the 
evaluations differently (“as randomised” as opposed to “as treated”). 
A clear definition of baseline has been added, and imputations of missing data have been clarified. 
CONFIDENTIAL
CONFIDENTIAL


1Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
23 of 551
It has been clarified that the analysis to confirm efficacy of oral semaglutide will be based on a 
comparison of the pool of two treatment arms (40 mg standard and 40 mg fast) to placebo using the 
standard MMRM model. 
The exploratory analysis to describe the dose-response relation of oral semaglutide and estimate the 
relative potency vs. s.c. semaglutide with regards to selected key endpoints, will be conducted by 
Quantitative Clinical Pharmacology. 
Statistical analysis of the number of subjects experiencing a confirmed hypoglycaemic episode 
during the on-treatment observation period is added to the planned analyses. In addition, severe or 
BG confirmed symptomatic hypoglycaemic episodes will be analysed in the same way as confirmed 
hypoglycaemic episodes. 
Analyses of relative change from baseline in body weight, of subjects with at least 5 % weight loss 
and of subjects with more than 10 % weight loss added after 26 weeks of treatment added in order 
to align with other projects. 
Evaluations of severe or BG confirmed symptomatic hypoglycaemia have been added to the 
planned investigations. 
Due to sparse data, country will not be included in the negative binomial model for hypoglycaemic
episodes.
Treatment emergent adverse events and hypoglycaemic episodes are referred to as on-treatment 
adverse event / on-treatment hypoglycaemic episodes. 
It has been clarified that the stratification variable “Treatment with metformin at screening 
(yes/no)” will based on the actual information on concomitant medication recorded through the 
eCRF. 
It has been clarified that values of laboratory parameters below the blower limit of quantification 
(LLOQ) will be set to LLOQ/2.
The evaluations of the pre-defined groups of adverse events have been added to the overview of 
planned investigations. 
CONFIDENTIAL
CONFIDENTIAL


Statistical Analysis Plan
UTN: U111-1136-4716 
Date:
21 January 2015
Status:
Final
Novo Nordisk
Trial ID: NN9924-3790
EudraCT No.: 2012-004994-16
Version:
1.0
Page:
24 of 551
4
Pre-defined groups of adverse events 
4.1
Gastrointestinal adverse events
Preferred term
High level term
High level group term
System organ class
Abdominal adhesions
Peritoneal and retroperitoneal fibrosis and adhesions
Peritoneal and retroperitoneal conditions
Gastrointestinal disorders
Abdominal discomfort
Gastrointestinal signs and symptoms NEC
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal distension
Flatulence, bloating and distension
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal mass
Abdominal findings abnormal
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal pain
Gastrointestinal and abdominal pains (excl oral and throat)
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal pain lower
Gastrointestinal and abdominal pains (excl oral and throat)
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal pain upper
Gastrointestinal and abdominal pains (excl oral and throat)
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal rigidity
Gastrointestinal and abdominal pains (excl oral and throat)
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abdominal tenderness
Gastrointestinal and abdominal pains (excl oral and throat)
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Abnormal faeces
Faecal abnormalities NEC
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Achlorhydria
Gastrointestinal mucosal dystrophies and secretion disorders
Gastrointestinal conditions NEC
Gastrointestinal disorders
Acute abdomen
Gastrointestinal signs and symptoms NEC
Gastrointestinal signs and symptoms
Gastrointestinal disorders
Amalgam tattoo
Gingival disorders NEC
Dental and gingival conditions
Gastrointestinal disorders
Anal dilatation
Anal and rectal disorders NEC
Anal and rectal conditions NEC
Gastrointestinal disorders
Anal fissure
Anal and rectal disorders NEC
Anal and rectal conditions NEC
Gastrointestinal disorders
Anal fistula
Gastrointestinal fistulae
Gastrointestinal conditions NEC
Gastrointestinal disorders
Anal leukoplakia
Anal and rectal disorders NEC
Anal and rectal conditions NEC
Gastrointestinal disorders


 
 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
21 January 2015
Novo Nordisk
Trial ID: NN9924-3790
Version:
1.0
UTN: U111-1136-4716 
Status:
Final
EudraCT No.: 2012-004994-16
Page:
551 of 551
5
References
i Casella, G. and Berger, R. L. (2002), Statistical Inference, 2nd ed.
ii 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):777-781.
iii 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):1384-1395.
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CONFIDENTIAL


From:
To:
DBL Team
Memo
Copy:
Ref.: 
23 January 2015
Novo Nordisk A/S
Biostatistics 1
Semaglutide & Oral GLP-1
Telephone:
+45 4444 8888
Internet:
www.novonordisk.com
Vandtårnsvej 114
DK-2860 Søborg
Denmark
NN9924-3790: Statistical memo for the pre-DBL meeting
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Page 2 of 2
Stratification variable
The stratification variable “Treatment with metformin at screening (yes/no)” was 
reconciled with concomitant medication data. For 7 subjects, discrepancies were 
identified and queried were issued. The stratification variable included in statistical 
analyses was defined to reflect the concomitant medication data, and this resulted in 
the following changes in the stratification variable for these subjects: 
Subject
Change in stratification variable
“No” -> “Yes”
“No” -> “Yes”
“Yes” -> “No”
“Yes” -> “No”
“Yes” -> “No”
“Yes” -> “No”
“Yes” -> “No”
Reporting of pregnancy tests
Results of pregnancy tests (based on human chorionic gonadotropin samples) for male 
subjects will not be summarised. 
Subjects lost to follow-up
1.
Lost to follow-up (Yes/No) will be defined based on comments to reasons for 
premature treatment discontinuation given on the end-of-trial electronic case 
report form. For the following subjects status is thus “Yes” for lost to follow-up: 
For these subjects, the on-treatment and the on-treatment without rescue 
observation periods will use the date of last drug from the IVRS system as end-
date. 
CONFIDENTIAL
CONFIDENTIAL