Clinical trial NCT02970942
Conditions: Hepatobiliary Disorders Non-alcoholic Steatohepatitis
Sponsor: Novo Nordisk A/S
Start date: 2016-11-30; Completion date: 2020-03-19
Enrollment: 320 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily versus placebo in subjects with non-alcoholic steatohepatitis

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None
Interventions: intervention 1: Semaglutide intervention 2: Placebo
Intervention descriptions: intervention 1: Once daily administration of semaglutide subcutaneously (s.c., under the skin) in three different doses (0.1 mg, 0.2 mg and 0.4 mg) intervention 2: Once daily administration subcutaneously ( s.c., under the skin)

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02970942  
Sponsor trial ID: 
NN9931-4296  
Official title of study: 
Investigation of efficacy and safety of three dose levels of 
subcutaneous semaglutide once daily versus placebo in 
subjects with non-alcoholic steatohepatitis 
Document date: 
09 January 2018 
 




Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
1 of 123
Protocol
Trial ID:NN9931-4296
Investigation of efficacy and safety of three dose levels of
subcutaneous semaglutide once daily versus placebo in subjects with 
non-alcoholic steatohepatitis 
A 72-week randomised, double-blind, placebo-controlled, six-armed parallel group, multi-centre, 
multinational trial
Trial phase: Phase 2
Protocol originator
 Senior International Trial Manager
ClinOps 2, GLP-1 and Obesity
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
 
 
 
 
 
Redacted protocol 
Includes redaction of personal identifiable information only. 
 
 
 
. 
 
 




Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
3 of 123
8.1.5
Premature discontinuation of trial product ................................................................43
8.1.6
Withdrawn subjects....................................................................................................44
8.1.7
Subject training..........................................................................................................44
8.2
Subject related information/assessments .....................................................................................45
8.2.1
Demography...............................................................................................................45
8.2.2
Concomitant illness and medical history...................................................................45
8.2.3
Concomitant medication............................................................................................45
8.2.4
Hypoglycaemia unawareness.....................................................................................46
8.2.5
Childbearing potential................................................................................................46
8.2.6
Tobacco use ...............................................................................................................46
8.3
Efficacy assessments....................................................................................................................47
8.3.1
Liver biopsy...............................................................................................................47
8.3.1.1
Central pathologist evaluation.............................................................47
8.3.2
Fibroscan® measurements..........................................................................................48
8.3.3
Body measurements...................................................................................................49
8.3.3.1
Body weight ........................................................................................49
8.3.3.2
Height..................................................................................................49
8.3.3.3
Body mass index .................................................................................49
8.3.3.4
Waist circumference............................................................................49
8.3.3.5
Vital signs............................................................................................49
8.3.4
SF-36 questionnaires..................................................................................................50
8.4
Safety assessments.......................................................................................................................51
8.4.1
Physical examination.................................................................................................51
8.4.2
Electrocardiogram......................................................................................................51
8.4.3
Adverse events...........................................................................................................52
8.4.4
Medication error ........................................................................................................52
8.4.5
Adverse events requiring additional data collection..................................................52
8.4.6
Self-measured plasma glucose...................................................................................53
8.4.7
Hypoglycaemic episodes ...........................................................................................53
8.4.8
Hyperglycaemic episodes ..........................................................................................56
8.5
Laboratory assessments ...............................................................................................................56
8.5.1
Review of laboratory reports .....................................................................................57
8.5.2
Laboratory assessments for efficacy..........................................................................57
8.5.2.1
Biochemistry .......................................................................................57
8.5.2.2
Glucose metabolism............................................................................57
8.5.2.3
Exploratory biomarkers.......................................................................58
8.5.2.4
Biosamples for future analysis:...........................................................58
8.5.3
Laboratory assessments for safety .............................................................................58
8.5.3.1
Biochemistry .......................................................................................58
8.5.3.2
Hormones ............................................................................................59
8.5.3.3
Haematology .......................................................................................59
8.5.3.4
Coagulation marker.............................................................................59
8.5.3.5
HIV and hepatitis ................................................................................59
8.5.3.6
Pregnancy test .....................................................................................59
8.5.3.7
Anti-semaglutide antibodies................................................................60
8.6
Other assessments........................................................................................................................60
8.6.1
Semaglutide plasma concentration ............................................................................60
8.6.2
Subject diaries............................................................................................................60
8.6.3
Nutritional and physical activity counselling ............................................................61
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
4 of 123
8.7
Specific safety requirements........................................................................................................61
8.7.1
Suspicion of acute pancreatitis...................................................................................61
8.7.2
Assessments in case of increased levels of liver blood parameters ...........................62
8.7.3
Training in the delivery device (NovoPen® 4)...........................................................63
8.8
Subject compliance......................................................................................................................63
9
Trial supplies ...........................................................................................................................................64
9.1
Trial products...............................................................................................................................64
9.2
Labelling......................................................................................................................................64
9.3
Storage .........................................................................................................................................65
9.4
Drug accountability and destruction............................................................................................65
9.5
Auxiliary supplies........................................................................................................................66
10 Interactive voice/web response system ..................................................................................................67
11 Randomisation procedure and breaking of blinded codes..................................................................68
11.1
Breaking of blinded codes ...........................................................................................................68
12 Adverse events, technical complaints and pregnancies .......................................................................69
12.1
Definitions ...................................................................................................................................69
12.1.1
Adverse event ............................................................................................................69
12.1.2
Serious adverse event.................................................................................................70
12.1.3
Non-serious adverse event.........................................................................................71
12.1.4
Medication errors.......................................................................................................71
12.1.5
Adverse events requiring additional data collection..................................................71
12.1.6
Technical complaints.................................................................................................73
12.2
Reporting of adverse events.........................................................................................................73
12.3
Follow-up of adverse events........................................................................................................76
12.4
Technical complaints and technical complaint samples ..............................................................77
12.4.1
Reporting of technical complaints .............................................................................77
12.4.2
Collection, storage and shipment of technical complaint samples ............................77
12.5
Pregnancies..................................................................................................................................78
12.5.1
Pregnancies in female subjects ..................................................................................78
12.6
Precautions and/or overdose ........................................................................................................79
12.7
Committees related to safety........................................................................................................79
12.7.1
Novo Nordisk safety committee ................................................................................79
12.7.2
Event adjudication committee....................................................................................80
13 Case report forms....................................................................................................................................82
13.1
Corrections to case report forms..................................................................................................82
13.2
Case report form flow..................................................................................................................83
14 Monitoring procedures ...........................................................................................................................83
15 Data management....................................................................................................................................84
16 Computerised systems.............................................................................................................................84
17 Statistical considerations ........................................................................................................................85
17.1
Sample size calculation................................................................................................................86
17.2
Definition of analysis sets............................................................................................................87
17.3
Primary endpoint..........................................................................................................................88
17.4
Secondary endpoints....................................................................................................................91
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
5 of 123
17.4.1
Supportive secondary endpoints ................................................................................91
17.4.1.1
Efficacy endpoints...............................................................................91
17.4.1.2
Safety endpoints..................................................................................98
17.4.1.3
Pharmacokinetic endpoints................................................................103
17.5
Interim analysis..........................................................................................................................103
17.6
Pharmacokinetic and/or pharmacodynamic modelling..............................................................103
17.7
Health economics and/or patient reported outcomes.................................................................103
18 Ethics......................................................................................................................................................104
18.1
Benefit-risk assessment of the trial............................................................................................104
18.2
Informed consent .......................................................................................................................107
18.3
Data handling.............................................................................................................................108
18.4
Information to subjects during trial............................................................................................108
18.5
Premature termination of the trial and/or trial site.....................................................................109
19 Protocol compliance..............................................................................................................................109
19.1
Protocol deviations ....................................................................................................................109
19.2
Prevention of missing data.........................................................................................................109
20 Audits and inspections ..........................................................................................................................110
21 Critical documents ................................................................................................................................110
22 Responsibilities......................................................................................................................................111
23 Reports and publications......................................................................................................................112
23.1
Communication of results..........................................................................................................112
23.1.1
Authorship ...............................................................................................................113
23.1.2
Site-specific publication(s) by investigator(s) .........................................................113
23.2
Investigator access to data and review of results.......................................................................114
24 Retention of clinical trial documentation and human biosamples....................................................115
24.1
Retention of clinical trial documentation...................................................................................115
24.2
Retention of human biosamples.................................................................................................115
24.2.1
Antibody samples ....................................................................................................115
24.2.2
Samples for future analysis......................................................................................116
25 Institutional Review Boards/Independent Ethics Committees and regulatory authorities............117
26 Indemnity statement .............................................................................................................................118
27 References..............................................................................................................................................119
Appendix A
Monitoring of calcitonin
Appendix B
Adverse events with additional data collection and adverse events requiring event 
adjudication
Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
6 of 123
Table of Figures
Page
Figure 5–1
Trial design.............................................................................................................................29
Figure 12–1
Reporting of AEs....................................................................................................................75
Figure 17–1
Novo Nordisk classification of hypoglycaemia...................................................................100
Figure 17–2
ADA classification of hypoglycaemia.................................................................................101
Table of Tables
Page
Table 5–1
Duration of dose escalation period ........................................................................................31
Table 5–2
Dose conversion table............................................................................................................32
Table 9–1
Trial products..........................................................................................................................64
Table 9–2
Storage conditions .................................................................................................................65
Table 12–1
Adverse events requiring completion of specific eCRF event forms and/or are subject 
to event adjudication...............................................................................................................72
Table 17–1
Sample size calculations for different scenarios - number of subjects per arm.....................87
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
7 of 123
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUDIT
Alcohol Use Disorders Identification 
Test 
BMI
body mass index
CAP
controlled attenuation parameter
CK-18
cytokeratin 18
CLAE
clinical laboratory adverse event
CMH
Cochran-Mantel-Haenszel 
CRF
case report form
CRN
Clinical Research Network
CTR
clinical trial report
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
ELF
enhanced liver fibrosis 
FAS
full analysis set
FGF-21
fibroblast growth factor 21
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
8 of 123
Fib-4
fibrosis 4
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase 
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor 
agonist
HbA1c
glycosylated haemoglobin A1c
hCG
human chorionic gonadotrophin
HCV-RNA
hepatitis C virus Ribonucleic acid
HDL
high-density lipoprotein
HIV
human immunodeficiency virus 
HOMA-IR
homeostatic model assessment -
insulin resistance 
ICH
International Conference on 
Harmonisation of Technical 
Requirements for Registration of 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical 
Journal Editors
IEC
independent ethics committee
IL-1R
interleukin-1 receptor 
IMP
investigational medicinal product
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
9 of 123
INR
international normalized ratio 
IRB
institutional review board
IWRS
interactive web response system
LDL
low-density lipoprotein
LLOQ
lower limit of quantification
LSLV
last subject last visit
MCP-1
monocyte chemoattractant protein 1
MedDRA
Medical Dictionary for Regulatory 
Activities
MELD
model for end-stage liver disease
MI
myocardial infarction 
miR-122
microRNA 122
NAFLD
non- alcoholic fatty liver disease
NAS
NAFLD activity score 
NASH
non- alcoholic steatohepatitis
NFS
NAFLD fibrosis score 
NOAEL
no observable adverse effect level
PG
plasma glucose
PRO
patient reported outcome
SAE
serious adverse event
SAF
steatosis-activity-fibrosis
SAP
statistical analysis plan
SAS
safety analysis set
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
10 of 123
s.c.
subcutaneous(ly)
SF-36
short form 36
SGLT-2
sodium–glucose cotransporter 2
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse 
reaction
T2D
type 2 diabetes
TMM
trial materials manual
TSH
thyroid-stimulating hormone 
UNL
upper normal limit
UTN
universal trial number
VLDL
very low density lipoprotein 
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
11 of 123
1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of semaglutide subcutaneous (s.c.) once daily versus placebo on histological 
resolution of non-alcoholic steatohepatitis (NASH).
Primary endpoint
!
NASH resolution without worsening of fibrosis after 72 weeks (yes/no)
Key secondary objectives
!
To investigate the dose-response relationship of three dose levels of semaglutide s.c. once daily 
(0.1 mg/day, 0.2 mg/day and 0.4 mg/day) on histological resolution of NASH.
!
To compare the effects of semaglutide s.c. once daily to placebo on liver-related histological 
parameters and biomarkers of NASH disease.
Key secondary endpoints
!
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or 
hepatocyte ballooning according to NASH clinical research network (CRN) criteria). 
Change from baseline to week 72 in:
!
Non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8)
!
Stage of fibrosis according to the Kleiner fibrosis classification (0-4)
!
Activity component of steatosis-activity-fibrosis (SAF) score (0-4)
!
Fasting plasma glucose (FPG)
!
Glycosylated haemoglobin A1c (HbA1c)
!
Serum enhanced liver fibrosis (ELF)
Trial design:
This is a 72-week, randomised, double-blind, placebo-controlled, six-armed, parallel group, multi-
centre, multi-national trial comparing once daily administration of semaglutide s.c. in three different 
doses (0.1 mg, 0.2 mg and 0.4 mg) with placebo in subjects with NASH. Subjects will be 
randomised in a 3:3:3:1:1:1 manner to receive daily dosing of semaglutide s.c. 0.1 mg, 0.2 mg, 0.4 
mg or corresponding injection volumes of placebo once daily. To avoid bias in the assessment of 
the different semaglutide doses, the trial will be double-blinded within dose levels. The dose levels
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
12 of 123
will not be blinded between each other because of different dose escalations and different target 
doses and volumes required.
The total trial duration for the individual subject will be up to 85 weeks (maximum).
Randomisation will be stratified in five strata based on region (Japanese or non-Japanese) and, 
within the non-Japanese group, based on diabetes status at screening (with or without type 2 
diabetes) and fibrosis stage for baseline liver biopsy (F2 or F3).
Trial population:
A total of 372 subjects are planned to be randomised. Based on an assumption of a 50% screening 
failure rate, 744 subjects are planned to be screened.
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
!
Male or female, aged 18-75 years (both inclusive) (for Japan: male or female aged 20-75 years
(both inclusive)) at the time of signing informed consent.
!
Local histological diagnosis of NASH followed by histological confirmation of NASH based on 
central pathologist evaluation of a liver biopsy obtained up to 21 weeks before screening.
!
A histological NAS > 4 with a score of 1 or more in each sub-component of the score based on 
central pathologist evaluation.
!
NASH fibrosis stage 2 or 3 according to the NASH CRN fibrosis staging system based on 
central pathologist evaluation.
Key exclusion criteria
!
Known or suspected abuse of alcohol (> 20 g/day for women or > 30 g/day for men), alcohol 
dependence* or narcotics. (* = assessed by the Alcohol Use Disorders Identification Test 
(AUDIT questionnaire)).
!
Diagnosis of type 1 diabetes according to medical records.
!
HbA1c > 9% at screening.
!
History or presence of pancreatitis (acute or chronic).
!
Calcitonin L 50 ng/L at screening.
!
Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
!
Body Mass Index (BMI) M 25.0 or L 45.0 kg/m2 at the screening visit.
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
13 of 123
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice).
Assessments:
Efficacy
!
Liver biopsy
!
Liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma 
glutamyltransferase (GGT))
!
Fibroscan® measurements (liver stiffness and liver steatosis (with controlled attenuation 
parameter (CAP))) 
!
HbA1c
!
Body measurements (body weight in kg)
!
Lipids (Total cholesterol, free fatty acids, high-density lipoprotein (HDL) cholesterol, low-
density lipoprotein (LDL) cholesterol, triglycerides, very low density lipoprotein (VLDL)
cholesterol)
Safety
!
Adverse events
!
Pulse
!
Biochemistry and haematology
!
Antibodies against semaglutide
Trial products:
The following trial products will be supplied by Novo Nordisk A/S:
!
Semaglutide 1.0 mg/ml, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Semaglutide placebo, solution for injection, 3.0 ml cartridge, for NovoPen® 4
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Protocol
UTN: U1111-1179-7464 
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT no.: 2016-000685-39
Version:
1.0
Page:
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Abbreviations: P = Phone visit, V = Clinic visit, ECG = Electrocardiogram, FU = follow-up, IWRS = interactive web response system, SF-36 = Short Form 36, HbA1c = glycosylated haemoglobin, BG-meter = blood glucose meter, EOT = End of treatment
1)
Subjects prematurely discontinuing trial product should attend an end of treatment visit (V18) as soon as possible and a follow-up visit 7 weeks thereafter (visit 19). In addition they should follow the trial visit 
schedule as planned and attend the trial product discontinuation 72 weeks FU visit 72 weeks after randomisation. However the following should not be done after visit 19 for subjects prematurely discontinuing trial 
product: Semaglutide plasma concentration, anti-semaglutide antibody assessment, hypo reporting and handing out subject diaries.
2)
A liver biopsy obtained 21 weeks or less before screening (visit 1) can be used. For subjects with no historical liver biopsy within 21 weeks prior to screening, a liver biopsy must be performed during the screening 
period.
3)
In selected countries only at sites with Fibroscan® equipment available.
4)
For subjects prematurely discontinuing trial product treatment, no biopsy at end of treatment visit (V18). Biopsy will be at visit 19A (trial product discontinuation 72 weeks FU).
5)
For subjects prematurely discontinuing trial product treatment, no Fibroscan
®
assessment at end of treatment visit (V18). Fibroscan® will be at visit 19A (trial product discontinuation 72 weeks FU).
6)
Exploratory biomarkers are: CK-18 fragments, ELF, miR-122, IL-1R antagonist, MCP-1, FGF-21.
7)
Blood samples for measurement of anti-semaglutide antibodies must be drawn prior to trial product dose.
8)
For subjects prematurely discontinuing trial product treatment a follow-up antibody sample and semaglutide plasma concentration sample must in addition to at the end of treatment vist (V18) be taken 7 weeks 
thereafter (visit 19).
9)
Hand out directions for use
10)
Only applicable for subjects with type 2 diabetes
11)
For women of childbearing potential: urine pregnancy test should be performed at any time during the trial if a menstrual period is missed, or as required by local law
12)
At these visits, urine pregnancy test will be performed
13)
Only applicable for subjects with type 2 diabetes
14)
Only applicable for female subjects
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Protocol
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
19 of 123
3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver damages ranging from 
simple steatosis (non-alcoholic fatty liver), non-alcoholic steatohepatitis (NASH) with or without 
fibrosis through to cirrhosis3. It is estimated that 70-90% of patients with obesity have some degree 
of steatosis, with the prevalence increasing with the severity of obesity. To that end, NAFLD is the 
most common chronic liver disorder in Western countries and in the USA 30% of the adult 
population suffers from NAFLD4 5. Obesity is associated with an increased risk of NAFLD, the risk 
increasing with increasing BMI6. Furthermore the risk rises to as much as 70-75% in patients with 
type 2 diabetes (T2D)7. NASH represents a more advanced form of NAFLD and is reported in 3-5% 
of the Western population8. The prevalence of NASH is ~12% and ~22% in patients with obesity 
and T2D, respectively9.  The incidence and prevalence of NASH is rising and it is estimated that 
20-30% of patients with simple steatosis develop NASH10. Persistent inflammation can lead to the 
formation of fibrous scar tissue in the liver, which eventually causes cirrhosis and in some cases 
hepatocellular carcinoma11.
An estimated 10% of patients with NASH develop cirrhosis12. Obesity-induced NASH leading to 
liver cirrhosis is the third most common cause of liver transplantation in the USA today and 
expected to be the primary cause of liver transplantation in 203013 14 15. The pathophysiology of 
NASH is not well understood, but weight gain, insulin resistance, T2D and hypertension are all 
recognised as key factors16. 
In most patients NASH is asymptomatic, but non-specific symptoms such as right upper quadrant 
discomfort or fatigue can occur.  Often, NASH is first suspected on the basis of elevated liver 
enzymes found at routine medical health checks or incidentally by imaging or bariatric surgery. 
Liver enzymes (e.g. alanine aminotransferase) are elevated in 50-80% of cases and typically around 
1.5 times the upper limit of the normal17.NASH is a histological diagnosis based on liver biopsy 
together with clinical exclusion of consumption of >20 g ethanol/day for women and >30g 
ethanol/day for men18. Histologically, NASH is defined by the presence of steatosis, lobular 
inflammation, portal inflammation, cellular ballooning and varying degrees of fibrosis. The degree 
of fibrosis is described by the Kleiner fibrosis staging system, ranging from F0 (absence of 
fibrosis), F1 (portal/perisinusoidal fibrosis), F2 (perisinusoidal and portal/periportal fibrosis), F3 
(septal or bridging fibrosis) through F4 (cirrhosis)19. Several non-invasive biomarkers are available 
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for the assessment NASH and liver fibrosis, however, there are currently no non-invasive methods 
for diagnosis or assessment of disease prognosis approved for regulatory pivotal trials20. 
Currently, no drugs are approved for the treatment of NASH. First-line treatment is lifestyle 
intervention to achieve weight loss and treatment of comorbidities (e.g. hyperlipidaemia, 
hypertension and diabetes). In the case of progression to cirrhosis and liver failure, liver 
transplantation is the only treatment option. The current sparse epidemiological information on 
progression rates and predictive factors has limited the ability to calculate risk and possible benefit 
of treatments21.
3.1.1 Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells in the small 
intestine. GLP-1 has a glucose-dependent stimulatory effect on insulin and inhibitory effect on 
glucagon secretion from the pancreatic islets (i.e. when plasma glucose levels are above normal)22
23. Furthermore, GLP-1 is a physiological regulator of appetite and food intake and GLP-1 receptors 
are present in several areas of the brain involved in appetite regulation. Physiologically, GLP-1 has 
a pronounced inhibitory effect on gastric emptying; however this effect seems to diminish upon 
chronic exposure24 25 26. Endogenous GLP-1 has a very short elimination half-life of <1.5 minutes 
after intravenous administration due to rapid degradation by ubiquitous dipeptidyl peptidase (DPP 
4)27. Development of a GLP-1 receptor agonist (GLP-1 RA) with longer half-life has been 
necessary to enable effective treatment option for T2D and obesity.
Both human and animal studies have shown a beneficial effect of GLP-1 RA including liraglutide 
on liver lipid metabolism and progression of fatty liver to NASH 28 29 30 31. The mechanism by 
which GLP-1 RAs affect NASH is not clear and neither murine nor human hepatocytes seem to 
have any GLP-1 receptor expression29 32. Semaglutide effectively lowers body weight and have 
been shown to indirectly increase insulin sensitivity31 33 34. Additionally, semaglutide also increase 
insulin and lower glucagon levels, all of which may be beneficial in patients with NASH. Other 
mechanisms of actions based on the GLP-1 biology are anti-inflammation and lipid lowering 
effects29.
In the liraglutide phase 3 programme for treatment of T2D, 50% of the more than 4000 subjectss 
had elevated ALT at baseline. Compared to placebo, liraglutide dose-dependently reduced ALT in 
these patients suggesting an improvement of hepatic steatosis35.
The investigator sponsored study Liraglutide Efficacy and Action in NASH (LEAN), enrolled 52 
overweight subjects with and without T2D, with biopsy-confirmed NASH to receive once daily 
liraglutide s.c or placebo. After 48 weeks of treatment, 9 out of 23 (39%) subjects treated with 
liraglutide compared to 2 out of 22 (9%) subjects treated with placebo had resolution of NASH with 
no worsening of fibrosis (relative risk 4R3 [95% CI 1R0–17R7]; p=0R019) compared to placebo.
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Furthermore, significantly fewer patients treated with liraglutide had worsening of fibrosis 
compared to placebo34.
Semaglutide
Semaglutide is a potent human GLP-1 RA with a half-life of approximately 160 hours, suitable for 
both once daily (subcutaneous (s.c.) and oral) and once weekly s.c. administration. It is structurally 
similar to liraglutide (Victoza® and Saxenda®), a once daily GLP-1 RA developed by Novo Nordisk 
and approved in several countries for the treatment of T2D and weight management, respectively. 
For the semaglutide molecule the principal mechanism of protraction is albumin binding facilitated 
by a large fatty acid derived chemical moiety attached to the lysine in position 26. The specific 
modifications in the molecule are: 1) a modification in position 8 (alanine to 2-aminoisobutyric 
acid) of the peptide backbone in order to further increase stability against DPP-4, and a change in 
position 34 from a lysine to an arginine in order to only have one (1) lysine in the sequence; 2) a 
large hydrophilic linker between the lysine in position 26 and the gamma glutamate whereto the 
fatty acid is attached; 3) a C18 fatty di-acid with a terminal acidic group. The latter two (2) 
contribute to increased albumin binding which results in decreased renal clearance. In addition to 
slowed degradation in plasma and decreased renal clearance, delayed absorption from subcutis 
possibly also contributes to a prolonged half-life t½ of 155-183 hours.
In vitro receptor studies have shown that semaglutide is a potent and selective GLP-1 analogue, and 
animal studies using non-diabetic rats, non-diabetic pigs and diabetic mice have shown lowering of 
BG and inhibition of food intake. A clinically relevant effect on glucose metabolism and body 
weight has also been observed in humans.
Nonclinical data
The nonclinical programme for semaglutide was designed according to the ICH M336 guideline to 
support the clinical development. The standard nonclinical 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 dose limiting in mice, rats and cynomolgus monkeys. Two potential safety issues have 
been identified.
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 
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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 RAs, including 
liraglutide. The relevance for human subjects is unknown. Recently published data have shown that
the GLP-1 receptor is not expressed in the normal human thyroid. Accordingly, the risk of GLP-1 
receptor mediated C-cell changes in humans is considered to be low37.
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 as described below. Preliminary and main 
embryofoetal development and pre- and postnatal development studies with doses corresponding to 
12-15 fold expected clinical exposure in cynomolgus monkeys have been finalised. In the main 
embryofoetal development study sporadic abnormalities were reported across all dose groups and in 
the pre- and postnatal development study a dose-dependent increase in early pregnancy losses was 
observed. The findings observed across the three studies in cynomolgus monkeys are not indicative 
of a 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 1- to 2 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 
embryo-foetal development and pre- and postnatal development studies in cynomolgus monkey 
decreases the level of concern.
A comprehensive review of results from the nonclinical studies can be found in the current edition 
of semaglutide s.c. (NN9535), T2D, Investigator’s Brochure (IB)38 or any updates hereof.
Clinical data
Semaglutide s.c. is currently being investigated in the T2D development programme (please refer to 
the semaglutide s.c. IB for T2D or any updates hereof 38) and in the obesity development 
programme. Novo Nordisk is also developing semaglutide for oral administration, and phase 3 trials 
with this formulation are ongoing. 
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As of 22 December 2015 (the cut-off date of the latest version of the semaglutide s.c. IB for T2D38), 
13 clinical pharmacology trials and 1 phase 2 trial have been completed with semaglutide once-
weekly s.c. In the completed once-weekly semaglutide s.c. trials, 802 subjects have been exposed to 
semaglutide: 411 healthy subjects (both single and multiple dosing), 313 subjects with type 2 
diabetes (up to 12 weeks of treatment), 48 subjects with varying degrees of renal impairment (4 
subjects had type 2 diabetes) (single dosing) and 30 subjects with obesity but otherwise healthy.
As of 22 December 2015, 8 therapeutic confirmatory trials with nearly 8000 subjects enrolled are 
ongoing including a 104-week trial comparing the long-term safety (including cardiovascular risk) 
and efficacy of semaglutide once-weekly s.c. 
Doses up to 1.6 mg with weekly dosing have been tested and doses up to 0.4 mg with daily dosing 
are being tested in the NN9536-4153 trial for the weight management indication. 
A recent finalised trial (not described in the current version of the semaglutide s.c. IB for T2D38), 
investigated subjects with hepatic impairment. Following administration of a single dose of 
semaglutide 0.5 mg, semaglutide pharmacokinetics were compared between subjects with mild, 
moderate and severe hepatic impairment and subjects with normal hepatic function. The primary 
endpoint, total exposure in terms of area under curve (AUC), met the criterion for ‘no effect’ for all 
3 hepatic impairment groups versus the group with normal hepatic function. Hence, exposure of 
semaglutide was not affected by hepatic impairment, and semaglutide pharmacokinetic properties 
for subjects with hepatic impairment were similar to those with normal function. No new safety or 
tolerability issues were observed for semaglutide following single dose administration to this 
subject group.
Efficacy
As of 22 December 2015, efficacy of semaglutide in 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 injection of 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. Mean changes in glycosylated haemoglobin (HbA1c) from baseline was up to -
1.19% (placebo adjusted estimated treatment difference). Dose-dependent improvements in fasting 
plasma glucose (FPG) and postprandial PG were also observed. The improvement in glycaemic 
control was accompanied by weight loss for semaglutide doses of 0.8 mg and above (estimated 
treatment difference compared to placebo up to a mean value of -3.64 kg).
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Safety
From the clinical trials completed so far the following safety observations have been made. In 
consistency with the findings obtained from evaluating other GLP-1 RAs, common adverse events 
(AEs) included nausea and vomiting; most of them were mild to moderate in severity.
Hypoglycaemia has occurred in subjects receiving semaglutide and these events have mainly been 
minor. As with other GLP-1 RAs, an increase in heart rate has been observed in subjects exposed to 
semaglutide. The implications of this increase are unknown. As with all protein based 
pharmaceuticals, subjects treated with 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, including urticaria, 
rash, pruritus and rare cases of angioedema have been observed. Injection site reactions have been 
infrequently reported. These have mainly been mild and transient in nature.
Please see the current edition of semaglutide s.c. (NN9535), T2D, Investigator’s Brochure (IB)38 or 
any updates hereof for further details.
For an assessment of benefits and risks of the trial, see Section 18.1.
3.2
Rationale for the trial
Currently, first-line treatment of NASH is lifestyle interventions to provide weight loss and to treat 
comorbidities (e.g. hyperlipidaemia, hypertension and diabetes) as no specific pharmaceutical 
therapies are approved and, thus, there is a substantial unmet medical need for effective treatment of 
NASH. 
The results from the LEAN trial34 showed beneficial treatment effects of liraglutide in overweight 
subjects with biopsy-confirmed NASH. Data from semaglutide trials, a human GLP-1 analogue 
structurally similar to liraglutide with similar mechanism of action, has suggested a more 
pronounced effect on glycaemic control and body weight loss compared to liraglutide. Therefore 
semaglutide is considered to have an even better potential as treatment for NASH. 
The purpose of the present trial is to investigate the potential of semaglutide s.c. once daily at three 
dose levels to resolve NASH compared to placebo. Furthermore, the trial is designed to explore the 
dose response relationship for semaglutide in NASH in order to inform dose selection for phase 3. 
Furthermore, safety and tolerability including the formation of anti-semaglutide antibodies will be 
investigated.
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4
Objectives and endpoints
4.1
Objectives
Primary objective
To compare the effect of semaglutide s.c. once daily versus placebo on histological resolution of 
NASH.
Secondary efficacy objectives
To investigate the dose-response relationship of three dose levels of semaglutide s.c. once daily (0.1 
mg/day, 0.2 mg/day and 0.4 mg/day) on histological resolution of NASH.
To compare the effects of semaglutide s.c. once daily to placebo on liver-related histological 
parameters and biomarkers of NASH disease.
To investigate the effects of semaglutide s.c. once daily versus placebo in subjects with NASH on:
!
Weight-related parameters
!
Glucose metabolism related parameters
!
Cardiovascular risk factors
!
Patient reported outcomes
Secondary safety objectives
To evaluate the safety and tolerability of three dose levels of semaglutide s.c. once daily in subjects 
with NASH.
4.2
Endpoints
4.2.1
Primary endpoint
!
NASH resolution* without worsening of fibrosis** after 72 weeks (yes/no)
*) Resolution of NASH as defined by comprehensive interpretation by two independent pathologists (central reading) 
blinded to treatment allocation and with complete resolution captured by terms such as “no fatty liver disease” or 
“simple steatosis or isolated steatosis” and defined by the NASH Clinical research network (CRN) as “no more than 
mild residual inflammatory cells and no ballooning”
**) worsening defined by an increase of at least one stage of the Kleiner fibrosis classification 
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4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
Liver-related histological parameters
!
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or 
hepatocyte ballooning according to NASH CRN criteria 19 39).*
Change from baseline to week 72 in:
!
NAFLD activity score (NAS)*
!
Stage of fibrosis according to the Kleiner fibrosis classification*
!
Activity component of steatosis-activity-fibrosis (SAF) score*
Biomarkers of NASH disease
Change from baseline to week 72 in:
Algorithms:
!
Fibrosis-4 score (Fib-4 score) 
!
NAFLD Fibrosis Score (NFS) 
Blood samples:
!
Liver enzymes 
o
ALT, AST and GGT
!
Liver synthesis function
o
Albumin, INR
!
Exploratory biomarkers
o
Serum enhanced liver fibrosis (ELF)*
o
CK-18 fragments
o
miR-122
o
IL-1R antagonist 
o
MCP-1
o
FGF-21
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Imaging:
!
Liver stiffness and liver steatosis (with controlled attenuation parameter) measurement by 
Fibroscan®
Weight related parameters
!
Weight loss of L 5% of baseline body weight at 72 weeks (yes/no)
!
Weight loss of L 10% of baseline body weight at 72 weeks (yes/no)
Change from baseline to 72 weeks in:
!
Body weight (% and kg)
!
Waist circumference 
!
Body mass index (BMI) 
Glucose metabolism related parameters
Change from baseline to 72 weeks in:
!
Glycosylated haemoglobin type A1c (HbA1c)*
!
Fasting plasma glucose (FPG)*
!
Fasting glucagon
!
Homeostatic model assessment of insulin resistance (HOMA-IR)
Cardiovascular risk factors
Change from baseline to 72 weeks in: 
!
Systolic and diastolic blood pressure 
!
Lipids (total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density 
lipoprotein cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL 
cholesterol), triglycerides, free fatty acids)
!
High sensitivity C reactive protein (hsCRP)
Patient reported outcomes
Change from baseline to 72 weeks in:
!
Short form 36 (SF-36): Physical and mental component summary scores and scores on the 
individual sub-domains: Physical functioning, role functioning, bodily pain, general health, 
vitality, social functioning, role emotional and mental health.
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4.2.2.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events during the trial
!
Number of treatment-emergent hypoglycaemic episodes during the trial
!
Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during the trial
!
Number of treatment-emergent severe hypoglycaemic episodes during the trial 
!
Number of subjects discontinuing treatment due to gastrointestinal adverse events
Occurrence of anti-semaglutide antibodies during and after 72 weeks treatment (yes/no):
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide binding antibodies with in vitro neutralising effect
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Cross-reacting anti-semaglutide binding antibodies with in vitro neutralising effect to native 
GLP-1
Anti-semaglutide antibody binding level during and after 72 weeks treatment
Change from baseline to 72 weeks in:
!
Pulse
!
ECG
!
Physical examination
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, differential 
count)
!
Biochemistry (creatinine, creatinine phosphokinase, urea, bilirubin (total), alkaline phosphatase, 
ferritin, sodium, potassium, calcium (total), amylase, lipase)
!
Hormones (calcitonin)
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
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5
Trial design
5.1
Type of trial
This is a 72-week, randomised, double-blind, placebo-controlled, six-armed, parallel group, multi-
centre, multi-national trial comparing once daily administration of semaglutide s.c. in three different 
doses (0.1 mg, 0.2 mg and 0.4 mg) with placebo in subjects with NASH.
A planned total of 372 subjects will be randomised. Based on an assumption of a 50% screening 
failure rate, 744 subjects will be screened. Subjects will be randomised in a 3:3:3:1:1:1 manner to 
receive daily dosing of semaglutide s.c. 0.1 mg, 0.2 mg, 0.4 mg or corresponding injection volumes 
of placebo once daily (for details see Figure 5–1). To avoid bias in the assessment of the different 
semaglutide doses, the trial will be double-blinded within dose levels. The dose levels will not be 
blinded between each other because of different dose escalations and different target doses and 
volumes required. It is expected that 15% will withdraw from the trial or prematurely discontinue 
treatment with trial product. 
Figure 5–1
Trial design
Subjects in all treatment groups including placebo will receive nutritional and physical activity
counselling by a member of the study team according to local site practice. 
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The randomisation of subjects to treatment will be stratified in five groups as described in section
5.2 and section 11).
The diagnosis of NASH as well as the histology based scores will be subject to central pathologist 
evaluation.
Subjects who prematurely discontinue the trial product treatment should continue with the 
originally scheduled site visits/contacts including a liver biopsy and final assessments 72 weeks 
after randomisation (visit 19A). However the following should not be done after visit 19 for 
subjects prematurely discontinuing trial product: Semaglutide plasma concentration, anti-
semaglutide antibody assessment, hypo reporting and handing out subject diaries.
Subjects who prematurely discontinue trial product treatment will continue to receive nutritional 
and physical exercise counselling throughout their trial participation.
The total trial duration for the individual subject will be up to 85 weeks (maximum).
5.2
Rationale for trial design
Trial duration of 72 weeks is considered adequate in terms of assessing the primary endpoint. 
Furthermore, a 72-week trial period is considered to be sufficient to characterise the semaglutide 
safety and tolerability profile in patients with NASH.
Randomisation will be stratified in five strata based on region (Japanese or non-Japanese) and, 
within the non-Japanese group, based on diabetes status at screening (with or without type 2 
diabetes) and fibrosis stage for baseline liver biopsy (F2 or F3). This is to ensure an even 
distribution of the treatment arms within the specified strata. Balance of treatment arms with respect 
to region can help an evaluation of consistency of treatment effect between the entire population 
and Japanese subjects. Diabetes status and fibrosis stage for baseline liver biopsy are considered 
important prognostic covariates and including them in the stratification may enhance the credibility 
of the results of the trial as well as improve the precision of the estimated treatment effect. 
Stratification based on diabetes status and fibrosis stage is not feasible within the Japanese group 
due to small sample sizes. 
As gastrointestinal AE rates are anticipated to increase with higher doses and with large excursions 
in the semaglutide plasma concentration, semaglutide is dosed once daily to ensure less variability 
in concentrations. Dose escalation every fourth week is chosen to reach steady state at each dose 
level before increasing the dose. This could potentially reduce gastrointestinal AEs.
The trial design and protocol has been developed with harmonised advice from the regulatory 
authorities of the USA and Germany, and based on the recommendation of the Liver Forum40 41.
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5.3
Treatment of subjects
The dosing of semaglutide or placebo will be once daily with increase to the next dose step every 
four weeks until the randomised dose level is reached. During the dose escalation period subjects 
will be allowed to stay up to one extra week on each dose level, if the dose is not tolerable due to 
gastrointestinal events or for other reasons as judged by the investigator. 
Table 5–1
Duration of dose escalation period 
Once the randomised target dose is reached the subject should not change the dose. In case the dose 
escalation regimen or the target dose cannot be tolerated the subject must be discontinued from 
treatment.
The following investigational medicinal products (IMP) will be supplied by Novo Nordisk A/S, 
Denmark:
!
Semaglutide 1.0 mg/ml, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Semaglutide placebo, solution for injection, 3.0 ml cartridge, for NovoPen® 4
Auxiliaries to IMP will be supplied by Novo Nordisk e.g. needles.
The NovoPen® 4 device that will be used in this trial will display a value and not mg. 
The conversion table below shows the connection between each volume matched dose level and the 
value shown in the display on the NovoPen® 4. Subjects must be instructed to administer the value
shown in the display.
Target dose
Scheduled time to target dose
Flexibility allowed if not tolerated
Maximum time to target dose
Semaglutide 0.4 mg/day 16 weeks
4 weeks
20 weeks
Semaglutide 0.2 mg/day 8 weeks
2 weeks
10 weeks
Semaglutide 0.1 mg/day 4 weeks
1 week
5 weeks
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Table 5–2
Dose conversion table
Value shown in display
Semaglutide (mg)
FL
5
0.05 mg
50 ZL
10
0.10 mg
100 ZL
20
0.20 mg
200 ZL
30
0.30 mg
300 ZL
40
0.40 mg
400 ZL
Throughout the trial subjects cannot initiate treatment with:
!
Glucose-lowering agents other than trial product
!
Vitamin E
!
Drugs with potential effect on steatosis (corticosteroids (topical and inhaled are allowed), 
methotrexate, tamoxifen, valproic acid, amiodarone or tetracycline)
!
Drugs that could promote weight loss (orlistat, zonisamide, topiramate, phentermine, lorcaserin, 
bupropion and naltrexone alone or in combination with any other medication that could promote 
weight loss).
Neither can subjects participate in any organised weight reduction programme throughout the trial.
5.3.1
Subjects treated with basal insulin
The following basal insulins are allowed:
!
Insulin glargine
!
Insulin detemir
!
Insulin degludec
!
Neutral protamine Hagedorn (NPH) insulin
Subjects treated with basal insulin:
Throughout the trial, insulin dose should be titrated at the discretion of the investigator. For the 
individual subject, increasing the insulin dose before two weeks after the end of the dose-escalation 
should be avoided, unless required to control acute hyperglycaemia and acute diabetic 
complications. 
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Subjects treated with basal insulin with HbA1c G 8.0 % at screening:
Subjects with HbA1c M 8.0 % at screening (visit 1) should have the insulin dose reduced by 30 % at 
start of trial product treatment to limit the potential risk of hypoglycaemia induced by the 
combination of insulin and semaglutide. 
5.3.2
Missed dose
If a subject forgets to inject a trial product dose, the dose can be administered as soon as the subject 
remembers. However, if it is more than 12 hours since the subject should have administered the 
dose, the subject should skip the missed dose and take the next dose as usual on the following day.
If a subject has missed several consecutive doses of trial product, trial product can be continued. 
Please refer to guidance document describing recommendations on how to re-initiate trial product.
5.3.3
Nutritional and physical activity counselling
All subjects will receive nutritional and physical activity counselling (see section 8.6.3).
5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued prematurely, the investigator should discuss other potential treatment options with the 
subject. For subjects with type 2 diabetes investigator should also discuss potential treatment 
options for type 2 diabetes.
5.5
Rationale for treatment
Subjects are enrolled for a treatment period of 72 weeks in order to be able to evaluate the full 
effect of treatment on the primary and secondary endpoints as well as to be able to make a 
reasonable safety assessment. This is based on the knowledge from the LEAN study (investigator 
sponsored study) where a statistically significant greater number of patients had resolution of 
NASH after 48 weeks of treatment with liraglutide 1.8 mg compared with placebo in patients with 
biopsy confirmed NASH. After 48 weeks of treatment, 9 out of 23 (39%) subjects treated with 
liraglutide compared to 2 out of 22 (9%) subjects treated with placebo had resolution of NASH with 
no worsening of fibrosis (relative risk 4R3 [95% CI 1R0–17R7]; p=0R019) compared to 
placebo34.Thus, given the relatively long time required to reach the target dose of the highest 
semaglutide doses, and in order to see the full effect of the different doses, trial duration of 
72 weeks was chosen.
The comparator in the trial is placebo. Placebo is used in order to evaluate the absolute safety and 
efficacy of once-daily semaglutide. Currently, there are no approved therapies for NASH. 
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The semaglutide dose levels of 0.1 mg/day to 0.4 mg/day have been chosen to get a wide range of 
exposure. This will allow for dose-response modelling which in combination with safety 
information related to the individual doses, will form the basis for selecting the optimal semaglutide 
dose for patients with NASH.
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 744.
Number of subjects planned to be randomised: 372 (50% screen failure rate).
Number of subjects expected to complete the trial on or off trial product: 335 (10% trial withdrawal 
rate).
Number of subjects expected to complete the trial on trial product: 316 (15% total trial product 
discontinuation rate).
The aim is that between 30 and 70% of subjects should have NASH and type 2 diabetes.
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, aged 18-75 years (both inclusive) (for Japan: male or female aged 20-75 
years (both inclusive)) at the time of signing informed consent.
3. Stable body weight (defined as less than 5% self-reported change in body weight in the 
period from 28 days prior to screening or if recent biopsy is used from 28 days prior to 
baseline liver biopsy until time of screening).
4. Accept to have one liver biopsy performed during the screening period (if no biopsy within 
21 weeks before screening is available) and one at 72 weeks after randomisation.
5. Local histological diagnosis of NASH followed by histological confirmation of NASH 
based on central pathologist evaluation of a liver biopsy obtained up to 21 weeks before 
screening.
6. A histological NAS > 4 with a score of 1 or more in each sub-component of the score based 
on central pathologist evaluation.
7. NASH fibrosis stage 2 or 3 according to the NASH CRN fibrosis staging system based on 
central pathologist evaluation.
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6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
Liver-related:
1. Documented causes of chronic liver disease other than NASH.
2. Positive HBsAg, positive anti-HIV, positive HCV-RNA.
3. AST greater than 5 times upper normal limit (UNL) at screening.
4. ALT greater than 5 times UNL at screening.
5. Elevated total bilirubin (> 1.5 mg/dL) at screening.
6. Prothrombin time (INR) > 1.3 at screening.
7. Known or suspected abuse of alcohol (> 20 g/day for women or > 30 g/day for men), 
alcohol dependence* or narcotics. (* = assessed by the Alcohol Use Disorders Identification 
Test (AUDIT questionnaire)).
8. Treatment with vitamin E which has not been at a stable dose in the period from 28 days 
prior to screening or if recent biopsy is used from 28 days prior to baseline liver biopsy until 
time of screening.
9. Treatment with drugs with potential effect on steatosis; Corticosteroids (topical and inhaled 
are allowed), Methotrexate, Tamoxifen, Valproic acid, Amiodarone or Tetracycline in the 
period from 28 days prior to screening or if recent biopsy is used from 28 days prior to 
baseline liver biopsy until time of screening.
Glycaemia related:
10. HbA1c > 9% at screening.
11. Treatment with GLP-1 RAs or SGLT-2 inhibitors in the period from 90 days prior to 
screening or if recent biopsy is used from 90 days prior to baseline liver biopsy until time of 
screening.
12. Treatment with bolus (fast-acting) insulin in the period from 28 days prior to screening or if 
recent biopsy is used from 28 days prior to baseline liver biopsy until time of screening.
13. Treatment with other glucose lowering agent(s) (apart from what is listed in exclusion 
criterion 11 and 12) not stable in the period from 28 days prior to screening or if recent 
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biopsy is used from 28 days prior to baseline liver biopsy until time of screening. Changes 
without clinical relevance in the opinion of the investigator are allowed.
14. Diagnosis of type 1 diabetes according to medical records.
Obesity related:
15. Body Mass Index (BMI) M 25.0 or L 45.0 kg/m2 at the screening visit (visit 1).
16. TSH > 6 mIU/L or < 0.4 mIU/L at screening.
17. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion and 
naltrexone alone or in combination or any other medication that could promote weight loss 
in the opinion of the investigator in the period from 28 days prior to screening or if recent 
biopsy is used from 28 days prior to baseline liver biopsy until time of screening.
18. Participation in an organised weight reduction program (e.g. WeightWatchers®) in the 
period from 28 days prior to screening or if recent biopsy is used from 28 days prior to 
baseline liver biopsy until time of screening.
19. Previous surgical treatment for obesity. However (1) liposuction and/or abdominoplasty if 
performed > 6 months before baseline liver biopsy is allowed or 2) lap banding where the 
band has been removed > 6 months before baseline liver biopsy is allowed 3) intragastric 
balloon where the balloon has been removed > 6 months before baseline liver biopsy is 
allowed.
General safety:
20. Proliferative retinopathy or maculopathy requiring acute treatment verified by fundus 
photography or dilated fundoscopy performed within the past 90 days prior to 
randomisation. 
21. History or presence of pancreatitis (acute or chronic).
22. Calcitonin L 50 ng/L at screening.
23. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
24. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
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25. Surgery scheduled for the trial duration period, except for minor surgical procedures, in the 
opinion of the investigator.
26. Any condition which, in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
27. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures.
28. Known or suspected hypersensitivity to trial product or related products.
29. Previous participation in this trial. Participation is defined as randomisation.
30. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
31. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures 
as required by local regulation or practice).
For EU countries: The following contraceptive measures are considered adequate:
!
Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal
!
Progestogen-only hormonal contraception associated with inhibition of ovulation :
o
oral
o
injectable
o
implantable
!
Placement of an 
o
intrauterine device (IUD) 
o
intrauterine hormone-releasing system ( IUS)
!
Bilateral tubal occlusion
!
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository) (not applicable for Belgium, Denmark, Finland, Greece, 
Spain, Sweden)
!
Vasectomised partner (where partner is sole partner of subject) (not applicable for Denmark)
!
True sexual abstinence (not applicable for Denmark). Sexual abstinence is defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
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study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.
. 
6.4
Criteria for premature discontinuation of trial product 
Efforts must be made so that subjects attend and complete all scheduled visit procedures. However 
the following should not be done after visit 19 for subjects prematurely discontinuing trial product:
Semaglutide plasma concentration, anti-semaglutide antibody assessment, hypo reporting and 
handing out subject diaries. Subjects should stay in the trial irrespective of lack of adherence to 
randomised treatment, lack of adherence to visit schedule or missing assessments. Only subjects 
who decline any further contact with the site in relation to the trial will be considered as withdrawn 
from the trial (see section 6.5).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The subject must be prematurely discontinued from trial product 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
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
5. In case of code break
6. If the target treatment dose of the randomised trial product is not tolerated by the subject
7. Diagnosis of acute pancreatitis
8. Diagnosis of medullary thyroid carcinoma
9. Surgical treatment for obesity
10. Treatment with other GLP-1 receptor agonists, SGLT-2 inhibitors or bolus (fast-acting) 
insulin 
See section 8.1.5 for procedures to be performed for subjects discontinuing trial product 
prematurely.
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6.5
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected.
Please see section 8.1.6 for procedures to be performed for subjects withdrawing consent.  
6.6
Subject replacement
Subjects who discontinue trial product prematurely or withdraw from the trial will not be replaced.
6.7
Rationale for trial population 
Patients with NASH have an increased risk of all cause and liver related mortality. As there is 
currently no established, safe and effective pharmacological treatment for NASH there is a 
significant unmet medical need. 
As the prevalence of NASH is high in patients with T2D (approximately 25% of patients with T2D 
have NASH) and considering the glycaemic properties of semaglutide it is appropriate not to 
exclude patients with T2D in the trial. Hence both patients with and without T2D can be included as 
it is the aim to include a broad NASH population. 
The trial population will consist of patients with NASH and a fibrosis stage of F2-F3. Patients with 
F0 and F1 will be excluded as they do not have fibrosis (F0) or are less progressed in the disease 
spectrum, why less benefit may be achieved on fibrosis (F1). Furthermore, subjects with fibrosis 
stage 4 (cirrhosis) will be excluded from the trial as an important endpoint addressing worsening in 
fibrosis cannot be addressed in this population (the Kleiner classification has a maximum score of 
4). 
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8
Methods and assessments
The following sections describe the assessments and procedures that must be performed during this 
trial. The overview of when they must be performed is included in the flow chart (section 2).
8.1
Visit procedures
8.1.1
Screening, re-screening and screen failures
Informed consent must be obtained before any trial related activity, see section 18.2. Separate 
informed consent forms for long-term storage of human samples and genotyping are available and 
informed consent must be obtained before activities related to any of these are undertaken.
At screening (visit 1), 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.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log and may be 
generated from the IWRS (see section 10).
Screening failures
For screening failures the screening failure form in the electronic case report form (eCRF) 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 eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to section 12.
A screening failure session must be made in the IWRS. The case book in the eCRF must be signed.
Re-screening
Re-screening of screening failures is allowed only once within the limits of the recruitment period. 
However, re-screening is NOT allowed if the subject has failed one of the inclusion/exclusion 
criteria related to laboratory parameters (histological NAS, NASH fibrosis stage, HBsAg, anti-HIV, 
HCV-RNA, AST, ALT, total bilirubin, INR, HbA1c, calcitonin or TSH). In the event of re-
screening, a new informed consent must be obtained and a new subject number must be allocated. 
All assessments and laboratory samples must be repeated.
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8.1.2
AUDIT questionnaire
The AUDIT questionnaire is used to assess the frequency of alcohol consumption and screen out 
alcohol-related problems, and dependence symptoms. 
8.1.3
Fasting visits
Subjects must attend some of the clinic visits in a fasting state (see section 2).
Fasting is defined as at least eight hours without food or liquids, except for water. Trial product and 
any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling has been performed. If the subject is not fasting as required, the subject 
must be called in for a new visit within the visit window to have the fasting procedures done. 
Fasting procedures include body weight, Fibroscan® measurements and blood sampling.
Prior to Fibroscan® measurements, only two hours of fasting is required.
At visit 19, the subject must be fasting for two hours prior to the anti-semaglutide antibody 
sampling (see section 8.5.3.7).
8.1.4
Missed visits
If an entire visit is missed and it is not possible to re-schedule the visit within the time window, 
every effort should be made to re-schedule the visit at the earliest possible date before the next visit.
8.1.5
Premature discontinuation of trial product
If a subject prematurely discontinues trial product treatment, the investigator must undertake 
procedures similar to those for visit 18 (end of treatment) as soon as possible and the follow up visit 
(visit 19) must be performed 7 weeks later. Females only: All female subjects using an adequate 
contraceptive method must be reminded to continue this for 7 weeks after discontinuation of trial 
product treatment.
Following visit 19, subjects should continue with the originally scheduled site visits/contacts up to 
and including visit 19A. Visit 19A should take place 72 weeks (± 7 days) after their randomisation 
date (for details refer to section 2). However the following should not be done after visit 19 for 
subjects prematurely discontinuing trial product: Semaglutide plasma concentration, anti-
semaglutide antibody assessment, hypo reporting and handing out subject diaries.
If a subject is not willing to attend one or more of the above mentioned visits, it should be 
documented in the subject’s medical record that the subject has refused to attend the visit and why.
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For subjects discontinued from trial product, final drug accountability must be performed and a 
treatment discontinuation session must be made in the IWRS. The primary reason for premature
discontinuation of trial product must be specified in subject’s medical records and the eCRF. 
8.1.6
Withdrawn subjects
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 18 (end of treatment) as soon as possible. If the subject agrees, the follow up visit (visit 19) 
must be performed 7 weeks later.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS. The case book must be signed.
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
8.1.7
Subject training
Subject diaries
The subject must be provided with diaries at the specified visits (section 2). The investigator should 
instruct the subjects in filling in the diary according to the provided diary instructions (see section
8.4.7 and 8.6.2). The diaries dispensed to subjects should be collected at the specified visits (section
2).
Trial product
Trial product must be dispensed to subjects at the specified visits (see section 2). Trial product will 
be dispensed to the subject by the site. At the visits specified in section 2 and as needed, the 
subjects will be instructed in the handling of trial product and trained in the use of the pen-injector 
and in the administration of s.c. injection of trial product.
Subjects must be instructed to administer the value shown in the display, see Table 5–2.
Hypoglycaemic episodes recognition
The investigator or delegate will train the subjects in symptom recognition and handling of 
hypoglycaemia.
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Suspected pregnancy
Female subjects must be instructed to contact site if a menstrual period is missed so they can come 
in for urine pregnancy test.
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at visit 1) or found as 
a result of a screening procedure or other trial procedures performed before exposure to trial 
product. 
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.
Medical history is a medical event that the subject has experienced in the past. Only relevant and 
significant medical history as judged by the investigator should be recorded. Specific medical 
history of gallbladder disease should only be entered on the specific form.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigator´s own practice; the investigator must make 
reasonable effort to obtain a copy of the subject’s medical record from any relevant party e.g. 
primary physician. The investigator must document any attempt to obtain external medical 
information by noting the date(s) when information was requested and who has been contacted.
8.2.3
Concomitant medication
A concomitant medication is any medication, other than the trial product(s), 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 date and stop date or continuation. 
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Hypoglycaemia unawareness
For subjects with type 2 diabetes information on hypoglycaemia unawareness will be recorded at 
screening according to Clarke’s questionnaire, question 847. The investigator must ask the subject in 
the following way: “To what extent can you tell by your symptoms that your blood glucose is low?” 
The subject can answer never, rarely, sometimes, often or always.
Subjects answering ‘never, rarely or sometimes’ are considered as having impaired awareness of 
hypoglycaemia.                                 
8.2.5
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
Pregnancy testing must be performed on female subjects of childbearing potential as described in 
section 8.5.3.6. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 7 weeks after end of treatment.
Female of non-childbearing potential is defined as:
–
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation 
–
Postmenopausal defined as no menses for 12 months without an alternative medical cause
–
Other medical reasons preventing childbearing potential
8.2.6
Tobacco use 
Details of tobacco use must be recorded at the first visit. Smoking is defined as smoking at least one 
cigarette or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker
!
Current smoker
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8.3
Efficacy assessments
8.3.1
Liver biopsy
Liver biopsies must be performed according to site standard procedures.
To be randomised, subjects must have a local histological diagnosis of NASH followed by
histological confirmation of NASH diagnosis based on central pathologist evaluation of a liver 
biopsy. Confirmation of NASH diagnosis can be based on a liver biopsy obtained up to 21 weeks 
prior to screening. For subjects with no historical liver biopsy within 21 weeks prior to screening, a 
liver biopsy must be performed during the screening period. The local NASH diagnosis and the 
confirmation of NASH diagnosis by central pathologist evaluation of the liver biopsy must be 
available prior to randomisation of the subject. The local NASH diagnosis and the confirmation of 
NASH diagnosis by central pathologist evaluation can be done on the same liver biopsy sample.
In case the liver biopsy obtained during the screening period or up to 21 weeks prior to screening
cannot be used for confirmation of NASH diagnosis due to technical issues with the biopsy sample,
the subject should be asked to have another liver biopsy performed. If the subject does not agree to 
that, the subject is a screen failure.
All randomised subjects should have a liver biopsy performed at end of treatment (if the 72 weeks
treatment period is completed) or at 72 weeks after randomisation (if trial product has been 
prematurely discontinued). In case conclusive evaluation of this biopsy is not possible due to 
technical issues with the biopsy sample, the subject should be asked to have another liver biopsy 
performed.
Handling of histology samples will be done by a central laboratory. Descriptions of laboratory 
supplies, procedures for preparation of tissue samples, handling, storage, shipments and return of 
tissue samples, will be given in the trial-specific laboratory manual provided by the central 
laboratory.
Histology results will be made available to the investigator.
Only tissue samples requested in the protocol must be sent to the central laboratory.
Tissue samples will be returned to the relevant sites no later than at finalisation of the clinical trial 
report (CTR).
8.3.1.1
Central pathologist evaluation
The NASH diagnosis and histology based scores will be centrally assessed by two independent 
pathologists with expertise and experience in NASH.
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The central pathologist evaluation will include the following:
!
Presence or absence of NASH
!
NAFLD Activity Score (NAS) components (steatosis, lobular inflammation and hepatocyte 
ballooning) 
!
Stage of fibrosis (according to Kleiner fibrosis classification)
The pathologists will be blinded to the subject and treatment and to each other’s assessment of the 
tissue until both have reached a final conclusion. Both pathologists have to agree on the outcome of 
the assessment. In case of misalignment of the conclusions, a consensus needs to be reached by 
discussion or joint assessment of the two pathologists. If not possible a third independent, qualified 
pathologist will make the final decision.
8.3.2
Fibroscan® measurements
At sites where Fibroscan® equipment is not available, no assessment should be done.
Liver stiffness
At sites with Fibroscan® equipment available, measurements of liver stiffness must be performed at 
the specified visits (section 2). A result measured in kPa must be available. The same equipment 
should preferably be used for all measurements throughout the trial.
All randomised subjects should have a liver stiffness measurement performed 72 weeks after 
randomisation regardless of whether trial product has been discontinued prematurely or not.
The liver stiffness measurements must be performed in fasting state (see section 8.1.3) and
according to site standard procedures. The result of the measurement must be documented and 
investigator evaluation of the result must be documented either on the actual report or in the
subject´s medical record.
Liver steatosis
At sites with Fibroscan® equipment available with Controlled Attenuation Parameter (CAP) option 
available, measurements of liver steatosis must be performed at the specified visits (section 2). A 
result measured in dB/m must be available. The same equipment should preferably be used for all 
measurements throughout the trial.
All randomised subjects should have a liver steatosis measurement performed 72 weeks after 
randomisation regardless of whether trial product has been discontinued prematurely or not.
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The liver steatosis measurements must be performed in fasting state (see section 8.1.3) and 
according to site standard procedures. The result of the measurement must be documented and 
investigator evaluation of the result must be documented either on the actual report or in the 
subject´s medical record.
8.3.3
Body measurements
8.3.3.1
Body weight
Body weight must be measured in a fasting state (except at visit 1), see flowchart (section 2) and 
will only be measured at visits where subjects are fasting due to blood sampling. 
The body weight should be measured with an empty bladder, without shoes and only wearing light 
clothing. It must be recorded with one decimal (kg or lb) and preferably using the same digital scale 
throughout the trial. The scale must be calibrated according to the directions for use.
8.3.3.2
Height
Height is measured at screening (visit 1) without shoes in centimetres or inches (one decimal).
8.3.3.3
Body mass index
Body mass index will be calculated by the eCRF from visit 1 height data and must be in accordance 
with exclusion criterion 15.
8.3.3.4
Waist circumference
The waist circumference is defined as the abdominal circumference located midway between the 
lower rib margin and the iliac crest and will be measured at the specified visits (section 2).
One waist measurement must be performed and is measured in the horizontal plane with one 
decimal using a non-stretchable measuring tape. The same measuring tape should preferably be 
used throughout the trial.
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing. The subject should be standing, feet together with arms at the side and waist accessible. 
The tape should touch the skin but not compress soft tissue and twists in the tape should be avoided. 
The subject should be asked to breathe normally.
8.3.3.5
Vital signs
Systolic and diastolic blood pressure
One measurement of blood pressure must be performed at the visits specified in section 2.
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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
!
Blood pressure should be measured in a sitting position, with the legs uncrossed, the back and 
arms supported
!
The subject should be sitting for five minutes before the measurement is taken
The same arm and an appropriate cuff size should be used for blood pressure measurement at all 
visits
Pulse
Pulse (beat/min) will be recorded in a sitting position after resting for five minutes at the specified 
visits (section 2).
8.3.4
SF-36 questionnaires
The Short Form 36 (SF-36) should be completed by subjects at the visits specified in section 2.
The questionnaires must be completed by the subject and should preferably be completed after 
conclusion of all fasting-related activities, but before any other visit-related activities. Subjects must
be given the opportunity to complete the questionnaires by themselves without interruption.
SF-36 measures the individual’s overall health-related quality of life (HRQoL) on 8 domains: 
physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role 
emotional and mental health.
Review of the questionnaires must be documented either on the documents and/or in the subject’s 
medical record. If clarification of entries or discrepancies in the patient reported outcomes 
questionnaires 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.
It is the responsibility of the investigator or delegated staff to review the questionnaires to report 
possible AEs immediately following completion. 
All results from the SF-36 questionnaires must be transferred into the eCRF.
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8.4
Safety assessments
8.4.1
Physical examination
Physical examination will be performed at the specified visits (section 2) according to local 
procedure. Physical examination must be recorded in the subject´s medical record and should 
include:
! General appearance 
! Thyroid gland 
! Respiratory system
! Cardiovascular system
! Gastrointestinal system including mouth
! Musculoskeletal system
! Central and peripheral nervous system
! Skin
! Lymph node palpation
! Head, ears, eyes, nose, throat and neck
Any abnormal, clinically significant findings at visit 1 must be recorded as a concomitant illness 
(see section 8.2.2).
8.4.2
Electrocardiogram
A 12-lead ECG will be performed at the visits specified in the flow chart (section 2). The 
investigator or delegate must sign, date and interpret the ECG by using the following categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
All ECGs will in addition undergo central evaluation. Sites will be informed of the central ECG 
evaluation in case this evaluation reveals an abnormal ECG reading. If the abnormality, in the 
opinion of the investigator, represents an unreported AE, such finding must be reported by the 
investigator (see section 12.2).
If the central ECG evaluation of a post-baseline ECG is suggestive of new MI, a confirmatory ECG 
should be performed. All findings suggestive of new MI detected by the central ECG reading will 
be adjudicated by the event adjudication committee (EAC) (see section 12.7.2).
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8.4.6
Self-measured plasma glucose
At the randomisation visit (visit 2) subjects with type 2 diabetes will be provided with a blood 
glucose meter (BG-meter) including auxiliaries as well as instructions for use. The subjects will be 
instructed in how to use the device and the instruction will be repeated at regular intervals as 
needed. Subjects must be instructed to measure their blood glucose in connection with symptoms of 
hypoglycaemia.
The blood glucose meters use test strips calibrated to plasma values. Therefore, all measurements 
performed with capillary blood are automatically calibrated to plasma equivalent glucose values, 
which will be shown on the display.
Only the blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol.
Subjects without type 2 diabetes at the randomisation visit will not be provided with BG-meters and 
hypoglycaemic episodes will only be identified by subjects via symptoms of hypoglycaemia.
In case a subject is diagnosed with type 2 diabetes during trial participation, the subject must be 
provided with a BG-meter and must be instructed in how to use the device and to measure their 
blood glucose in connection with symptoms of hypoglycaemia in the remaining trial period.
Subjects with type 2 diabetes should be instructed in how to record the results of the SMPG values 
in the diaries. The record of each SMPG value should include date, time and value. All data from 
the diary must be transcribed into the eCRF during or following the contact. If obtained via phone
and a discrepancy is later detected, the values in the eCRF must be corrected.
Occasional review by the investigator of the values stored in the memory of the blood glucose meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the trial database.  
8.4.7
Hypoglycaemic episodes
All subjects will at randomisation be instructed in symptom recognition and handling of 
hypoglycaemia.
All subjects will be provided with diaries for capturing information related to hypoglycaemic 
episodes throughout the trial from visit 2 to visit 19 (7 weeks after end of treatment visit (visit 18)).
For subjects with type 2 diabetes plasma glucose should always be measured and recorded when a 
hypoglycaemic episode is suspected.
All plasma glucose values:
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!
M 3.9 mmol/L (70 mg/dL) or
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below throughout the trial from visit 2 
to visit 19 (7 weeks after end of treatment visit (visit 18)).
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelines48.
An SMPG value M 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is > 3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements M 3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 min period shall trigger the reporting of a new hypoglycaemia episode and 
prompt the subject to fill out a new hypoglycaemic episode form until a succeeding measurement is 
> 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
For all subjects the records on hypoglycaemic episodes should include the following information (in 
subject diaries):
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the plasma glucose 
value is > 3.9 mmol/L (70 mg/dL) (only applicable for subjects with type 2 diabetes) and/or 
symptoms have been resolved).
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements (only applicable for subjects with type 2 diabetes).
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode.
!
Whether the subject was able to treat him/herself.  
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If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported, reflecting the most severe degree of hypoglycaemia.
!
Date, time and dose of last trial product administration prior to the episode.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness.
!
Any sign of fever and/or other acute disease.
!
Whether the subject was asleep when the episode occurred.
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration48.
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person, please specify)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not, please specify)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, intravenous 
(IV) glucose or other, please specify)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), miscalculation of dose 
of antidiabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?    
!
Did the subject experience any of the following symptoms49 (layman term used in the diary is 
specified in brackets if different from the protocol term)?
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
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!
Other symptoms
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety
information form must also be filled in, see section 12.
8.4.8
Hyperglycaemic episodes
Self-measured plasma glucose values or central laboratory FPG values > 16.7 mmol/L (300 mg/dL) 
must be reported as adverse events (see section 12.2). Subjects should be instructed to contact site 
staff in case of hyperglycaemia. Applicable for subjects with type 2 diabetes only: Whenever a 
hyperglycaemic episode is suspected, plasma glucose should be measured with the BG-meter 
handed out.
8.5
Laboratory assessments
The laboratory analyses will be performed by a central laboratory except for analysis of anti-
semaglutide antibodies and semaglutide plasma concentration analysis and some exploratory 
biomarkers which will be performed at specialised laboratories. The central laboratory may utilise 
subcontractors for their analyses.
Descriptions of laboratory supplies, procedures for obtaining samples, handling, storage and 
shipments of samples, will be given in the trial-specific laboratory manual provided by the central 
laboratory.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
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 will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Laboratory samples may be drawn on another day than the day of the actual visit, as long as it is 
within the visit window outlined in the flow chart (see section 2). 
Laboratory results will be made available to the investigator on an on-going basis except for the 
anti-semaglutide antibody results, the results of the semaglutide plasma concentration analysis and 
the exploratory biomarker results. Anti-semaglutide antibody results and the results of the
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semaglutide plasma concentration analysis will not be provided to the investigator, as these results 
will not be used for any clinical evaluation during the trial and would potentially unblind the 
treatment. Exploratory biomarker results will not be provided to the investigator, as these results 
will not be used for any clinical evaluation during the trial.
Laboratory samples, including specific safety assessments, will be destroyed no later than at 
finalisation of the clinical trial report (CTR).
Antibody samples and biosamples for future analysis will be stored as described in section 24.2.
8.5.1
Review of laboratory reports
Review of laboratory reports must be documented either on the documents and/or in the subject’s 
medical record. 
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not. The evaluation of screening results must be documented prior 
to visit 2 (randomisation), for the subsequent visits preferably on the day of evaluation.
It is the responsibility of the investigator or delegated staff to review the laboratory reports and to 
report possible AEs immediately following completion of the review.
8.5.2
Laboratory assessments for efficacy
8.5.2.1
Biochemistry
!
ALT
!
AST
!
GGT
!
hsCRP
!
Lipids (Total cholesterol, free fatty acids, HDL cholesterol, LDL cholesterol, triglycerides,
VLDL cholesterol)
!
Fib-4 and NFS (refer to section 17.4.1.1)
8.5.2.2
Glucose metabolism
!
FPG
!
HbA1c
!
Fasting insulin
!
Fasting glucagon
!
HOMA-IR (refer to section 17.4.1.1) 
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FPG is measured to evaluate metabolic control. The subjects must attend these visits fasting (for 
definition of fasting, see section 8.1.3). An FPG result M3.9 mmol/L (70 mg/dL) should not be 
reported as a hypoglycaemic episode but as a clinical laboratory adverse event (CLAE) at the 
discretion of the investigator (see section 12.1.1). 
8.5.2.3
Exploratory biomarkers
!
CK-18 fragments
!
ELF (refer to section 17.4.1.1)
!
miR-122
!
IL-1R antagonist
!
MCP-1
!
FGF-21
8.5.2.4
Biosamples for future analysis:
Biosamples for future analysis must be drawn/collected and shipped to the central lab at the visits 
specified in section 2. The details and instructions around these samples are described in the trial-
specific central laboratory manual. Please refer to section 24.2 for more information about the 
planned use of the samples.
8.5.3
Laboratory assessments for safety
Blood samples for haematology and biochemistry must be collected at the specified visits (section
2).
8.5.3.1
Biochemistry
!
Bilirubin, total
!
Calcium
!
Creatinine phosphokinase
!
Creatinine
!
Lipase
!
Potassium
!
Sodium
!
Alkaline phosphatase
!
Amylase
!
Albumin
!
Ferritin
!
Urea
!
MELD score50
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8.5.3.7
Anti-semaglutide antibodies
Blood samples will be drawn during the trial and analysed at a specialised laboratory for 
determination of serum antibodies against semaglutide, including cross reactivity to endogenous 
GLP-1 (see flow chart, section 2). 
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
has been performed at the visit. 
Samples taken at the follow-up visit (visit 19) must be taken fasting (as a minimum by only having 
consumed water for at least 2 hours). Samples taken at the follow-up visit which are positive for 
anti-semaglutide antibodies will be further characterised for in vitro neutralising effect towards 
semaglutide. In addition, samples taken at the follow-up visit which are positive for cross-reactivity 
against endogenous GLP-1 will be analysed for in vitro neutralising effect towards endogenous 
GLP-1.
8.6
Other assessments
8.6.1
Semaglutide plasma concentration
For all subjects a single blood sample for measurement of plasma semaglutide concentration will be 
drawn at selected visits (see section 2).
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
is performed on the visit. In addition subjects must be instructed to complete their diary (see section 
8.6.2) and bring it to the visits.
8.6.2
Subject diaries
Review of subject diaries must be documented either on the documents and/or in the subject’s 
medical record. If clarification of entries or discrepancies in the diary 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.
The following information will be captured in subject diaries:
!
Information regarding first trial product dose (date, time, dose, injection site)
!
Information regarding trial product doses (prior to each visit with blood sampling for 
measurement of semaglutide plasma concentration after randomisation until the end of 
treatment visit)
!
Information regarding hypoglycaemic episodes
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Trial product dosing information
The subject must record the date, time, dose and injection site of the last trial product injection prior 
to the clinic visit. Furthermore, the subject must fill in if any trial product doses were not taken in 
the previous two weeks. This information will be collected at all visits with blood sampling for 
measurement of semaglutide plasma concentration until the end of treatment visit. The information 
will be transcribed to the eCRF by the investigator or delegate together with the exact date and time 
for blood sampling, when applicable.
Hypoglycaemic episodes
For information to be captured regarding hypoglycaemic episodes, please refer to section 8.4.7.
8.6.3
Nutritional and physical activity counselling
Subjects will recieve nutritional and physical activity counselling in accordance with site practice at 
the visits specified in section 2.
8.7
Specific safety requirements
8.7.1
Suspicion of acute pancreatitis
Assessments in case of suspicion of acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following three features: 
!
abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric 
pain often radiating to the back)
!
serum lipase activity (and/or amylase activity) at least three times greater than the upper limit of 
normal
!
characteristic findings of acute pancreatitis on imaging.
Abdominal pain
Most patients with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 minutes, it is frequently unbearable and characteristically persists for more than 
24 hours without relief. The pain is often associated with nausea and vomiting. Physical 
examination usually reveals severe upper abdominal tenderness at times associated with guarding. 
Lipase and amylase
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
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8.7.3
Training in the delivery device (NovoPen® 4)
Trial product must be dispensed to subjects at the specified visits (see section 2). At the visits 
specified in section 2 and as needed, the subjects will be instructed in the handling of trial product 
and trained in the use of NovoPen® 4 and in the administration of s.c. injection of trial product.
The subjects must be trained in how to handle the delivery device (NovoPen® 4) and in use of the 
pen-injector when handed out the first time. Training must be repeated during the trial at regular 
intervals and as needed in order to ensure correct use of the device. 
The following should be emphasised:
!
Always use a new needle for each injection as this will prevent contamination and blocked 
needles
!
Priming the pen to ensure product flow 
!
The needle should be kept in the skin while counting slowly to 6 after the dose counter has 
returned to zero after injection. If the needle is removed too early then the full dose may not 
have been delivered.
8.8
Subject compliance
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. If the subject continues to be non-compliant the investigator 
may discontinue the subject from trial product (see section 6.4).
Treatment 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 trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
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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. 
Trial product must not be used, if it does not appear clear and colourless.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/delivery 
device
Semaglutide 1.0 mg/mL 
(Investigational 
medicinal product 
(IMP))
1.0 mg/mL
Solution for 
injection
Subcutaneous 
(s.c.) injection 
3 mL Cartridge 
for NovoPen® 4
Semaglutide placebo 
(Investigational 
medicinal product 
(IMP))
N/A
Semaglutide 1.0 mg/mL and semaglutide placebo are visually identical.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1351, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS.
Each dispensing unit (DU) is uniquely numbered with a Dispensing Unit Number (DUN).
NovoPen® 4 is a CE-marked, US FDA and Japan MHLW (Ministry of Health, Labour and Welfare) 
approved pen injector device for subcutaneous administration of insulin. This trial is investigating 
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an indication outside the approved intended use or indication for use and the NovoPen® 4 will 
therefore be labelled "exclusively for clinical investigations" worded in accordance with national 
legislation. A description of the device is included in the Investigator's Brochure.
The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (visit 2). At the later dispensing visits the investigator or delegate 
should ensure that subjects comply with injection procedures and re-dispense DFU, if needed.
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Semaglutide 1.0 mg/mL 
Store in a 
refrigerator 
between 2°C - 8°C 
(36°F – 46°F)
Do not freeze
Protect from light
Store below 30°C 
(86°F)
Do not refrigerate
Do not freeze
Protect from light
Use within 28 days
Semaglutide placebo 
a In-use time starts when the product is taken out of the refrigerator at subjects home
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the trial materials manual 
(TMM).
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
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Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product to the subject at randomisation and each dispensing visit. The 
correct dispensing unit number(s) (DUN(s)) must be dispensed to the subject.
Drug accountability is performed using the IWRS drug accountability module. The trial products 
must be accounted for at pen level and either recorded as used/partly used, unused or lost. Returned 
pens must be sent for destruction, thus may not be re-allocated to new subjects. 
Subjects must be instructed to return all used, partly used and unused trial product including empty 
packaging material at each dispensing visit and at end of treatment visit.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of trial 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following auxiliary supplies will be provided by Novo Nordisk in accordance with the TMM:
!
Needles for NovoPen® 4 pen injector (maximum length to be used is 8 mm)
!
Direction for use for NovoPen® 4 pen injector
!
Blood glucose meters (including lancets, plasma-calibrated test strips and control solutions). 
User manual will be provided along with the blood glucose meter.
Only needles provided by Novo Nordisk must be used for administration of trial product.  
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
In this trial, the IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site. DUNs will be allocated using the IWRS. It is 
important to dispense the exact allocated DUNs to a subject.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow-up due to 
the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see section 8.4.7.
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild – no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities.
–
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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•
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) 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 the definition of SAEd. 
a. The term “life threatening” in the definition of SAE refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
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not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product 
!
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug or use of wrong device. 
Note: Use of wrong DUN is not considered a medication error.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product.
!
Accidental administration of a lower or higher dose than intended; however, the administered 
dose must deviate from the intended dose to an extent where clinical consequences for the trial 
subject were likely to happen as judged by the investigator, although they did not necessarily 
occur.
Medication errors must be reported on an AE form and a specific event form, see section 8.4.4.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety. Some events in this trial will be adjudicated by an independent 
external committee as described in section 12.7.2.
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responsibility also covers uploading of clinical data for events identified in the preferred term 
(PT) search and evaluated to be relevant to adjudication by the event adjudication supplier or 
the committee chair or appointed delegate. In case copies of source data cannot be retrieved or 
are pending for a long time, the investigator should prepare and provide a narrative describing 
the event based on the information which the investigator has access to.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, 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 (visit 19) or visit 19A for subjects discontinuing trial product 
prematurely. 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?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. 
All AEs must be recorded by the investigator 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, a safety information form 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. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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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. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
Events for Adjudication: The adjudication form should be completed within 14 calendar days of
the investigator’s first knowledge of the AE and all relevant predefined documents provided within
4 weeks, see Section 12.7.2.
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF.
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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Novo Nordisk products used as concomitant medication:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as 
concomitant medication in the trial, it is important that the suspected relationship is reported to 
Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. Novo 
Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
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 until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
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.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
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in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
12.5
Pregnancies
12.5.1
Pregnancies in female subjects 
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
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2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
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.
a 
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Limited data are available with regard to overdose and semaglutide. Expected adverse events in 
connection to an overdose of subcutaneous semaglutide are gastrointestinal AEs and hypoglycaemia 
(if combined with SU and insulin). Events of nausea, vomiting and headache have been reported in 
connection with accidental administration of up to 4 mg semaglutide. No symptoms of 
hypoglycaemia have been reported in connection with overdose of semaglutide. In the event of 
overdosage, appropriate supportive treatment should be initiated according to the subject's clinical 
signs and symptoms.
12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
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Novo Nordisk will constitute an internal semaglutide safety committee to perform ongoing safety 
surveillance. The semaglutide safety committee may recommend unblinding of any data for further 
analysis, and in this case an independent ad hoc group will be established in order to maintain the
blinding of the trial personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee is established to perform validation of 
selected AEs according to pre-defined diagnostic criteria. The validation is based on review of pre-
defined clinical source data related to the specific AE. The pre-defined clinical source data consist 
of copies of source documents collected and delivered by the investigational sites.
The EAC is composed of permanent members covering required medical specialities. The EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk.
The events are reviewed by the event adjudication committee in a blinded manner. The EAC will 
have no authorisation to impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee.
The AEs for adjudication are listed in Table 12–1. In addition, cardiovascular events are being 
adjudicated according to FDA requirements1 52.
There are different processes for capturing events for adjudication:
1. Direct reporting by investigator:
All AEs need to be assessed by the investigator if any AE category is applicable. If the AE category 
selected is in scope for adjudication, the adjudication form in the eCRF will be populated for sites to 
complete. For AEs with fatal outcome the Fatal Adjudication form will appear in the eCRF when a 
fatal outcome is selected for an AE.
2. Screening: 
All AEs will be screened by Novo Nordisk for potential missed events for adjudication and if 
needed, the investigator will be asked to provide additional information such as an alternative 
aetiology, underlying cause(s) and/or clinical details.
All ECGs will be centrally read. If the central reading conclusion is suggestive of new MI, the ECG 
adjudication form will be populated for sites to complete for all post-baseline ECGs.
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3. EAC identified events:
The EAC can decide to have an AE adjudicated even if not initially reported as an event for 
adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures. 
AEs for adjudication must be reported according to section 12.2. In addition the specific
adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
reports and death certificates). The investigator must provide medical documentation as soon as 
possible, when they receive the request from Novo Nordisk or the event adjudication vendor.
The assessment made by the event adjudication committee will be included in the clinical trial 
report as well as the assessments made by the investigator. However, the adjudication made by the 
event adjudication committee, given its independent analysis of each event, will be attributed with 
greater importance of the two. The outcome of adjudication will be kept in the clinical trial 
database.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms 
!
Technical complaint forms (also to be used to report complaints that are not subject related e.g. 
discovered at trial site before allocation)
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the 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 delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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.
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 at 
the trial site 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 8 weeks during recruitment and 12 
weeks after end of recruitment until LSLV at the trial site for sites with subjects between visit 1 and 
visit 19/19A.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and PROs must not be removed from the trial site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
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`The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Reason for screening failure
!
Serious adverse events (if any)
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs)
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. They should address any action to be taken.
15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract research organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
The estimand addressing the primary objective is defined as the de-facto (effectiveness) treatment 
effect on NASH resolution without worsening in fibrosis for all randomised subjects after 72 weeks. 
All post-baseline scheduled visit data will be included in the statistical analysis, including data 
collected after discontinuation of trial product. The chosen estimand assesses the difference in 
resolution of NASH in a future population that results from initiating treatment with semaglutide as 
compared to placebo. Generalisation of this estimand depends among other things on the extent to 
which treatment adherence in this trial reflects clinical practice.
The three different placebo arms will be pooled into one placebo treatment arm in all planned 
analyses. This pooling assumes that there is no substantial effect of different semaglutide placebo 
volumes on the efficacy and safety endpoints. The validity of this assumption will be checked for 
the primary endpoint and treatment-emergent adverse events by evaluating summaries for each 
placebo arm. Should the placebo arms demonstrate substantial differences, appropriate sensitivity 
analyses will be included.
The statistical analyses will in general consist of the following three pairwise treatment 
comparisons:
!
semaglutide 0.4 mg versus placebo
!
semaglutide 0.2 mg versus placebo
!
semaglutide 0.1 mg versus placebo
The results of the comparisons will be presented as estimated treatment contrasts together with two-
sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference. The 
problem of multiple testing will be taken into account with respect to the primary endpoint (see 
section 17.2) but not for any of the secondary endpoints.
The full analysis set (FAS) will be used in the analysis of the efficacy endpoints whereas the safety 
analysis set (SAS) will be used for the safety endpoints (see the definition of the sets in section
17.2).
The baseline measurement is defined as the latest available measurement at or prior to the 
randomisation visit. An exception is made for identifying abnormal laboratory findings (including 
ALT, AST, GGT, bilirubin and INR) in which case the baseline value is defined as the mean of the 
available measurements at the screening and randomisation visits.
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Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
17.1
Sample size calculation
The sample size calculation is based on an aim to detect a difference in the probability of achieving 
NASH resolution (without worsening in fibrosis) between the highest semaglutide dose and the 
pooled placebo arm at 5% significance level, using Pearson chi-square test with normal 
approximation. The power is set to 90%.
It is expected that some subjects will respond to standard care. In the LEAN trial, 2 (9%) of 22 
placebo subjects had improvement in liver histology. In the FLINT53 and PIVENS54 trials, clearance 
of NASH was a secondary endpoint and the corresponding numbers were 13 (13%) of 98 subjects 
and 17 (21%) of 83 subjects, respectively. However, these figures also included patients that had 
worsening of fibrosis. As a conservative assumption, it is anticipated that up to 20% of the placebo 
completers will achieve resolution of NASH with no worsening of fibrosis.
It is uncertain how many subjects on semaglutide should be expected to achieve resolution of 
NASH. In the LEAN trial, an improvement was found in 9 (39%) of 23 subjects who received 
liraglutide 1.8 mg. In communication with medical advisers, a treatment difference of 20-30 
percentage points was deemed to be a realistic target as well as clinically relevant. Therefore, it is 
assumed that 45% of the subjects who complete treatment with semaglutide 0.4 mg achieve 
resolution of NASH.
Based on the previous NASH trials, 15% of the randomised subjects are anticipated to prematurely 
discontinue trial product before week 72. These will be included in the main analysis either by 
using the observed outcome at week 72 (if the outcome is known) or by using imputation (if the 
outcome is not known). In either case, it is assumed that none of these subjects will achieve 
resolution of NASH.
Based on the assumptions above, the required number of randomised subjects per arm for the 3 
semaglutide arms and the pooled placebo arm is found to be 91. Since the number in the pooled 
placebo arm needs to be divisible by 3, the number of subjects in each arm is adjusted to 93. Hence, 
the total number of subjects to be randomised is 372.
In order to investigate the influence of the values of the model parameters such as treatment 
difference and rate of premature discontinuation of trial product on the calculation, sample sizes 
have been calculated for different alternative scenarios. The results can be seen in Table 17–1.
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Table 17–1
Sample size calculations for different scenarios - number of subjects per arm
Probability of achieving resolution of 
NASH
Semaglutide 
completers
Placebo completers
Rate of premature 
discontinuation
N per arm
50%
20%
10%
61
15%
66
20%
72
45%
20%
10%
84
15%
91
20%
99
40%
20%
10%
126
15%
137
30%
176
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance55:
!
The FAS includes all randomised subjects. Subjects in the FAS will contribute to the evaluation 
“as randomised”.
!
The SAS includes all subjects receiving at least one dose of randomised treatment. 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 
trial statistician, the international trial manager and the medical specialist. Exclusion of data from 
analyses will be used restrictively and normally no data should be excluded from the FAS. If any 
data is excluded, the decision will be justified and documented. The subjects and observations 
excluded from analysis sets, and the reason for their exclusion, will be described in the clinical trial 
report.
Observation periods
Data will be evaluated based on different observation periods which will be derived individually for 
each subject. The following two observation periods are defined:
!
In-trial: This period starts on the date of the randomisation visit and ends on the date of the 
last trial-related procedure/assessment whether or not the subject has stopped taking trial 
product.
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!
On-treatment: For evaluation of AEs and hypoglycaemic episodes, this period starts on the 
date of first administration of trial product and ends on the date of whatever comes first of: 
a) last dose of trial product + 49 days (7 half-lives of semaglutide), b) follow-up visit (V19), 
or c) end of the in-trial period. For evaluation of all other data, the period ends at the date of 
the last dose of trial product +1 day in order to ensure specificity to reversible effects of 
treatment. 
The statistical analyses of the efficacy endpoints will primarily be based on the in-trial period. The 
on-treatment period is used for some supportive efficacy analyses and all statistical analyses of 
safety endpoints. Summary statistics will in general be presented for both observation periods.
Data collected after the observation period in question will be excluded from any summary or 
analysis based on that observation period.
Missing data
With respect to the primary analysis of the primary endpoint, missing week 72 data will be imputed 
as no resolution of NASH. Sensitivity analyses will be performed using imputation methods based 
on treatment adherence and unconditional reference, respectively (see section 17.3). For the 
secondary endpoints, the handling of missing data depends on the type of endpoint and analysis (see 
section 17.4). 
In the analyses based on the in-trial period, the proportion of missing data is expected to be 
maximum 10%. These data would be missing due to subjects withdrawing from trial or being lost to 
follow-up. In the analyses based on the on-treatment period, the proportion of missing data is 
expected to be higher (15%) since data collected after discontinuation of trial product will be 
excluded. The most common reasons for premature discontinuation of trial product are anticipated 
to be AEs, ineffective therapy, and noneligibility (subjects randomised although not fulfilling 
inclusion/exclusion criteria). AEs leading to treatment discontinuation are expected to be equally 
common across treatment arms except possibly for a higher incidence of AEs due to gastrointestinal 
side effects in the semaglutide arms. On the other hand, more subjects in the placebo arms may be 
expected to drop out due to an experienced lack of effect with respect to body weight loss. Overall, 
the proportion of missing data is expected to be similar across treatment arms.
17.3
Primary endpoint
The primary endpoint is the binary outcome NASH resolution without worsening in fibrosis after 72 
weeks (yes/no).The primary analysis will be based on the Cochran-Mantel-Haenszel (CMH) test54
which will be performed separately for the comparisons between each of the semaglutide arms and 
placebo. The test will adjust for baseline diabetes status (with or without T2D) and baseline fibrosis 
stage (F2 or F3). The response data will consist of the outcomes of the week 72 biopsy including 
assessments taken after premature discontinuation of trial product. Missing response data will be 
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imputed as no resolution of NASH. This approach does not rely on an assumption of missing at 
random and should be considered conservative for estimating the treatment effect. 
The result of each comparison will be presented as the p-value for testing the null hypothesis of no 
treatment difference versus a two-sided alternative. The asymptotic p-value obtained from a chi-
square distribution will be used unless it is not considered a valid approximation based on the 
Mantel-Fleiss criterion55, in which case the exact p-value will be calculated. Besides the p-value, 
the common odds ratio will be estimated together with a 95% confidence interval using the Mantel-
Haenszel estimator associated with the CMH test.
Hierarchical testing procedure
In order to confirm the effect of semaglutide without risk of inflation of the type 1 error, the 
comparisons will be evaluated hierarchically according to descending semaglutide dose using a 
family-wise error rate of 5%. The testing procedure will start with the comparison of semaglutide 
0.4 mg versus placebo and then continue by in turn comparing semaglutide 0.2 mg versus placebo
and semaglutide 0.1 mg versus placebo. Each test will use a local two-sided significance level of 
5%. If one of the tests fails to reject the null hypothesis, the testing procedure will stop and no 
further conclusions will be made.
Sensitivity analyses
To investigate the sensitivity of the results of the primary analysis with regard to the handling of 
missing data, the following four sensitivity analyses will be performed:
!
Analysis using imputation based on treatment adherence: An analysis based on the same type of 
non-parametric method as for the primary analysis but with missing data handled by a multiple 
imputation (MI) method which assumes that the unobserved outcomes are well described by the 
observed outcomes from subjects who at week 72 are similar in terms of treatment adherence. 
This will be done as follows:
1. Missing data are imputed by sampling with replacement from the empirical distribution of 
observed outcomes separately within the 8 groups of subjects defined by randomised treatment 
arm and whether subjects complete the 72-week treatment or not.  If a group completely lacks 
observed outcomes, missing data within this group will be imputed as no resolution of NASH. 
Multiple (1000) replicates of a complete data set are generated in this way.
2. For each complete data set, the log odds ratios are estimated using the same method as in the 
primary analysis.
3. The estimates and standard errors for the 1000 complete data sets are pooled using Rubin’s 
rule56:
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 = 1
	 
 


,
 = 1
	 
 



+ 1 + 1
	 
1
	  1 
(  )


,
where mi and SEi are the estimated log odds ratios and standard errors for the N = 1000 data 
sets, and mMI  and SEMI are the pooled estimates. From mMI and SEMI, the 95% confidence 
intervals for the odds ratios and associated p-values are calculated.
This analysis differs from the primary analysis in that it assumes that subjects with missing week 72 
data have the same chances of NASH resolution as subjects with week 72 data in the same 
treatment group, accounting for whether they completed or discontinued the randomised treatment. 
This is a less conservative assumption than the one used in the primary analysis since it includes the 
possibility that subjects with missing week 72 data may have NASH resolution. The analysis 
intends to address missing data relative to what the measurements would have been had the 
measurements been taken.
!
Analysis using imputation based on unconditional reference: An analysis based on the same 
type of non-parametric method as for the primary analysis but with missing data handled by an 
MI method which assumes that the unobserved outcomes are well described by the observed 
outcomes of the subjects in the placebo arm with similar baseline characteristics. The 
imputation will be done by random sampling of observed outcomes from subjects with the same 
baseline diabetes status and baseline fibrosis stage. 1000 replicates of a complete data set will be 
generated that will then be analysed in the same way as in the MI analysis based on treatment 
adherence. This analysis differs from the primary analysis in that it assumes that subjects with 
missing week 72 data have the same chances of NASH resolution as subjects with week 72 data 
in the placebo group. If there are more missing week 72 data in the semaglutide group than in 
the placebo group, this analysis is less conservative than the primary analysis and probably 
gives better estimate of the treatment effect. Compared to the first sensitivity analysis, this 
analysis is more conservative since it assumes that subjects with missing week 72 data in the 
semaglutide group have the same chance of NASH resolution as subjects in the placebo group.
!
Complete case in-trial analysis: The same as the primary analysis but where subjects with 
missing week 72 data are excluded from the analysis.
!
Complete case on-treatment analysis: The same as the primary analysis but where subjects with 
missing week 72 data or for whom the data were collected after the on-treatment period are 
excluded from the analysis. 
The two complete case analyses are included as benchmarks. They are not based on the 
randomisation principle and do not estimate any causal effect of semaglutide treatment. The results 
are expected to be biased in favour of semaglutide and must be interpreted with extreme caution.
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The adjustment for covariates in the primary analysis does not exactly match the stratification used 
for the randomisation. The rationale is that it will not be possible to adjust for region (Japanese or 
non-Japanese) and, at the same time, adjust for diabetes status and baseline fibrosis stage within the 
Japanese group due to small sample sizes. Adjustment for region is not expected to influence the 
overall results but is included in the stratification to facilitate an evaluation of consistency of 
treatment effect between the entire population and Japanese subjects. Region has therefore been 
excluded from the primary analysis. However, a CMH test stratified according to the five strata 
used for the randomisation will be performed as a sensitivity analysis.
Adjustment for baseline body weight as a continuous covariate may potentially give more precise 
estimates of the treatment effects. To investigate the influence of such an adjustment, a sensitivity 
analysis will be performed using a logistic regression model which includes treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline 
body weight as a covariate.
Exploratory analysis
The dose-response relationship with respect to the primary endpoint will be further explored by 
fitting a modified logistic regression model with baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and the log-transformed dose level and baseline body 
weight as covariates. The model may be expressed as
 =  +
(  )
 +  KLXi
where is the probability of NASH resolution for subject i, and  are the asymptotic 
probabilities of NASH resolution at zero and infinite dose levels, respectively, and KLXi is the linear 
prediction function of factors and covariates. The response in the placebo arm will be included in 
the analysis to help estimate . If the model does not describe the dose-response relationship well 
or if there are convergence problems, a different approximation may be investigated.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
Liver-related histological parameters
The following secondary histological endpoint will be analysed:
!
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) 
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The analysis of this binary endpoint will be based on a logistic regression model which includes 
treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction as 
factors and baseline body weight as a covariate. The analysis will include all assessments taken 
during the in-trial period. Missing week 72 data will be imputed as no improvement in fibrosis.
In addition, separate analyses will be performed for the change from baseline to week 72 in the 
following histological feature scores: 
!
Total NAS (0-8) and each of the components:
o
Steatosis (0-3)
o
Lobular inflammation (0-3)
o
Hepatocyte ballooning (0-2)
!
Stage of fibrosis according to the Kleiner fibrosis classification (0-4)
!
Activity component of SAF score (0-4)
The activity component of the SAF score is defined as the unweighted sum of hepatocyte 
ballooning and lobular inflammation. The definition of the lobular inflammation score is modified 
in this calculation so that the scores 2 and 3 on the original scale are merged to a score 2. The 
possible range of the sum is thus 0 to 4. For all scores, a higher value indicates a more severe state 
of disease. 
The histological feature scores will be analysed by an ordered logistic regression model (also 
known as a proportional odds model) with the score at week 72 as response; treatment, baseline 
diabetes status, baseline fibrosis stage, diabetes-by-fibrosis interaction and corresponding baseline 
score as factors; and baseline body weight as a covariate. The analyses will be based on the in-trial 
period and missing week 72 data will be imputed as no change from baseline in agreement with the 
analyses of the binary histological endpoints. The results will be presented as an estimate of the 
cumulative odds ratio for each treatment comparison together with the associated 95% confidence 
intervals and p-values.
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Biomarkers of NASH disease
Analyses will be performed for the change from baseline to week 72 in the following biomarkers 
for NASH disease:
!
Algorithms
o
Fibrosis-4 score 
o
NAFLD Fibrosis Score 
!
Blood samples
o
Liver enzymes 

ALT 

AST

GGT
o
Liver synthesis function

Albumin 

INR
o
Exploratory biomarkers

ELF 

CK-18 fragments

miR-122

IL-1R antagonist 

MCP-1

FGF-21
!
Imaging
o
Liver stiffness
o
CAP (liver steatosis)
The Fib-4 score will be derived according to the formula57: 
Fib-4 =
Age (years) × AST (U/L)
Thrombocyte count (109/L) × "ALT (U/L)
The derivation will be performed at each visit where ALT, AST and thrombocyte count have been 
assessed. If any of the three laboratory parameters is missing at a specific visit, the Fib-4 score will 
be considered missing as well.  
The NAFLD Fibrosis Score will be derived according to the linear regression formula58:
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NFS = 1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13
× Hyperglycaemia (yes/no) + 0.99 × AST/ALT + 0.013
× Thrombocyte count (109/L) + 0.66 × Albumin (g/dL)
Hyperglycaemia (yes/no) is a binary variable defined as 1 if FPG L 6.1 mmol/L (110 mg/dL) at the 
corresponding visit of assessment or the subject has been diagnosed with T2D at screening; 
otherwise, the variable is defined as 0. NFS will be derived at each visit where body weight, FPG, 
ALT, AST, thrombocyte count and albumin have been assessed.  
The ELF discriminant score will be derived as a log-linear combination of the markers hyaluronic 
acid (HA), amino-terminal propeptide of type III collagen (PIIINP) and tissue inhibitor of 
metalloproteinase 1 (TIMP1) according to the formula59:
ELF = 7.412 + 0.681 × ln(HA (ng/mL)) + 0.775
× ln(P3NP (ng/mL)) + 0.494 × ln(TIMP1 (ng/mL))
Analyses of liver stiffness and CAP (liver steatosis) will only be applicable to sites where these 
assessments were possible. Subjects at sites which did not have capability to assess liver stiffness or 
CAP (liver steatosis) will be excluded from the corresponding analysis.
All biomarkers except for NFS, ELF and CAP (liver steatosis) will be logarithmically transformed 
before the statistical analysis. The treatment differences will subsequently be back-transformed to 
the original scale and expressed as treatment ratios.
The main analysis of each of the biomarkers will be analysis of covariance (ANCOVA) with 
missing data handled by unconditional reference-based imputation. This will be done as follows:
1. An ANCOVA model with baseline diabetes status, baseline fibrosis stage and diabetes-by-
fibrosis interaction as factors and baseline body weight and baseline value of the corresponding 
biomarker as covariates is fitted to the change from baseline to 72 weeks for the placebo group 
only. 
2. 1000 sets of values of the model parameters are drawn from the posterior distribution. For each 
replicated set of parameter values, the model is used to generate a complete data set by imputing 
missing values at 72 weeks for subjects in all treatment groups based on their baseline diabetes 
status, baseline fibrosis stage, baseline body weight and baseline value of the corresponding 
biomarker.
3. For each complete data set, the change from baseline to 72 weeks is analysed using an 
ANCOVA model with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-
by-fibrosis interaction as factors and baseline body weight and baseline value of the 
corresponding biomarker as covariates.
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4. The estimated treatment differences and standard errors for the 1000 complete data sets are 
pooled using Rubin’s rule. From the pooled estimates and standard errors, the 95% confidence 
intervals for the treatment differences and associated p-values are calculated.
A supportive on-treatment analysis using a mixed model for repeated measurements (MMRM) will 
be performed for each of the biomarkers. In this model, all scheduled post-baseline measurements 
taken during the individual subject’s on-treatment period will enter as response; treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction will be included as 
factors; and baseline body weight and baseline value of the corresponding biomarker will be 
included as covariates. All factors and covariates will be nested within visit and an unstructured 
covariance matrix for measurements within subject will be employed. There will be no explicit 
imputation of missing values. As for the main analysis, the estimated treatment differences at week 
72 with associated 95% confidence intervals and p-values will be presented.
Whereas the main analysis attempts to estimate the de-facto treatment effect (in agreement with the 
chosen estimand for the primary objective), the supportive analysis aims to estimate the de-jure 
effect that would have been observed if all subjects had remained on treatment and completed all 
visits. The latter analysis relies on the assumption that data are missing at random, which means that 
given the observed data, the events that lead to data being missing are independent of the 
unobserved data.
Additional exploratory analyses will be conducted to evaluate the performance of the biomarkers as 
predictors of NASH (yes/no), fibrosis (stage L2, L3 and 4, respectively) and/or steatosis (score L1, 
L2 and 3, respectively) as applicable using the liver biopsy as the gold-standard reference. Separate 
analyses will be performed at baseline and week 72 for each predictor. A measurement will be 
classified as “positive” if the value of the predictor exceeds a chosen cut-point. The performance 
will be illustrated by the receiver operating characteristic (ROC) curve which describes the 
relationship of the true positive rate (sensitivity) versus the false positive rate (1 - specificity) as one 
moves the cut-point. The area under the ROC curve will be used to summarise the overall 
performance of  a predictor and the optimal cut-point will be determined by finding the maximum 
of Youden’s index (sensitivity + specificity - 1). In addition, new algorithms may be explored by 
constructing a logistic regression model which includes a large set of potential predictors and then 
selecting the most useful ones using stepwise backward elimination. 
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Weight-related parameters
The secondary endpoints related to weight are defined as change from baseline to 72 weeks in:
!
Body weight (% and kg)
!
Waist circumference
!
BMI
These endpoints will be analysed separately using the same type of ANCOVA with MI as for the 
biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis 
interaction as factors and corresponding baseline value as a single covariate. Supportive on-
treatment analyses will be performed based on MMRM in the same way as for the biomarkers with 
factors and covariates specified as in the ANCOVA model.
In addition to the continuous endpoints, the following binary endpoints related to weight will be 
analysed separately:
!
Weight loss of L 5% of baseline body weight at 72 weeks (yes/no)
!
Weight loss of L 10% of baseline body weight at 72 weeks (yes/no)
The binary endpoints will be compared between treatment arms using an MI approach similar to the 
continuous endpoints but based on logistic regression. The 1000 data sets with imputed values for 
percent change in body weight will be reused to derive an equal number of complete data sets for 
the binary outcomes. For each data set, the binary outcomes will be analysed using a logistic 
regression model which includes treatment, diabetes status, baseline fibrosis stage and diabetes-by-
fibrosis interaction as factors and baseline body weight as a covariate. The estimated log odds ratios 
and standard errors for the 1000 complete data sets are then pooled using Rubin’s rule. From the 
pooled estimates and standard errors, the 95% confidence intervals for the odds ratios and 
associated p-values are calculated.
Glucose metabolism related parameters
The secondary endpoints related to glucose metabolism are defined as change from baseline to 72 
weeks in:
!
HbA1c
!
FPG
!
Fasting glucagon
!
HOMA-IR, derived through the approximation formula60:
HOMA -IR = FPG (mmol/L) × Fasting insulin (mmol/L) 22.5
/
These endpoints will be analysed using the same type of ANCOVA with MI as for the biomarkers. 
For each endpoint, the ANCOVA will be performed separately for subjects with and without type 2 
diabetes at screening. The model will include treatment and baseline fibrosis stage as factors and 
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corresponding baseline value as covariate. Supportive on-treatment analyses will be performed 
based on MMRM in the same way as for the biomarkers with factors and covariates specified as in 
the ANCOVA model. Fasting glucagon and HOMA-IR will be logarithmically transformed before 
analysis.
Cardiovascular risk factors
The secondary endpoints related to cardiovascular risk factors are defined as change from baseline 
to 72 weeks in: 
!
Systolic and diastolic blood pressure
!
Lipids (total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, triglycerides, 
free fatty acids)
!
hsCRP
These endpoints will be analysed separately using the same type of ANCOVA with MI as for the 
biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis 
interaction as factors and corresponding baseline value as a single covariate. Supportive on-
treatment analyses will be performed based on MMRM in the same way as for the biomarkers with 
factors and covariates specified as in the ANCOVA model. The lipids and hsCRP will be 
logarithmically transformed before analysis.
Patient reported outcomes
The results from SF-36 questionnaire will be analysed as the change from baseline to 72 weeks in 
overall mental and physical scores, respectively, as well as the change in each of the 8 domains: 
!
Physical functioning
!
Role functioning
!
Bodily pain
!
General health
!
Vitality
!
Social functioning
!
Role emotional 
!
Mental health
The change in score will be analysed as a continuous endpoint using the same type of ANCOVA 
with MI as for the biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and corresponding baseline score as a single covariate. 
Supportive on-treatment analyses will be performed based on MMRM in the same way as for the 
biomarkers with factors and covariates specified as in the ANCOVA model.
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17.4.1.2
Safety endpoints
The following secondary endpoints are used to support the safety objectives:
!
Number of treatment-emergent adverse events during the trial
!
Number of treatment-emergent hypoglycaemic episodes during the trial
!
Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during the trial
!
Number of treatment-emergent severe hypoglycaemic episodes during the trial 
!
Number of subjects discontinuing treatment due to gastrointestinal adverse events
!
Change from baseline to 72 weeks in:
o
Pulse
o
ECG
o
Physical examination
o
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
o
Biochemistry (creatinine, creatinine phosphokinase, urea, bilirubin (total), alkaline 
phosphatase, ferritin, sodium, potassium, calcium (total), amylase, lipase)
o
Hormones (calcitonin)
!
Occurrence of anti-semaglutide antibodies during and after 72 weeks treatment (yes/no):
o
Anti-semaglutide binding antibodies
o
Anti-semaglutide binding antibodies with in vitro neutralising effect
o
Anti-semaglutide binding antibodies cross reacting with native GLP-1
o
Cross-reacting anti-semaglutide binding antibodies with in vitro neutralising effect to 
native GLP-1
!
Anti-semaglutide antibody binding level during and after 72 weeks treatment
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for regulatory Activities 
(MedDRA) coding. A treatment emergent adverse event (TEAE) is defined as an event that has 
onset date during the on-treatment period (see section 17.2). 
AE data will be displayed in terms of the number of subjects with at least one event, the percentage 
of subjects with at least one event, the number of events and the event rate per 100 patient years of 
exposure. The main AE summaries will only contain TEAEs. Non-treatment emergent AEs will be 
included in listings and overview summaries.
Hypoglycaemic episodes
Hypoglycaemic episodes will be classified and then summarised descriptively in terms of the 
number of subjects with at least one event, the percentage of subjects with at least one event, the 
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number of events and the event rate per 100 patient years of exposure. The summaries will be made 
separately for subjects with and without type 2 diabetes at randomisation.
For subjects with type 2 diabetes at randomisation, the severe or BG confirmed symptomatic 
hypoglycaemic episodes will be analysed using a negative binomial regression model with the 
number of treatment emergent episodes as response, the logarithmic function as link function and 
the logarithm of the time period during which episodes are considered treatment emergent as offset. 
The model will include treatment and baseline fibrosis stage as factors and baseline HbA1c as a 
covariate. The results will be described by the rate ratio for the comparison of each semaglutide 
dose versus placebo with the associated 95% confidence interval and two-sided p-value.
Classification of Hypoglycaemia:
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs during the on-treatment period (see section 17.2). 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.   
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
For subjects without type 2 diabetes, the episodes will only be classified as either severe or probable 
symptomatic according to the ADA classification. 
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)63. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
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ADA classification48 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 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 M 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 M 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 M 3.9 mmol/L (70 mg/dL).
Hypoglycaemic 
episode 
PG  3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
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Pulse
Pulse will be summarised by descriptive statistics and analysed using the same type of MMRM as 
for the on-treatment analyses of the biomarkers with treatment, baseline diabetes status, baseline 
fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline pulse as a covariate.
ECG
ECG will be described by summarising the number and percentage of subjects with normal and 
abnormal readings (separated into clinically significant and not clinically significant). The 
summaries will be presented by visit and as shift tables from baseline to week 72.
Physical examination
The results of the physical examination will be summarised descriptively in the same way as ECG.
Laboratory assessments
The haematology and biochemistry parameters will be summarised and evaluated by descriptive 
statistics. 
Amylase and lipase will be analysed separately using the same type of MMRM as for the on-
treatment analyses of the biomarkers with treatment, baseline diabetes status, baseline fibrosis stage 
and diabetes-by-fibrosis interaction as factors and the baseline value of the corresponding 
laboratory parameter as a covariate. A logarithmic transformation will be applied for both amylase 
and lipase
Calcitonin will be summarised in tables including number and percentage of observations > and M 
LLOQ, quartiles, minimum and maximum. Persistent and incidental abnormal elevation of 
calcitonin will further be displayed in terms of the number and percentage of subjects and the event 
rate per 100 patient years of exposure.
Antibodies
The occurrence of anti-semaglutide antibodies will be described by summarising the number and 
percentage of subjects with antibodies in the different treatment arms. The antibody binding level 
will be presented in listings.
In addition, a comparison of the change in HbA1c and body weight between antibody-positive and 
antibody-negative subjects will be performed using descriptive statistics and graphs. The impact of 
anti-semaglutide antibodies on safety will be similarly assessed by descriptive statistics.
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17.4.1.3
Pharmacokinetic endpoints
The plasma concentrations of semaglutide will be summarised by descriptive statistics. In addition, 
the data will be used for population pharmacokinetic (PK) modelling, see section 17.6.
17.5
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
17.6
Pharmacokinetic and/or pharmacodynamic modelling
Exploratory population PK and PK/PD modelling will be used to evaluate the semaglutide dose-
exposure, the effects of pre-specified covariates on the exposure and the semaglutide exposure-
response on selected efficacy and safety parameters. It will follow a modelling analysis plan that is 
to be finalised before database lock, describing criteria for inclusion of data, pre-specification of 
covariates and criteria for presentation of results. 
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk A/S and 
will be reported separately from the CTR.
17.7
Health economics and/or patient reported outcomes
The PRO questionnaire SF-36 will be used to evaluate the effects on quality of life, see section
17.4.1.1 for the details of the statistical analysis. The results will be included in the CTR.
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or generalised reactions including urticaria, rash or pruritus. Severe allergic reactions such as 
anaphylactic reactions could potentially also pose a risk for subjects treated with semaglutide.
Hypoglycaemia
Based on current knowledge about the GLP-1 RA drug class, there is a risk of hypoglycaemic 
episodes. Hypoglycaemic episodes have mainly been observed when a GLP-1 RA is combined with 
sulphonylurea (SU) or insulin in patients with T2D. The risk for development of hypoglycaemia 
specifically with semaglutide in combination with SU and insulin is unknown due to limited data.
To reduce the risk of hypoglycemia the insulin dose will be reduced by 30% in subjects with HbA1c
M 8.0% at screening.
Altered renal function
Based on current knowledge about the GLP-1 RA drug class, there is a risk of volume depletion, 
resulting from nausea, vomiting and dehydration, such as acute renal failure have been observed in 
subjects treated with other GLP-1 RAs. As a precaution serum creatinine is measured regularly.
Acute pancreatitis
Based on current knowledge about the GLP-1 RA drug class, there is a risk of acute pancreatitis, 
including severe necrotising and haemorrhagic forms. As a precaution patients with a history of 
acute or chronic pancreatitis will be excluded from the trial. Subjects will be monitored for elevated 
activity levels of amylase and lipase and be informed of the characteristic symptoms of acute 
pancreatitis.
Pancreatic cancer
There is currently no support from non-clinical or clinical trials or post-marketing data that GLP-1-
based therapies increase the risk of pancreatic cancer. However, as the long-term effects of 
stimulation of d-cells and suppression of e-cells are largely unknown, pancreatic cancer is 
considered a potential risk by the European Medicine Agency (EMA).
Other safety considerations
Teratogenicity (nonclinical embryo-foetal toxicity)
Semaglutide has been concluded teratogenic in rats. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function. As 
the yolk sac does not play such a role for nutrition of the embryo in humans, this effect is unlikely 
to be relevant for humans. However, as a precaution subjects fulfilling exclusion criterion 31 will be 
excluded from trial participation. Furthermore, as specified in the flowchart, female subjects 
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included in the trial will have pregnancy testing performed frequently during the entire duration of 
the trial. 
General risks and precautions
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.
All subjects will have one or two liver biopsies performed as part of participation in the trial. Pain is 
the most common complication of percutaneous liver biopsy, occurring in up to 84% of patients, 
including those with relatively mild discomfort. The most important complication of liver biopsy is 
bleeding. Severe bleeding may require hospitalization blood transfusion, or even radiological 
intervention or surgery. Such bleeding has been estimated to occur in between 1 in 2500 to 1 in 
10,000 biopsies after an intercostal percutaneous liver biopsy. Mortality after liver biopsy is usually 
related to hemorrhage. It is very uncommon after percutaneous biopsy, but precise figures vary 
widely. The most commonly quoted mortality rate is less than or equal to 1 in 10,000 liver 
biopsies64. The risk of liver biosy is minimised by excluding patients with liver cirrhosis and 
coagulopathy, and by requiring that liver biopsy is performed according to standard practice.
Benefits
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.
In the LEAN trial significantly more patients who received liraglutide 1.8 mg/day had resolution of 
NASH compared with patients in the placebo group. Further, significantly fewer patients in the 
liraglutide had progression of fibrosis compared to the placebo group34. Currently the standard of 
care of NASH is weight loss, and reduction of body weight was speculated to be one of the modes 
of action of liraglutide by the authors of the LEAN study34. In a phase 2 trial (NN9535-1821), 
semaglutide resulted in a clinical meaningful and dose-dependent weight loss. Doses L 0.8 mg/week
semaglutide provided a greater weight loss than liraglutide 1.8 mg/day. In clinical studies with 
liraglutide 3.0 mg/day, approximately 2/3 of the subjects lost more than 5% of their initial body 
weight and approximately 1/3 lost more than 10% of their initial body weight. Additionally, 
semaglutide also increase insulin, lower glucagon levels and improves insulin sensitivity and blood 
lipids, all of which are beneficial in patients with NASH. Finally, semaglutide may have anti-
inflammatory effects.
Although subjects will have to spend time on site visits and procedures required by trial 
participation, it is expected that all subjects (including those subjects randomised to placebo) will 
benefit from participation through close contact with the trial site, with close follow-up of their 
NASH and general metabolic state, and a careful medical examination. Furthermore, all subjects 
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will receive nutritional and physical activity counselling throughout the trial. All of which will 
probably result in a better management of their NASH.
Conclusion
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 informed 
about possible AEs and inconveniences and will be instructed to contact the investigator in case of 
any concerns regarding the trial participation.
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks
including the risk related to the liver biopsy. The safety profile of semaglutide generated from the 
clinical and nonclinical development programme in T2D has not revealed any safety issues that 
would prohibit administration of once weekly doses of 0.5 mg or 1.0 mg semaglutide. Based on the 
nature and frequency of the AEs in the T2D trials, it appears to be safe to investigate daily doses of 
up to 0.4 mg as in the current trial. Additional safety surveillance will be instituted in all treatment 
arms during the dose escalation period until 4 weeks after last target dose is reached (steady state).
It is concluded that the risk to the subjects in this trial is low and acceptable in view of the potential 
benefits a long-acting GLP-1 analogue would provide subjects with NASH.
18.2
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. This includes the use of an impartial witness where required.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
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A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.  
Separate informed consent forms for long-term storage of human biosamples and genotyping are 
available for this trial, and informed consent must be obtained before activities related to any of 
these are undertaken.
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow up visits
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may 
receive a “welcome to the trial letter” and a “thank you for your participation letter” after 
completion of the trial. Further the subject may receive letters during the trial. 
Initiatives for subject retention will be instituted for this trial. These may include retention 
activities, materials and items, if locally acceptable. The retention items will be relevant for the 
subjects’ participation in the trial and/or their disease.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
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18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Novo Nordisk will monitor protocol deviations on an on-going basis throughout the trial followed 
by appropriate actions (e.g. re-training of site staff).
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. The investigator will make every effort to 
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ensure that all assessments are performed and data is collected (see section 8.1.5). If missing data 
does occur the reason will be collected via the protocol deviation process described in section 19.1.
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.
21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
Only applicable for US trial sites: 
!
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 the investigator at each site
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FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
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The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications65.
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 
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scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure42.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. All authors will be given the relevant 
statistical tables, figures, and reports needed to evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors65 (sometimes referred to as the Vancouver 
Criteria).
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 
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such individual reports do not precede the primary manuscript and should always reference the 
primary manuscript of the trial.
Novo Nordisk reserves the right to prior review of such publications. Further to allow for the 
primary manuscript to be published as the first, Novo Nordisk asks for deferment of publication of 
individual site results until the primary manuscript is accepted for publication. As Novo Nordisk 
wants to live up to the industry publication policy, submission of a primary publication will take 
place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by Novo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
section 7), or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
24.2
Retention of human biosamples
24.2.1
Antibody samples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities or for safety reasons. The samples will not 
be used for other purposes.
The samples will be stored at a bio-repository after end of trial and until marketing authorisation 
approval or until the research project terminates, but no longer than 15 years from end of trial after 
which they will be destroyed. 
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The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples. 
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples. 
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body. 
24.2.2
Samples for future analysis
As new biomarkers related to the disease and/or safety, efficacy, or mechanism of action of 
semaglutide may evolve during the conduct of the trial or after end of trial, the analyses of the 
stored biosamples may also include biomarkers that are unknown at present or have not been 
included in the scientific hypotheses at initiation of the trial. Likewise if genetic high risk 
population or populations are described for NASH, Novo Nordisk may want to investigate if such 
genetic predispositions are associated with different response to semaglutide.
Subjects must sign and date a separate informed consent form before biosamples to be stored for 
future analysis are drawn/collected (refer to section 8.1.1).
After trial completion the biosamples will be stored at a central storage facility contracted by Novo 
Nordisk A/S. Only Novo Nordisk and storage facility employees will be able to access the stored 
biosamples. The biosamples may be transferred to other countries for analysis and will be destroyed 
at the latest 15 years after end of trial. 
The subject may request the stored biosamples to be destroyed by withdrawing consent. The results 
obtained from any already performed analyses of the samples will still be used.
In the event that the collected biosamples (blood and urine) will be used in the future, the 
investigator will become directly informed by Novo Nordisk about the results if the findings are 
deemed clinically relevant and analytically valid and quantifiable. In such case, a written summary 
of the findings, including listings of subject specific values, will be provided once a firm conclusion 
from the results has been drawn by Novo Nordisk.
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-treatable 
diseases, or any other abnormal findings could be part of the observations. Subjects can contact the 
investigator if they wish to be informed about results derived from stored biosamples obtained from 
their own body.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with: 
For Netherlands only: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 
(Medicines Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 
1 maart 2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit verplichte 
verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 november 2014 (Decree 
compulsory insurance in medical research involving human subjects 2015, 24 November 2014).” 
The national protocol requirement is also here under compliance: 
http://globeshare.novonordisk.com/rd/gd/gdareas/qrd/gcc/Pages/Default.aspx
For France only: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 
2004 art. 88 I, IX Journal Officiel of 11 August 2004. "The sponsor is responsible for identification 
of the harmful consequences of the biomedical research for the person lending himself thereto and 
for indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice 
is not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.
For Austria only: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBI Nr. 105/2015.
For Russia only: Federal law of 12 April 2010 No. 61-FZ ‘On Medicinal Drugs’ Circulation.
For Belgium only: Law concerning experiments on the human person of 07 May 2004 - Article 29:
§1. Even if without fault, the sponsor is liable for the damage which the subject and/or his rightful
claimants sustain and which shows either a direct or an indirect connection with the trial.
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27 References
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46.
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Official Journal of the European Communities. April 2001.
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Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced 
awareness of hypoglycemia in adults with IDDM. A prospective study of hypoglycemic 
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48.
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95.
49.
McAulay V, Deary IJ, Frier BM. Symptoms of hypoglycaemia in people with diabetes. 
Diabet Med. 2001;18(9):690-705.
50.
Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict 
poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. 
Hepatology. 2000;31(4):864-71.
51.
European Commission. The Rules Governing Medicinal Products in the European Union, 
Volume 4, Annex 13, Investigational Medicinal Products (ENTR/F/2/AM/an D(2010) 
3374). 3 February 2010.
52.
Hicks KA, Hung HMJ, Mahaffey KW, Mehran R, Nissen SE, Strockbridge NL, et al. 
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials 
(Draft). 20 Aug 2014.
53.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek 
MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-
alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. 
Lancet. 2015;385(9972):956-65.
54.
Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. 
Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 
2010;362(18):1675-85.
55.
Group IEEW. Statistical principles for Clinical Trials: ICH Harmonised Tripartite 
Guideline. Statistics in Medicine. 1999. p. 1905-42.
56.
A A. Categorical Data Analysis. 2nd ed. New York ed: John Wiley & Sons; 2002.
57.
Mantel N, Fleiss JL. Minimum expected cell size requirements for the Mantel-Haenszel one-
degree-of-freedom chi-square test and a related rapid procedure. Am J Epidemiol. 
1980;112(1):129-34.
58.
Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & 
Sons. 1987.
59.
Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a 
simple noninvasive index to predict significant fibrosis in patients with HIV/HCV 
coinfection. Hepatology. 2006;43(6):1317-25.
60.
Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD 
fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. 
Hepatology. 2007;45(4):846-54.
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
1 of 127
Protocol
Trial ID:NN9931-4296 
Investigation of efficacy and safety of three dose levels of
subcutaneous semaglutide once daily versus placebo in subjects with 
non-alcoholic steatohepatitis 
A 72-week randomised, double-blind, placebo-controlled, six-armed parallel group, multi-centre, 
multinational trial
Updated protocol including:
-
Original protocol, version 1.0, dated 20 June 2016
-
Global protocol amendment number 1, version 1.0, dated 26 August 2016
-
Global protocol amendment number 2, version 1.0, dated 29 November 2016
-
Global protocol amendment number 3, version 1.0, dated 25 August 2017
-
Global protocol amendment number 4, version 1.0, dated 01 March 2018
-
Local protocol amendment number 5 in Sweden, version 1.0, dated 09 January 2018
Trial phase: Phase 2
Protocol originator
 Senior International Trial Manager
TrialOps 2, GLP-1 Diabetes, NADs & Complications 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
2 of 127
Table of Contents
         Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................7
Table of Tables............................................................................................................................................7
List of abbreviations ...................................................................................................................................8
1
Summary............................................................................................................................................12
2
Flow chart ..........................................................................................................................................15
3
Background information and rationale for the trial.........................................................................20
3.1
Background information..........................................................................................................20
3.1.1 Glucagon-like peptide-1 .................................................................................................21
3.2
Rationale for the trial...............................................................................................................25
4
Objectives and endpoints...................................................................................................................26
4.1
Objectives...............................................................................................................................26
4.2
Endpoints................................................................................................................................26
4.2.1
Primary endpoint ...................................................................................................26
4.2.2
Secondary endpoints ..............................................................................................27
4.2.2.1
Supportive secondary efficacy endpoints ..........................................27
4.2.2.2
Supportive secondary safety endpoints .............................................29
5
Trial design ........................................................................................................................................30
5.1
Type of trial ............................................................................................................................30
5.2
Rationale for trial design .........................................................................................................31
5.3
Treatment of subjects ..............................................................................................................32
5.3.1
Subjects treated with insulin...................................................................................33
5.3.2
Treatment of subjects with poorly controlled glycaemia .........................................34
5.3.3
Subjects developing type 2 diabetes .......................................................................34
5.3.4
Missed dose...........................................................................................................34
5.3.5
Nutritional and physical activity counselling..........................................................34
5.4
Treatment after discontinuation of trial product .......................................................................35
5.5
Rationale for treatment............................................................................................................35
6
Trial population .................................................................................................................................36
6.1
Number of subjects .................................................................................................................36
6.2
Inclusion criteria .....................................................................................................................36
6.3
Exclusion criteria ....................................................................................................................37
6.4
Criteria for premature discontinuation of trial product .............................................................40
6.5
Withdrawal from trial..............................................................................................................41
6.6
Subject replacement ................................................................................................................41
6.7
Rationale for trial population...................................................................................................41
7
Milestones...........................................................................................................................................42
8
Methods and assessments ..................................................................................................................43
8.1
Visit procedures ......................................................................................................................43
8.1.1
Screening, re-screening and screen failures ............................................................43
8.1.2
Optional pre-screening (not applicable for Sweden) ...............................................44
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
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8.1.3
AUDIT questionnaire.............................................................................................44
8.1.4
Fasting visits..........................................................................................................44
8.1.5
Missed visits..........................................................................................................45
8.1.6
Premature discontinuation of trial product..............................................................45
8.1.7
Withdrawn subjects................................................................................................45
8.1.8
Subject training......................................................................................................46
8.2
Subject related information/assessments..................................................................................46
8.2.1
Demography ..........................................................................................................46
8.2.2
Concomitant illness and medical history.................................................................46
8.2.3
Concomitant medication ........................................................................................47
8.2.4
Hypoglycaemia unawareness .................................................................................47
8.2.5
Childbearing potential............................................................................................47
8.2.6
Tobacco use...........................................................................................................48
8.2.7
Fundoscopy/Fundus photography...........................................................................48
8.3
Efficacy assessments...............................................................................................................49
8.3.1
Liver biopsy...........................................................................................................49
8.3.1.1
Central pathologist evaluation ..........................................................50
8.3.2
Fibroscan® measurements ......................................................................................50
8.3.3
Body measurements...............................................................................................51
8.3.3.1
Body weight.....................................................................................51
8.3.3.2
Height..............................................................................................51
8.3.3.3
Body mass index..............................................................................51
8.3.3.4
Waist circumference.........................................................................51
8.3.3.5
Vital signs........................................................................................52
8.3.4
SF-36 questionnaires..............................................................................................52
8.4
Safety assessments ..................................................................................................................53
8.4.1
Physical examination .............................................................................................53
8.4.2
Electrocardiogram..................................................................................................53
8.4.3
Adverse events.......................................................................................................54
8.4.4
Medication error ....................................................................................................54
8.4.5
Adverse events requiring additional data collection................................................54
8.4.6
Self-measured plasma glucose................................................................................55
8.4.7
Hypoglycaemic episodes........................................................................................55
8.4.8
Hyperglycaemic episodes.......................................................................................58
8.5
Laboratory assessments...........................................................................................................58
8.5.1
Review of laboratory reports..................................................................................59
8.5.2
Laboratory assessments for efficacy.......................................................................59
8.5.2.1
Biochemistry....................................................................................59
8.5.2.2
Glucose metabolism.........................................................................59
8.5.2.3
Exploratory biomarkers....................................................................60
8.5.2.4
Biosamples for future analysis:.........................................................60
8.5.3
Laboratory assessments for safety ..........................................................................60
8.5.3.1
Biochemistry....................................................................................60
8.5.3.2
Hormones ........................................................................................61
8.5.3.3
Haematology....................................................................................61
8.5.3.4
Coagulation marker..........................................................................61
8.5.3.5
HIV and hepatitis .............................................................................61
8.5.3.6
Pregnancy test..................................................................................61
8.5.3.7
Anti-semaglutide antibodies .............................................................62
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Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464 
Status:
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8.6
Other assessments ...................................................................................................................62
8.6.1
Semaglutide plasma concentration .........................................................................62
8.6.2
Subject diaries .......................................................................................................62
8.6.3
Nutritional and physical activity counselling..........................................................63
8.7
Specific safety requirements....................................................................................................63
8.7.1
Suspicion of acute pancreatitis ...............................................................................63
8.7.2
Assessments in case of increased levels of liver blood parameters ..........................64
8.7.3
Training in the delivery device (NovoPen® 4).........................................................65
8.8
Subject compliance .................................................................................................................66
9
Trial supplies......................................................................................................................................67
9.1
Trial products..........................................................................................................................67
9.2
Labelling.................................................................................................................................67
9.3
Storage....................................................................................................................................68
9.4
Drug accountability and destruction ........................................................................................68
9.5
Auxiliary supplies ...................................................................................................................69
10
Interactive voice/web response system ..............................................................................................70
11
Randomisation procedure and breaking of blinded codes................................................................71
11.1
Breaking of blinded codes .......................................................................................................71
12
Adverse events, technical complaints and pregnancies.....................................................................72
12.1
Definitions ..............................................................................................................................72
12.1.1
Adverse event ........................................................................................................72
12.1.2
Serious adverse event.............................................................................................73
12.1.3
Non-serious adverse event......................................................................................74
12.1.4
Medication errors...................................................................................................74
12.1.5
Adverse events requiring additional data collection................................................74
12.1.6
Technical complaints .............................................................................................76
12.2
Reporting of adverse events.....................................................................................................76
12.3
Follow-up of adverse events....................................................................................................79
12.4
Technical complaints and technical complaint samples............................................................80
12.4.1
Reporting of technical complaints ..........................................................................80
12.4.2
Collection, storage and shipment of technical complaint samples ...........................80
12.5
Pregnancies.............................................................................................................................81
12.5.1
Pregnancies in female subjects ...............................................................................81
12.6
Precautions and/or overdose....................................................................................................82
12.7
Committees related to safety ...................................................................................................83
12.7.1
Novo Nordisk safety committee .............................................................................83
12.7.2
Event adjudication committee ................................................................................83
13
Case report forms ..............................................................................................................................85
13.1
Corrections to case report forms..............................................................................................85
13.2
Case report form flow .............................................................................................................86
14
Monitoring procedures ......................................................................................................................86
15
Data management ..............................................................................................................................87
16
Computerised systems .......................................................................................................................87
17
Statistical considerations ...................................................................................................................88
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
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17.1
Sample size calculation ...........................................................................................................89
17.2
Definition of analysis sets........................................................................................................90
17.3
Primary endpoint.....................................................................................................................91
17.4
Secondary endpoints ...............................................................................................................95
17.4.1
Supportive secondary endpoints.............................................................................95
17.4.1.1
Efficacy endpoints............................................................................95
17.4.1.2
Safety endpoints.............................................................................101
17.4.1.3
Pharmacokinetic endpoints.............................................................105
17.5
Interim analysis.....................................................................................................................105
17.6
Pharmacokinetic and/or pharmacodynamic modelling ...........................................................105
17.7
Health economics and/or patient reported outcomes...............................................................106
18
Ethics................................................................................................................................................107
18.1
Benefit-risk assessment of the trial ........................................................................................107
18.2
Informed consent ..................................................................................................................111
18.3
Data handling........................................................................................................................111
18.4
Information to subjects during trial........................................................................................112
18.5
Premature termination of the trial and/or trial site..................................................................112
19
Protocol compliance.........................................................................................................................113
19.1
Protocol deviations................................................................................................................113
19.2
Prevention of missing data ....................................................................................................113
20
Audits and inspections .....................................................................................................................113
21
Critical documents...........................................................................................................................114
22
Responsibilities.................................................................................................................................115
23
Reports and publications .................................................................................................................116
23.1
Communication of results......................................................................................................116
23.1.1
Authorship...........................................................................................................117
23.1.2
Site-specific publication(s) by investigator(s).......................................................117
23.2
Investigator access to data and review of results ....................................................................117
24
Retention of clinical trial documentation and human biosamples..................................................118
24.1
Retention of clinical trial documentation ...............................................................................118
24.2
Retention of human biosamples.............................................................................................118
24.2.1
Antibody samples ................................................................................................118
24.2.2
Samples for future analysis ..................................................................................119
25
Institutional Review Boards/Independent Ethics Committees and regulatory authorities ...........120
26
Indemnity statement ........................................................................................................................121
27
References ........................................................................................................................................122
Appendix A
Monitoring of calcitonin 
Appendix B
Adverse events with additional data collection and adverse events requiring event 
adjudication
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
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Attachment I  Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments
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Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
7 of 127
Table of Figures
Page
Figure 5–1
Trial design........................................................................................................................30
Figure 12–1
Reporting of AEs ...............................................................................................................78
Figure 17–1
Novo Nordisk classification of hypoglycaemia ................................................................103
Figure 17–2
ADA classification of hypoglycaemia..............................................................................104
Table of Tables
Page
Table 5–1
Duration of dose escalation period.....................................................................................32
Table 5–2
Dose conversion table .......................................................................................................33
Table 9–1
Trial products.....................................................................................................................67
Table 9–2
Storage conditions.............................................................................................................68
Table 12–1
Adverse events requiring completion of specific eCRF event forms and/or are subject 
to event adjudication ..........................................................................................................75
Table 17–1
Sample size calculations for different scenarios - number of subjects per arm....................90
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
Page:
8 of 127
List of abbreviations
ADA
American Diabetes Association
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUDIT
Alcohol Use Disorders Identification 
Test 
BMI
body mass index
CAP
controlled attenuation parameter 
CK-18
cytokeratin 18
CLAE
clinical laboratory adverse event
CMH
Cochran-Mantel-Haenszel 
CRF
case report form
CRN
Clinical Research Network
CTR
clinical trial report
DILI
drug induced liver injury
DUN
dispensing unit number
EAC
event adjudication committee
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ELF
enhanced liver fibrosis 
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
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FAS
full analysis set
FGF-21
fibroblast growth factor 21
Fib-4
fibrosis 4
FPG
fasting plasma glucose
FSFV
first subject first visit
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase 
GLP-1
glucagon-like peptide-1
GLP-1 RA
glucagon-like peptide-1 receptor 
agonist
HbA1c
glycosylated haemoglobin A1c
hCG
human chorionic gonadotrophin
HCV-RNA
hepatitis C virus Ribonucleic acid
HDL
high-density lipoprotein
HIV
human immunodeficiency virus 
HOMA-IR
homeostatic model assessment -
insulin resistance 
ICH
International Conference on 
Harmonisation of Technical 
Requirements for Registration of 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical 
Journal Editors
IEC
independent ethics committee
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Date:
09 March 2018
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Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
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IL-1R
interleukin-1 receptor 
IMP
investigational medicinal product
INR
international normalized ratio 
IRB
institutional review board
IWRS
interactive web response system
LDL
low-density lipoprotein
LLOQ
lower limit of quantification
LSLV
last subject last visit
MCP-1
monocyte chemoattractant protein 1
MedDRA
Medical Dictionary for Regulatory 
Activities
MELD
model for end-stage liver disease
MI
myocardial infarction 
miR-122
microRNA 122
NAFLD
non- alcoholic fatty liver disease
NAS
NAFLD activity score 
NASH
non- alcoholic steatohepatitis
NFS
NAFLD fibrosis score 
NOAEL
no observable adverse effect level
PG
plasma glucose
PRO
patient reported outcome
SAE
serious adverse event
SAF
steatosis-activity-fibrosis
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
5.0
UTN: U1111-1179-7464 
Status:
Final
EudraCT no.: 2016-000685-39
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SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous(ly)
SF-36
short form 36
SGLT-2
sodium–glucose cotransporter 2
SMPG
self-measured plasma glucose
SUSAR
suspected unexpected serious adverse 
reaction
T2D
type 2 diabetes
TSH (applicable for Sweden)
thyroid-stimulating hormone 
TMM
trial materials manual
UNL
upper normal limit
UTN
universal trial number
VLDL
very low density lipoprotein 
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Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464 
Status:
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1
Summary
Objectives and endpoints:
Primary objective
To compare the effect of semaglutide subcutaneous (s.c.) once daily versus placebo on histological 
resolution of non-alcoholic steatohepatitis (NASH).
Primary endpoint
!
NASH resolution without worsening of fibrosis after 72 weeks (yes/no)
Key secondary objectives
!
To investigate the dose-response relationship of three dose levels of semaglutide s.c. once daily 
(0.1 mg/day, 0.2 mg/day and 0.4 mg/day) on histological resolution of NASH.
!
To compare the effects of semaglutide s.c. once daily to placebo on liver-related histological 
parameters and biomarkers of NASH disease.
Key secondary endpoints
!
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or 
hepatocyte ballooning according to NASH clinical research network (CRN) criteria). 
Change from baseline to week 72 in:
!
Non-alcoholic fatty liver disease (NAFLD) activity score (NAS) (0-8)
!
Stage of fibrosis according to the Kleiner fibrosis classification (0-4)
!
Activity component of steatosis-activity-fibrosis (SAF) score (0-4)
!
Fasting plasma glucose (FPG)
!
Glycosylated haemoglobin A1c (HbA1c)
!
Serum enhanced liver fibrosis (ELF)
Trial design:
This is a 72-week, randomised, double-blind, placebo-controlled, six-armed, parallel group, multi-
centre, multi-national trial comparing once daily administration of semaglutide s.c. in three different 
doses (0.1 mg, 0.2 mg and 0.4 mg) with placebo in subjects with NASH. Subjects will be 
randomised in a 3:3:3:1:1:1 manner to receive daily dosing of semaglutide s.c. 0.1 mg, 0.2 mg, 0.4 
mg or corresponding injection volumes of placebo once daily. To avoid bias in the assessment of 
the different semaglutide doses, the trial will be double-blinded within dose levels. The dose levels
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464 
Status:
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will not be blinded between each other because of different dose escalations and different target 
doses and volumes required.
The total trial duration for the individual subject will be up to 85 weeks (maximum).
Randomisation will be stratified in five strata based on region (Japanese or non-Japanese) and, 
within the non-Japanese group, based on diabetes status at screening (with or without type 2 
diabetes) and fibrosis stage for baseline liver biopsy (F1/F2 or F3).
Trial population:
A total of 288 subjects are planned to be randomised. Based on an assumption of a 65% screening 
failure rate, 823 subjects are planned to be screened.
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial except for protocol described pre-screening activities which require a separate informed 
consent.
Applicable for Sweden: Informed consent obtained before any trial-related activities. Trial-
related activities are any procedures that are carried out as part of the trial, including activities to 
determine suitability for the trial.
!
Male or female, aged 18-75 years (both inclusive) (for Japan: male or female aged 20-75 years 
(both inclusive)) at the time of signing informed consent.
!
Histologic evidence of NASH based on central pathologist evaluation of a liver biopsy obtained 
up to 21 weeks before screening.
!
A histological NAS > 4 with a score of 1 or more in each sub-component of the score based on 
central pathologist evaluation.
!
NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on 
central pathologist evaluation.
Key exclusion criteria
!
Known or suspected abuse of alcohol (> 20 g/day for women or > 30 g/day for men), alcohol 
dependence* or narcotics. (* = assessed by the Alcohol Use Disorders Identification Test 
(AUDIT questionnaire)).
!
Diagnosis of type 1 diabetes according to medical records.
!
HbA1c > 10% at screening.
!
History or presence of pancreatitis (acute or chronic).
!
Calcitonin M 50 ng/L at screening.
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464 
Status:
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!
Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
!
Body Mass Index (BMI) N 25.0 kg/m2 at the screening visit (visit 1).
!
Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice).
Assessments:
Efficacy
!
Liver biopsy
!
Liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma 
glutamyltransferase  (GGT))
!
Fibroscan® measurements (liver stiffness and liver steatosis (with controlled attenuation 
parameter (CAP))) 
!
HbA1c
!
Body measurements (body weight in kg)
!
Lipids (Total cholesterol, free fatty acids, high-density lipoprotein (HDL) cholesterol, low-
density lipoprotein (LDL) cholesterol, triglycerides, very low density lipoprotein (VLDL)
cholesterol)
Safety
!
Adverse events
!
Pulse
!
Biochemistry and haematology
!
Antibodies against semaglutide
Trial products:
The following trial products will be supplied by Novo Nordisk A/S:
!
Semaglutide 1.0 mg/ml, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Semaglutide placebo, solution for injection, 3.0 ml cartridge, for NovoPen® 4
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Protocol
UTN: U1111-1179-7464 
Date:
09 March 2018
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT no.: 2016-000685-39
Version:
5.0
Page:
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Abbreviations: P = Phone visit, V = Clinic visit, ECG = Electrocardiogram, FU = follow-up, IWRS = interactive web response system, SF-36 = Short Form 36, HbA1c = glycosylated haemoglobin, BG-meter = blood glucose meter, EOT = End of treatment
1)
Subjects prematurely discontinuing trial product should attend an end of treatment visit (V18) as soon as possible and a follow-up visit 7 weeks thereafter (visit 19). In addition they should follow the trial visit 
schedule as planned and attend the trial product discontinuation 72 weeks FU visit 72 weeks after randomisation. However the following should not be done after visit 19 for subjects prematurely discontinuing trial 
product: Semaglutide plasma concentration, anti-semaglutide antibody assessment, hypo reporting and handing out subject diaries.
2)
A liver biopsy obtained 21 weeks or less before screening (visit 1) can be used. For subjects with no historical liver biopsy within 21 weeks prior to screening, a liver biopsy must be performed during the screening 
period.
3)
In selected countries only at sites with Fibroscan® equipment available.
4)
For subjects prematurely discontinuing trial product treatment, no biopsy at end of treatment visit (V18). Biopsy will be at visit 19A (trial product discontinuation 72 weeks FU).
5)
For subjects prematurely discontinuing trial product treatment, no Fibroscan
®
assessment at end of treatment visit (V18). Fibroscan® will be at visit 19A (trial product discontinuation 72 weeks FU).
6)
Exploratory biomarkers are: CK-18 fragments, ELF, miR-122, IL-1R antagonist, MCP-1, FGF-21.
7)
Blood samples for measurement of anti-semaglutide antibodies must be drawn prior to trial product dose.
8)
For subjects prematurely discontinuing trial product treatment a follow-up antibody sample and semaglutide plasma concentration sample must in addition to at the end of treatment vist (V18) be taken 7 weeks 
thereafter (visit 19).
9)
Hand out directions for use
10)
Only applicable for subjects with type 2 diabetes
11)
For women of childbearing potential: urine pregnancy test should be performed at any time during the trial if a menstrual period is missed, or as required by local law
12)
At these visits, urine pregnancy test will be performed
13)
Only applicable for subjects with type 2 diabetes
14)
Only applicable for female subjects
15)
Only applicable for patients with type 2 diabetes: Dilated fundoscopy/fundus photography performed within 90 days prior to visit 2 is acceptable if results are available for evaluation at visit 2 and there has been no 
deterioration in visual function since last assessment. Dilated fundoscopy/fundus photography can be performed between visit 1 and visit 2.
16)
All visit 2 assessments must be carried out prior to first trial product dose.
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Date:
09 March 2018
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Version:
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UTN: U1111-1179-7464 
Status:
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3
Background information and rationale for the trial
The trial will be conducted in compliance with this protocol, ICH GCP1 and applicable regulatory 
requirements, and in accordance with the Declaration of Helsinki2.
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site.
3.1
Background information
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of liver damages ranging from 
simple steatosis (non-alcoholic fatty liver), non-alcoholic steatohepatitis (NASH) with or without 
fibrosis through to cirrhosis3. It is estimated that 70-90% of patients with obesity have some degree 
of steatosis, with the prevalence increasing with the severity of obesity. To that end, NAFLD is the 
most common chronic liver disorder in Western countries and in the USA 30% of the adult 
population suffers from NAFLD4 5. Obesity is associated with an increased risk of NAFLD, the risk 
increasing with increasing BMI6. Furthermore the risk rises to as much as 70-75% in patients with 
type 2 diabetes (T2D)7. NASH represents a more advanced form of NAFLD and is reported in 3-5% 
of the Western population8. The prevalence of NASH is ~12% and ~22% in patients with obesity 
and T2D, respectively9.  The incidence and prevalence of NASH is rising and it is estimated that 
20-30% of patients with simple steatosis develop NASH10. Persistent inflammation can lead to the 
formation of fibrous scar tissue in the liver, which eventually causes cirrhosis and in some cases 
hepatocellular carcinoma11.
An estimated 10% of patients with NASH develop cirrhosis12. Obesity-induced NASH leading to 
liver cirrhosis is the third most common cause of liver transplantation in the USA today and 
expected to be the primary cause of liver transplantation in 203013 14 15. The pathophysiology of 
NASH is not well understood, but weight gain, insulin resistance, T2D and hypertension are all 
recognised as key factors16. 
In most patients NASH is asymptomatic, but non-specific symptoms such as right upper quadrant 
discomfort or fatigue can occur.  Often, NASH is first suspected on the basis of elevated liver 
enzymes found at routine medical health checks or incidentally by imaging or bariatric surgery. 
Liver enzymes (e.g. alanine aminotransferase) are elevated in 50-80% of cases and typically around 
1.5 times the upper limit of the normal17.NASH is a histological diagnosis based on liver biopsy 
together with clinical exclusion of consumption of >20 g ethanol/day for women and >30g 
ethanol/day for men18. Histologically, NASH is defined by the presence of steatosis, lobular 
inflammation, portal inflammation, cellular ballooning and varying degrees of fibrosis. The degree 
of fibrosis is described by the Kleiner fibrosis staging system, ranging from F0 (absence of 
fibrosis), F1 (portal/perisinusoidal fibrosis), F2 (perisinusoidal and portal/periportal fibrosis), F3 
(septal or bridging fibrosis) through F4 (cirrhosis)19. Several non-invasive biomarkers are available 
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for the assessment NASH and liver fibrosis, however, there are currently no non-invasive methods 
for diagnosis or assessment of disease prognosis approved for regulatory pivotal trials20. 
Currently, no drugs are approved for the treatment of NASH. First-line treatment is lifestyle 
intervention to achieve weight loss and treatment of comorbidities (e.g. hyperlipidaemia, 
hypertension and diabetes). In the case of progression to cirrhosis and liver failure, liver 
transplantation is the only treatment option. The current sparse epidemiological information on 
progression rates and predictive factors has limited the ability to calculate risk and possible benefit 
of treatments21.
3.1.1 Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells in the small 
intestine. GLP-1 has a glucose-dependent stimulatory effect on insulin and inhibitory effect on 
glucagon secretion from the pancreatic islets (i.e. when plasma glucose levels are above normal)22
23. Furthermore, GLP-1 is a physiological regulator of appetite and food intake and GLP-1 receptors 
are present in several areas of the brain involved in appetite regulation. Physiologically, GLP-1 has 
a pronounced inhibitory effect on gastric emptying; however this effect seems to diminish upon 
chronic exposure24 25 26. Endogenous GLP-1 has a very short elimination half-life of <1.5 minutes 
after intravenous administration due to rapid degradation by ubiquitous dipeptidyl peptidase (DPP 
4)27. Development of a GLP-1 receptor agonist (GLP-1 RA) with longer half-life has been 
necessary to enable effective treatment option for T2D and obesity.
Both human and animal studies have shown a beneficial effect of GLP-1 RA including liraglutide 
on liver lipid metabolism and progression of fatty liver to NASH 28 29 30 31. The mechanism by 
which GLP-1 RAs affect NASH is not clear and neither murine nor human hepatocytes seem to 
have any GLP-1 receptor expression29 32. Semaglutide effectively lowers body weight and have 
been shown to indirectly increase insulin sensitivity31
33 34. Additionally, semaglutide also increase 
insulin and lower glucagon levels, all of which may be beneficial in patients with NASH. Other 
mechanisms of actions based on the GLP-1 biology are anti-inflammation and lipid lowering 
effects29.
In the liraglutide phase 3 programme for treatment of T2D, 50% of the more than 4000 subjectss 
had elevated ALT at baseline. Compared to placebo, liraglutide dose-dependently reduced ALT in 
these patients suggesting an improvement of hepatic steatosis35.
The investigator sponsored study Liraglutide Efficacy and Action in NASH (LEAN), enrolled 52 
overweight subjects with and without T2D, with biopsy-confirmed NASH to receive once daily 
liraglutide s.c or placebo. After 48 weeks of treatment, 9 out of 23 (39%) subjects treated with 
liraglutide compared to 2 out of 22 (9%) subjects treated with placebo had resolution of NASH with 
no worsening of fibrosis (relative risk 4S3 [95% CI 1S0–17S7]; p=0S019) compared to placebo.
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Furthermore, significantly fewer patients treated with liraglutide had worsening of fibrosis 
compared to placebo34.
Semaglutide
Semaglutide is a potent human GLP-1 RA with a half-life of approximately 160 hours, suitable for 
both once daily (subcutaneous (s.c.) and oral) and once weekly s.c. administration. It is structurally 
similar to liraglutide (Victoza® and Saxenda®), a once daily GLP-1 RA developed by Novo Nordisk 
and approved in several countries for the treatment of T2D and weight management, respectively. 
For the semaglutide molecule the principal mechanism of protraction is albumin binding facilitated 
by a large fatty acid derived chemical moiety attached to the lysine in position 26. The specific 
modifications in the molecule are: 1) a modification in position 8 (alanine to 2-aminoisobutyric 
acid) of the peptide backbone in order to further increase stability against DPP-4, and a change in 
position 34 from a lysine to an arginine in order to only have one (1) lysine in the sequence; 2) a 
large hydrophilic linker between the lysine in position 26 and the gamma glutamate whereto the 
fatty acid is attached; 3) a C18 fatty di-acid with a terminal acidic group. The latter two (2) 
contribute to increased albumin binding which results in decreased renal clearance. In addition to 
slowed degradation in plasma and decreased renal clearance, delayed absorption from subcutis 
possibly also contributes to a prolonged half-life t½ of 155-183 hours.
In vitro receptor studies have shown that semaglutide is a potent and selective GLP-1 analogue, and 
animal studies using non-diabetic rats, non-diabetic pigs and diabetic mice have shown lowering of 
BG and inhibition of food intake. A clinically relevant effect on glucose metabolism and body 
weight has also been observed in humans.
Nonclinical data
The nonclinical programme for semaglutide was designed according to the ICH M336 guideline to 
support the clinical development. The standard nonclinical 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 dose limiting in mice, rats and cynomolgus monkeys. Two potential safety issues have 
been identified.
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 
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Status:
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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 RAs, including 
liraglutide. The relevance for human subjects is unknown. Recently published data have shown that 
the GLP-1 receptor is not expressed in the normal human thyroid. Accordingly, the risk of GLP-1 
receptor mediated C-cell changes in humans is considered to be low37.
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 as described below. Preliminary and main 
embryofoetal development and pre- and postnatal development studies with doses corresponding to 
12-15 fold expected clinical exposure in cynomolgus monkeys have been finalised. In the main 
embryofoetal development study sporadic abnormalities were reported across all dose groups and in 
the pre- and postnatal development study a dose-dependent increase in early pregnancy losses was 
observed. The findings observed across the three studies in cynomolgus monkeys are not indicative 
of a 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 1- to 2 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 
embryo-foetal development and pre- and postnatal development studies in cynomolgus monkey 
decreases the level of concern.
A comprehensive review of results from the nonclinical studies can be found in the current edition 
of semaglutide s.c. (NN9535), T2D, Investigator’s Brochure (IB)38 or any updates hereof.
Clinical data
Semaglutide s.c. is currently being investigated in the T2D development programme (please refer to 
the semaglutide s.c. IB for T2D or any updates hereof 38) and in the obesity development 
programme. Novo Nordisk is also developing semaglutide for oral administration, and phase 3 trials 
with this formulation are ongoing. 
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Date:
09 March 2018
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Version:
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UTN: U1111-1179-7464 
Status:
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As of 22 December 2015 (the cut-off date of the latest version of the semaglutide s.c. IB for T2D38), 
13 clinical pharmacology trials and 1 phase 2 trial have been completed with semaglutide once-
weekly s.c. In the completed once-weekly semaglutide s.c. trials, 802 subjects have been exposed to 
semaglutide: 411 healthy subjects (both single and multiple dosing), 313 subjects with type 2 
diabetes (up to 12 weeks of treatment), 48 subjects with varying degrees of renal impairment (4 
subjects had type 2 diabetes) (single dosing) and 30 subjects with obesity but otherwise healthy.
As of 22 December 2015, 8 therapeutic confirmatory trials with nearly 8000 subjects enrolled are 
ongoing including a 104-week trial comparing the long-term safety (including cardiovascular risk) 
and efficacy of semaglutide once-weekly s.c. 
Doses up to 1.6 mg with weekly dosing have been tested and doses up to 0.4 mg with daily dosing 
are being tested in the NN9536-4153 trial for the weight management indication. 
A recent finalised trial (not described in the current version of the semaglutide s.c. IB for T2D38), 
investigated subjects with hepatic impairment. Following administration of a single dose of 
semaglutide 0.5 mg, semaglutide pharmacokinetics were compared between subjects with mild, 
moderate and severe hepatic impairment and subjects with normal hepatic function. The primary 
endpoint, total exposure in terms of area under curve (AUC), met the criterion for ‘no effect’ for all 
3 hepatic impairment groups versus the group with normal hepatic function. Hence, exposure of 
semaglutide was not affected by hepatic impairment, and semaglutide pharmacokinetic properties 
for subjects with hepatic impairment were similar to those with normal function. No new safety or 
tolerability issues were observed for semaglutide following single dose administration to this 
subject group.
Efficacy
As of 22 December 2015, efficacy of semaglutide in 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 injection of 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. Mean changes in glycosylated haemoglobin (HbA1c) from baseline was up to -
1.19% (placebo adjusted estimated treatment difference). Dose-dependent improvements in fasting 
plasma glucose (FPG) and postprandial PG were also observed. The improvement in glycaemic 
control was accompanied by weight loss for semaglutide doses of 0.8 mg and above (estimated 
treatment difference compared to placebo up to a mean value of -3.64 kg).
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Date:
09 March 2018
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Version:
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UTN: U1111-1179-7464 
Status:
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Safety
From the clinical trials completed so far the following safety observations have been made. In 
consistency with the findings obtained from evaluating other GLP-1 RAs, common adverse events 
(AEs) included nausea and vomiting; most of them were mild to moderate in severity.
Hypoglycaemia has occurred in subjects receiving semaglutide and these events have mainly been 
minor. As with other GLP-1 RAs, an increase in heart rate has been observed in subjects exposed to 
semaglutide. The implications of this increase are unknown. As with all protein based 
pharmaceuticals, subjects treated with 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, including urticaria, 
rash, pruritus and rare cases of angioedema have been observed. Injection site reactions have been 
infrequently reported. These have mainly been mild and transient in nature.
Please see the current edition of semaglutide s.c. (NN9535), T2D, Investigator’s Brochure (IB)38 or 
any updates hereof for further details. 
For an assessment of benefits and risks of the trial, see Section 18.1.
3.2
Rationale for the trial
Currently, first-line treatment of NASH is lifestyle interventions to provide weight loss and to treat 
comorbidities (e.g. hyperlipidaemia, hypertension and diabetes) as no specific pharmaceutical 
therapies are approved and, thus, there is a substantial unmet medical need for effective treatment of 
NASH. 
The results from the LEAN trial34 showed beneficial treatment effects of liraglutide in overweight 
subjects with biopsy-confirmed NASH. Data from semaglutide trials, a human GLP-1 analogue 
structurally similar to liraglutide with similar mechanism of action, has suggested a more 
pronounced effect on glycaemic control and body weight loss compared to liraglutide. Therefore 
semaglutide is considered to have an even better potential as treatment for NASH. 
The purpose of the present trial is to investigate the potential of semaglutide s.c. once daily at three 
dose levels to resolve NASH compared to placebo. Furthermore, the trial is designed to explore the 
dose response relationship for semaglutide in NASH in order to inform dose selection for phase 3. 
Furthermore, safety and tolerability including the formation of anti-semaglutide antibodies will be 
investigated.
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4
Objectives and endpoints
4.1
Objectives
Primary objective
To compare the effect of semaglutide s.c. once daily versus placebo on histological resolution of 
NASH.
Secondary efficacy objectives
To investigate the dose-response relationship of three dose levels of semaglutide s.c. once daily (0.1 
mg/day, 0.2 mg/day and 0.4 mg/day) on histological resolution of NASH.
To compare the effects of semaglutide s.c. once daily to placebo on liver-related histological 
parameters and biomarkers of NASH disease.
To investigate the effects of semaglutide s.c. once daily versus placebo in subjects with NASH on:
!
Weight-related parameters
!
Glucose metabolism related parameters
!
Cardiovascular risk factors
!
Patient reported outcomes
Secondary safety objectives
To evaluate the safety and tolerability of three dose levels of semaglutide s.c. once daily in subjects 
with NASH.
4.2
Endpoints
4.2.1
Primary endpoint
!
NASH resolution* without worsening of fibrosis** after 72 weeks (yes/no)
*) Resolution of NASH defined by the NASH Clinical research network (CRN) as “no more than mild residual 
inflammatory cells (0 – 1) and no ballooning (0)” based on comprehensive interpretation by two independent 
pathologists (central reading) blinded to treatment allocation.
**) worsening defined by an increase of at least one stage of the Kleiner fibrosis classification 
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4.2.2
Secondary endpoints
4.2.2.1
Supportive secondary efficacy endpoints
Liver-related histological parameters
!
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or 
hepatocyte ballooning according to NASH CRN criteria 19 39).*
Change from baseline to week 72 in:
!
NAFLD activity score (NAS)*
!
Stage of fibrosis according to the Kleiner fibrosis classification*
!
Activity component of steatosis-activity-fibrosis (SAF) score*
Biomarkers of NASH disease
Change from baseline to week 72 in:
Algorithms:
!
Fibrosis-4 score (Fib-4 score) 
!
NAFLD Fibrosis Score (NFS) 
Blood samples:
!
Liver enzymes 
o
ALT, AST and GGT
!
Liver synthesis function
o
Albumin, INR
!
Exploratory biomarkers
o
Serum enhanced liver fibrosis (ELF)*
o
CK-18 fragments
o
miR-122
o
IL-1R antagonist 
o
MCP-1
o
FGF-21
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Imaging:
!
Liver stiffness and liver steatosis (with controlled attenuation parameter) measurement by 
Fibroscan®
Weight related parameters
!
Weight loss of M 5% of baseline body weight at 72 weeks (yes/no)
!
Weight loss of M 10% of baseline body weight at 72 weeks (yes/no)
Change from baseline to 72 weeks in:
!
Body weight (% and kg)
!
Waist circumference 
!
Body mass index (BMI) 
Glucose metabolism related parameters
Change from baseline to 72 weeks in:
!
Glycosylated haemoglobin type A1c (HbA1c)*
!
Fasting plasma glucose (FPG)*
!
Fasting glucagon
!
Homeostatic model assessment of insulin resistance (HOMA-IR)
Cardiovascular risk factors
Change from baseline to 72 weeks in: 
!
Systolic and diastolic blood pressure 
!
Lipids (total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density 
lipoprotein cholesterol (HDL cholesterol), very low density lipoprotein cholesterol (VLDL 
cholesterol), triglycerides, free fatty acids)
!
High sensitivity C reactive protein (hsCRP)
Patient reported outcomes
Change from baseline to 72 weeks in:
!
Short form 36 (SF-36): Physical and mental component summary scores and scores on the 
individual sub-domains: Physical functioning, role functioning, bodily pain, general health, 
vitality, social functioning, role emotional and mental health.
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4.2.2.2
Supportive secondary safety endpoints
!
Number of treatment-emergent adverse events during the trial
!
Number of treatment-emergent hypoglycaemic episodes during the trial
!
Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during the trial
!
Number of treatment-emergent severe hypoglycaemic episodes during the trial 
!
Number of subjects discontinuing treatment due to gastrointestinal adverse events
Occurrence of anti-semaglutide antibodies during and after 72 weeks treatment (yes/no):
!
Anti-semaglutide binding antibodies
!
Anti-semaglutide binding antibodies with in vitro neutralising effect
!
Anti-semaglutide binding antibodies cross reacting with native GLP-1
!
Cross-reacting anti-semaglutide binding antibodies with in vitro neutralising effect to native 
GLP-1
Anti-semaglutide antibody binding level during and after 72 weeks treatment
Change from baseline to 72 weeks in:
!
Pulse
!
ECG
!
Physical examination
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, differential 
count)
!
Biochemistry (creatinine, estimated glomerular filtration rate (eGFR), creatine phosphokinase, 
urea, bilirubin (total), alkaline phosphatase, ferritin, sodium, potassium, calcium (total), 
amylase, lipase)
!
Hormones (calcitonin)
Key supportive secondary endpoints prospectively selected for disclosure (e.g. clinicaltrials.gov and 
EudraCT) are marked with an asterisk (*).
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5
Trial design
5.1
Type of trial
This is a 72-week, randomised, double-blind, placebo-controlled, six-armed, parallel group, multi-
centre, multi-national trial comparing once daily administration of semaglutide s.c. in three different 
doses (0.1 mg, 0.2 mg and 0.4 mg) with placebo in subjects with NASH.
A planned total of 288 subjects will be randomised. Based on an assumption of a 65% screening 
failure rate, 823 subjects will be screened. Subjects will be randomised in a 3:3:3:1:1:1 manner to 
receive daily dosing of semaglutide s.c. 0.1 mg, 0.2 mg, 0.4 mg or corresponding injection volumes 
of placebo once daily (for details see Figure 5–1). To avoid bias in the assessment of the different 
semaglutide doses, the trial will be double-blinded within dose levels. The dose levels will not be 
blinded between each other because of different dose escalations and different target doses and 
volumes required. It is expected that 15% will withdraw from the trial or prematurely discontinue 
treatment with trial product. 
Figure 5–1
Trial design
Subjects in all treatment groups including placebo will receive nutritional and physical activity
counselling by a member of the study team according to local site practice. 
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CONFIDENTIAL


Protocol
Date:
09 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
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The randomisation of subjects to treatment will be stratified in five groups as described in section
5.2 and section 11).
The diagnosis of NASH as well as the histology based scores will be subject to central pathologist 
evaluation.
Subjects who prematurely discontinue the trial product treatment should continue with the 
originally scheduled site visits/contacts including a liver biopsy and final assessments 72 weeks 
after randomisation (visit 19A). However the following should not be done after visit 19 for 
subjects prematurely discontinuing trial product: Semaglutide plasma concentration, anti-
semaglutide antibody assessment, hypo reporting and handing out subject diaries.
Subjects who prematurely discontinue trial product treatment will continue to receive nutritional 
and physical exercise counselling throughout their trial participation.
The total trial duration for the individual subject will be up to 85 weeks (maximum).
5.2
Rationale for trial design
Trial duration of 72 weeks is considered adequate in terms of assessing the primary endpoint. 
Furthermore, a 72-week trial period is considered to be sufficient to characterise the semaglutide 
safety and tolerability profile in patients with NASH.
Randomisation will be stratified in five strata based on region (Japanese or non-Japanese) and, 
within the non-Japanese group, based on diabetes status at screening (with or without type 2 
diabetes) and fibrosis stage for baseline liver biopsy (F1/F2 or F3). This is to ensure an even 
distribution of the treatment arms within the specified strata. Balance of treatment arms with respect 
to region can help an evaluation of consistency of treatment effect between the entire population 
and Japanese subjects. Diabetes status and fibrosis stage for baseline liver biopsy are considered 
important prognostic covariates and including them in the stratification may enhance the credibility 
of the results of the trial as well as improve the precision of the estimated treatment effect. 
Stratification based on diabetes status and fibrosis stage is not feasible within the Japanese group 
due to small sample sizes. 
As gastrointestinal AE rates are anticipated to increase with higher doses and with large excursions 
in the semaglutide plasma concentration, semaglutide is dosed once daily to ensure less variability 
in concentrations. Dose escalation every fourth week is chosen to reach steady state at each dose 
level before increasing the dose. This could potentially reduce gastrointestinal AEs.
The trial design and protocol has been developed with harmonised advice from the regulatory 
authorities of the USA and Germany, and based on the recommendation of the Liver Forum40 41.
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Protocol
Date:
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464 
Status:
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5.3
Treatment of subjects
The dosing of semaglutide or placebo will be once daily with increase to the next dose step every 
four weeks until the randomised dose level is reached. During the dose escalation period subjects 
will be allowed to stay up to one extra week on each dose level, if the dose is not tolerable due to 
gastrointestinal events or for other reasons as judged by the investigator. 
Table 5–1
Duration of dose escalation period 
Once the randomised target dose is reached the subject should not change the dose. In case the dose 
escalation regimen or the target dose cannot be tolerated the subject must be discontinued from 
treatment.
The following investigational medicinal products (IMP) will be supplied by Novo Nordisk A/S, 
Denmark:
!
Semaglutide 1.0 mg/ml, solution for injection, 3.0 ml cartridge, for NovoPen® 4
!
Semaglutide placebo, solution for injection, 3.0 ml cartridge, for NovoPen® 4
Auxiliaries to IMP will be supplied by Novo Nordisk e.g. needles.
The NovoPen® 4 device that will be used in this trial will display a value and not mg. 
The conversion table below shows the connection between each volume matched dose level and the 
value shown in the display on the NovoPen® 4. Subjects must be instructed to administer the value
shown in the display.
Target dose
Scheduled time to target dose
Flexibility allowed if not tolerated
Maximum time to target dose
Semaglutide 0.4 mg/day 16 weeks
4 weeks
20 weeks
Semaglutide 0.2 mg/day 8 weeks
2 weeks
10 weeks
Semaglutide 0.1 mg/day 4 weeks
1 week
5 weeks
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Date:
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Version:
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Table 5–2
Dose conversion table
Value shown in display
Semaglutide (mg)
FL
5
0.05 mg
50 [L
10
0.10 mg
100 [L
20
0.20 mg
200 [L
30
0.30 mg
300 [L
40
0.40 mg
400 [L
Injections may be administered in the thigh, abdomen or upper arm, at any time of day irrespective 
of meals. The injections should be administered at approximately the same time of day during the 
trial.
Throughout the trial subjects cannot initiate treatment with:
!
GLP-1 RAs (other than trial product) or SGLT-2 inhibitors 
!
Vitamin E or pioglitazone
!
Drugs with potential effect on steatosis (corticosteroids (topical, inhaled and short term systemic 
use (N 14 days) are allowed), methotrexate, tamoxifen, valproic acid, amiodarone or 
tetracycline)
!
Drugs that could promote weight loss (orlistat, zonisamide, topiramate, phentermine, lorcaserin, 
bupropion and naltrexone alone or in combination with any other medication that could promote 
weight loss).
Neither can subjects participate in any organised weight reduction programme throughout the trial.
For subjects treated with vitamin E or pioglitazone according to exclusion criterion 8, these 
medications must be kept at a stable dose throughout the trial.
5.3.1
Subjects treated with insulin
Throughout the trial, insulin dose should be titrated at the discretion of the investigator. For the 
individual subject, increasing the insulin dose before two weeks after the end of the final dose-
escalation should be avoided, unless required to control acute hyperglycaemia and acute diabetic 
complications. 
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Version:
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Subjects treated with insulin and HbA1c G 8.0 % at screening:
Subjects with HbA1c N 8.0 % at screening (visit 1) should have the total daily insulin dose reduced 
by 30 % at start of trial product treatment to limit the potential risk of hypoglycaemia induced by 
the combination of insulin and semaglutide. 
5.3.2
Treatment of subjects with poorly controlled glycaemia
Subjects with type 2 diabetes and with persistent and unacceptable hyperglycaemia should be 
offered treatment intensification. If any HbA1c value reported by central laboratory exceeds 9% 
from at least 4 weeks after end of dose escalation, the subject should be offered treatment 
intensification at the discretion of the investigator. However, the following treatment types must not 
be used: GLP-1 RAs (other than trial product) and SGLT-2 inhibitors. Subjects that are started on 
treatment intensification medication should continue to follow the protocol specified visit schedule 
and stay on trial product treatment unless the investigator judges that this will jeopardise the safety 
of the subject. 
All treatment intensification medication given should be documented in medical records and 
reported in the eCRF. Treatment intensification medication will not be provided nor reimbursed by 
Novo Nordisk.
5.3.3
Subjects developing type 2 diabetes
Subjects who are diagnosed with T2D as a result of a screening procedure or are diagnosed with 
T2D during the trial should receive diabetes treatment at the discretion of the investigator. However 
the following treatments must not be used: GLP-1 RAs (other than trial product) and SGLT-2 
inhibitors. 
The antidiabetic medication prescribed by the investigator will not be provided nor reimbursed by 
Novo Nordisk. 
5.3.4
Missed dose
If a subject forgets to inject a trial product dose, the dose can be administered as soon as the subject 
remembers. However, if it is more than 12 hours since the subject should have administered the 
dose, the subject should skip the missed dose and take the next dose as usual on the following day.
If a subject has missed several consecutive doses of trial product, trial product can be continued. 
Please refer to guidance document describing recommendations on how to re-initiate trial product.
5.3.5
Nutritional and physical activity counselling
All subjects will receive nutritional and physical activity counselling (see section 8.6.3).
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5.4
Treatment after discontinuation of trial product
When discontinuing trial products, either at the scheduled end of treatment visit or if trial product is 
discontinued prematurely, the investigator should discuss other potential treatment options with the 
subject. For subjects with type 2 diabetes investigator should also discuss potential treatment 
options for type 2 diabetes.
5.5
Rationale for treatment
Subjects are enrolled for a treatment period of 72 weeks in order to be able to evaluate the full 
effect of treatment on the primary and secondary endpoints as well as to be able to make a 
reasonable safety assessment. This is based on the knowledge from the LEAN study (investigator 
sponsored study) where a statistically significant greater number of patients had resolution of 
NASH after 48 weeks of treatment with liraglutide 1.8 mg compared with placebo in patients with 
biopsy confirmed NASH. After 48 weeks of treatment, 9 out of 23 (39%) subjects treated with 
liraglutide compared to 2 out of 22 (9%) subjects treated with placebo had resolution of NASH with 
no worsening of fibrosis (relative risk 4S3 [95% CI 1S0–17S7]; p=0S019) compared to placebo34.
Thus, given the relatively long time required to reach the target dose of the highest semaglutide 
doses, and in order to see the full effect of the different doses, trial duration of 72 weeks was 
chosen.
The comparator in the trial is placebo. Placebo is used in order to evaluate the absolute safety and 
efficacy of once-daily semaglutide. Currently, there are no approved therapies for NASH. 
The semaglutide dose levels of 0.1 mg/day to 0.4 mg/day have been chosen to get a wide range of 
exposure. This will allow for dose-response modelling which in combination with safety 
information related to the individual doses, will form the basis for selecting the optimal semaglutide 
dose for patients with NASH.
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Date:
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464 
Status:
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6
Trial population
6.1
Number of subjects 
Number of subjects planned to be screened: 823.
Number of subjects planned to be randomised: 288 (65% screen failure rate).
Number of subjects expected to complete the trial on or off trial product: 259 (10% trial withdrawal 
rate).
Number of subjects expected to complete the trial on trial product: 245 (15% total trial product 
discontinuation rate).
The aim is that between 30 and 70% of subjects should have NASH and type 2 diabetes.
To ensure that a sufficient number of subjects with F2 and F3 are included in the trial the aim is to 
randomise a maximum of approximately 30% subjects with F1.
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 except for protocol described pre-screening activities which require a separate 
informed consent.
Applicable for Sweden: 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, aged 18-75 years (both inclusive) (for Japan: male or female aged 20-75 
years (both inclusive)) at the time of signing informed consent.
3. Stable body weight (defined as less than 5% self-reported change in body weight in the 
period from 28 days prior to screening or if recent biopsy is used from 28 days prior to 
baseline liver biopsy until time of screening).
4. Accept to have one liver biopsy performed during the screening period (if no biopsy within 
21 weeks before screening is available) and one at 72 weeks after randomisation.
5. Histologic evidence of NASH based on central pathologist evaluation of a liver biopsy 
obtained up to 21 weeks before screening.
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6. A histological NAS > 4 with a score of 1 or more in each sub-component of the score based 
on central pathologist evaluation.
7. NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on 
central pathologist evaluation.
6.3
Exclusion criteria
For an eligible subject, all exclusion criteria must be answered “no”. 
Liver-related:
1. Documented causes of chronic liver disease other than NASH.
2. Positive HBsAg, positive anti-HIV, positive HCV-RNA.
3. AST greater than 5 times upper normal limit (UNL) at screening.
4. ALT greater than 5 times UNL at screening.
5. Elevated total bilirubin (> 1.5 mg/dL) at screening. Total bilirubin level >1.5 mg/dL is 
allowed if conjugated bilirubin is < 1.5 × UNL.
6. International normalized ratio (INR) of prothrombin time > 1.3 at screening.
7. Known or suspected abuse of alcohol (> 20 g/day for women or > 30 g/day for men), 
alcohol dependence* or narcotics. (* = assessed by the Alcohol Use Disorders Identification 
Test (AUDIT questionnaire)).
8. Treatment with vitamin E or pioglitazone which has not been at a stable dose in the period 
from 90 days prior to screening or if recent biopsy is used from 90 days prior to baseline 
liver biopsy until time of screening.
9. Treatment or anticipated initiation (for more than 14 consecutive days) of medications 
known to have an effect on steatosis (e.g. treatment with Corticosteroids (topical and inhaled 
are allowed), Methotrexate, Tamoxifen, Valproic acid, Amiodarone or Tetracycline) in the 
period from 28 days prior to screening or if recent biopsy is used from 28 days prior to 
baseline liver biopsy until time of screening.
Glycaemia related:
10. HbA1c > 10% at screening.
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11. Treatment with GLP-1 RAs or SGLT-2 inhibitors in the period from 90 days prior to 
screening or if recent biopsy is used from 90 days prior to baseline liver biopsy until time of 
screening.
12. Treatment with other glucose lowering agent(s) (apart from GLP-1 RAs or SGLT-2 
inhibitors) not stable in the period from 28 days prior to screening or if recent biopsy is used 
from 28 days prior to baseline liver biopsy until time of screening. Changes without clinical 
relevance in the opinion of the investigator are allowed.
13. Diagnosis of type 1 diabetes according to medical records.
Obesity related:
14. Body Mass Index (BMI) N 25.0 kg/m2 at the screening visit (visit 1).
15. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion and 
naltrexone alone or in combination or any other medication that could promote weight loss 
in the opinion of the investigator in the period from 28 days prior to screening or if recent 
biopsy is used from 28 days prior to baseline liver biopsy until time of screening.
16. Participation in an organised weight reduction program (e.g. WeightWatchers®) in the 
period from 28 days prior to screening or if recent biopsy is used from 28 days prior to 
baseline liver biopsy until time of screening.
17. Previous surgical treatment for obesity. However (1) liposuction and/or abdominoplasty if 
performed > 6 months before baseline liver biopsy is allowed or 2) lap banding where the 
band has been removed > 6 months before baseline liver biopsy is allowed 3) intragastric 
balloon where the balloon has been removed > 6 months before baseline liver biopsy is 
allowed.
General safety:
18. For patients with type 2 diabetes only: Proliferative retinopathy or maculopathy requiring 
acute treatment verified by fundus photography or dilated fundoscopy performed within the 
past 90 days prior to randomisation. 
19. History or presence of pancreatitis (acute or chronic).
20. Calcitonin M 50 ng/L at screening.
21. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
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22. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
23. Surgery scheduled for the trial duration period, except for minor surgical procedures, in the 
opinion of the investigator.
24. Any condition which, in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
25. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures.
26. Known or suspected hypersensitivity to trial product or related products.
27. Previous participation in this trial. Participation is defined as randomisation.
28. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
29. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures 
as required by local regulation or practice).
For EU countries: The following contraceptive measures are considered adequate:
!
Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal
!
Progestogen-only hormonal contraception associated with inhibition of ovulation :
o
oral
o
injectable
o
implantable
!
Placement of an 
o
intrauterine device (IUD) 
o
intrauterine hormone-releasing system ( IUS)
!
Bilateral tubal occlusion
!
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository) (not applicable for Belgium, Denmark, Finland, Greece, 
Spain, Sweden)
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!
Vasectomised partner (where partner is sole partner of subject) (not applicable for Denmark)
!
True sexual abstinence (not applicable for Denmark). Sexual abstinence is defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.
30. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
< 30 ml/min/1.73 m2 as defined by Kidney Disease: Improving Global Outcomes 
(KDIGO).42
31. Applicable for Sweden: TSH > 6 mIU/L or < 0.4 mIU/L at screening.
6.4
Criteria for premature discontinuation of trial product 
Efforts must be made so that subjects attend and complete all scheduled visit procedures. However 
the following should not be done after visit 19 for subjects prematurely discontinuing trial product: 
Semaglutide plasma concentration, anti-semaglutide antibody assessment, hypo reporting and 
handing out subject diaries. Subjects should stay in the trial irrespective of lack of adherence to 
randomised treatment, lack of adherence to visit schedule or missing assessments. Only subjects 
who decline any further contact with the site in relation to the trial will be considered as withdrawn 
from the trial (see section 6.5).
The subject may be prematurely discontinued from trial product at the discretion of the investigator 
due to a safety concern.
The subject must be prematurely discontinued from trial product 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
4. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product.
5. In case of code break
6. If the target treatment dose of the randomised trial product is not tolerated by the subject
7. Diagnosis of acute pancreatitis
8. Diagnosis of medullary thyroid carcinoma
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9. Surgical treatment for obesity
10. Treatment with other GLP-1 receptor agonists or SGLT-2 inhibitors
11. Persistent abnormal liver blood parameters indicating drug induced liver injury (DILI) (see
details in section 8.7.2)    
See section 8.1.6 for procedures to be performed for subjects discontinuing trial product 
prematurely.
6.5
Withdrawal from trial
The subject may withdraw consent at will at any time. The subject’s request to withdraw from the 
trial must always be respected. 
Please see section 8.1.7 for procedures to be performed for subjects withdrawing consent.  
6.6
Subject replacement
Subjects who discontinue trial product prematurely or withdraw from the trial will not be replaced.
6.7
Rationale for trial population 
Patients with NASH have an increased risk of all cause and liver related mortality. As there is 
currently no established, safe and effective pharmacological treatment for NASH there is a 
significant unmet medical need. 
As the prevalence of NASH is high in patients with T2D (approximately 25% of patients with T2D 
have NASH) and considering the glycaemic properties of semaglutide it is appropriate not to 
exclude patients with T2D in the trial. Hence both patients with and without T2D can be included as 
it is the aim to include a broad NASH population. 
The trial population will consist of patients with NASH and a fibrosis stage of F1-F3. Patients with 
F0 will be excluded as they do not have fibrosis. Furthermore, subjects with fibrosis stage 4 
(cirrhosis) will be excluded from the trial as an important endpoint addressing worsening in fibrosis 
cannot be addressed in this population (the Kleiner classification has a maximum score of 4). 
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Version:
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UTN: U1111-1179-7464 
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7
Milestones
Planned duration of recruitment period: 103 weeks
End of trial is defined as LSLV
Recruitment:
The screening and randomisation rate will be followed closely via the interactive web response 
system (IWRS) in order to estimate when to stop screening. All investigators will be notified 
immediately when the recruitment period ends, after which no further subjects may be screened and 
the IWRS will be closed for further screening. All subjects screened during the recruitment period 
and found eligible for randomisation can be randomised within the timelines specified in the 
flowchart (see section 2).
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 Disclosure43, it will also be disclosed 
according to other applicable requirements such as those of the International Committee of Medical 
Journal Editors (ICMJE)44, the Food and Drug Administration Amendment Act (FDAAA)45,
European Commission Requirements46 47 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.
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8
Methods and assessments
The following sections describe the assessments and procedures that must be performed during this 
trial. The overview of when they must be performed is included in the flow chart (section 2).
8.1
Visit procedures
8.1.1
Screening, re-screening and screen failures
Informed consent must be obtained before any trial related activity, see section 18.2. Separate 
informed consent forms for long-term storage of human samples and genotyping are available and 
informed consent must be obtained before activities related to any of these are undertaken.
Additionally a separate informed consent form for optional pre -screening is available. This must be 
signed before any optional pre-screening activities are performed (see section 8.1.2).
At screening (visit 1), 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.
Each subject will be assigned a unique 6-digit subject number which will remain the same 
throughout the trial.
The investigator must keep a subject screening log, a subject identification code list and a subject 
enrolment log. Only subjects who have signed the informed consent form should be included on the 
logs. The subject screening log and subject enrolment log may be combined in one log and may be 
generated from the IWRS (see section 10).
Screening failures
For screening failures the screening failure form in the electronic case report form (eCRF) 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 eCRF. Follow-up on serious 
adverse events (SAEs) must be carried out according to section 12.
A screening failure session must be made in the IWRS. The case book in the eCRF must be signed.
Re-screening
Re-screening of screening failures is allowed only once within the limits of the recruitment period. 
However, re-screening is NOT allowed if the subject has failed one of the inclusion/exclusion 
criteria related to laboratory parameters (pathology and/or blood parameters). In the event of re-
screening, a new informed consent must be obtained and a new subject number must be allocated. 
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All assessments and laboratory samples must be repeated.
For subjects meeting exclusion criterion number 6, re-test of INR is allowed once within the limits 
of the screening period for that subject. To be eligible for INR re-test the subject must have a 
screening albumin within central laboratory reference range. Re-test of INR does not require a new 
informed consent or new subject number. 
8.1.2
Optional pre-screening (not applicable for Sweden)
The Investigator may, after obtaining separate informed consent, perform pre-screening of potential 
trial candidates. Pre-screening assessments include blood parameters and imaging (except for 
imaging methods with radiation involved).The purpose of such assessments is to assess trial 
eligibility potential.
Pre-screening assessments are not defined as trial-related procedures. Results of pre-screening 
assessments will not be collected in the trial database and will not be monitored. Concerns related to 
any pre-screening assessment must not be reported as an adverse event.   
Pre-screening assessments (blood parameters and imaging) performed after signature of the separate 
informed consent can be reimbursed by Novo Nordisk A/S.
8.1.3
AUDIT questionnaire
The AUDIT questionnaire is used to assess the frequency of alcohol consumption and screen out 
alcohol-related problems, and dependence symptoms. 
8.1.4
Fasting visits
Subjects must attend most clinic visits in a fasting state (see section 2).
Fasting is defined as at least eight hours without food or liquids, except for water. Trial product and 
any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling has been performed. If the subject is not fasting as required, the subject 
must be called in for a new visit within the visit window to have the fasting procedures done. 
Fasting procedures include body weight, Fibroscan® measurements and blood sampling (FPG, 
fasting insulin, fasting glucagon, calcitonin and lipids (Total cholesterol, free fatty acids, HDL 
cholesterol, LDL cholesterol, triglycerides, VLDL cholesterol)).
Prior to Fibroscan® measurements, only two hours of fasting is required.
At visit 19, the subject must be fasting for two hours prior to the anti-semaglutide antibody 
sampling (see section 8.5.3.7).
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8.1.5
Missed visits
If an entire visit is missed and it is not possible to re-schedule the visit within the time window, 
every effort should be made to re-schedule the visit at the earliest possible date before the next visit.
8.1.6
Premature discontinuation of trial product
If a subject prematurely discontinues trial product treatment, the investigator must undertake 
procedures similar to those for visit 18 (end of treatment) as soon as possible and the follow up visit 
(visit 19) must be performed 7 weeks later. Females only: All female subjects using an adequate 
contraceptive method must be reminded to continue this for 7 weeks after discontinuation of trial 
product treatment.
Following visit 19, subjects should continue with the originally scheduled site visits/contacts up to 
and including visit 19A. Visit 19A should take place 72 weeks (± 7 days) after their randomisation 
date (for details refer to section 2). However the following should not be done after visit 19 for 
subjects prematurely discontinuing trial product: Semaglutide plasma concentration, anti-
semaglutide antibody assessment, hypo reporting and handing out subject diaries.
If a subject is not willing to attend one or more of the above mentioned visits, it should be 
documented in the subject’s medical record that the subject has refused to attend the visit and why.
For subjects discontinued from trial product, final drug accountability must be performed and a 
treatment discontinuation session must be made in the IWRS. The primary reason for premature
discontinuation of trial product must be specified in subject’s medical records and the eCRF. 
8.1.7
Withdrawn subjects
If a subject withdraws consent, the investigator must aim to undertake procedures similar to those 
for visit 18 (end of treatment) as soon as possible. If the subject agrees, the follow up visit (visit 19) 
must be performed 7 weeks later.
The end-of-trial form must be completed, and final drug accountability must be performed even if 
the subject is not able to come to the trial site. A treatment discontinuation session must be made in 
the IWRS. The case book must be signed. 
Although a subject is not obliged to give his/her reason(s) for withdrawing consent, the investigator 
must make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawing consent must be specified in 
the end-of-trial form in the eCRF.
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8.1.8
Subject training
Subject diaries
The subject must be provided with diaries at the specified visits (section 2). The investigator should 
instruct the subjects in filling in the diary according to the provided diary instructions (see section
8.4.7 and 8.6.2). The diaries dispensed to subjects should be collected at the specified visits (section
2).
Trial product
Trial product must be dispensed to subjects at the specified visits (see section 2). Trial product will 
be dispensed to the subject by the site. At the visits specified in section 2 and as needed, the 
subjects will be instructed in the handling of trial product and trained in the use of the pen-injector 
and in the administration of s.c. injection of trial product.
Subjects must be instructed to administer the value shown in the display, see Table 5–2.
Hypoglycaemic episodes recognition
The investigator or delegate will train the subjects in symptom recognition and handling of 
hypoglycaemia.
Suspected pregnancy
Female subjects must be instructed to contact site if a menstrual period is missed so they can come 
in for urine pregnancy test.
8.2
Subject related information/assessments 
8.2.1
Demography
Demography will be recorded at screening and consists of:
!
Date of birth (according to local regulation)
!
Sex
!
Ethnicity (according to local regulation)
!
Race (according to local regulation)
8.2.2
Concomitant illness and medical history
A concomitant illness is any illness that is present at the start of the trial (i.e. at visit 1) or found as 
a result of a screening procedure or other trial procedures performed before exposure to trial 
product. 
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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.
Medical history is a medical event that the subject has experienced in the past. Only relevant and 
significant medical history as judged by the investigator should be recorded. Specific medical 
history of gallbladder disease should only be entered on the specific form.
The information collected for concomitant illness and medical history should include diagnosis, 
date of onset and date of resolution or continuation, as applicable.
It must be possible to verify the subject’s medical history in source documents such as subject’s 
medical record. If a subject is not from the investigator´s own practice; the investigator must make 
reasonable effort to obtain a copy of the subject’s medical record from any relevant party e.g. 
primary physician. The investigator must document any attempt to obtain external medical 
information by noting the date(s) when information was requested and who has been contacted.
8.2.3
Concomitant medication
A concomitant medication is any medication, other than the trial product(s), 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. 
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation. For vitamin E and pioglitazone the daily dose 
must be recorded as well.
If a change is due to an AE, then this must be reported according to section 12. If the change 
influences the subject’s eligibility to continue in the trial, the monitor must be informed.
8.2.4
Hypoglycaemia unawareness
For subjects with type 2 diabetes information on hypoglycaemia unawareness will be recorded at 
screening according to Clarke’s questionnaire, question 848. The investigator must ask the subject in 
the following way: “To what extent can you tell by your symptoms that your blood glucose is low?” 
The subject can answer never, rarely, sometimes, often or always.
Subjects answering ‘never, rarely or sometimes’ are considered as having impaired awareness of 
hypoglycaemia.                                 
8.2.5
Childbearing potential  
It must be recorded in the eCRF whether female subjects are of childbearing potential. 
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Pregnancy testing must be performed on female subjects of childbearing potential as described in 
section 8.5.3.6. Female subjects of childbearing potential must be instructed to use adequate 
contraceptive methods throughout the trial and until 7 weeks after end of treatment.
Female of non-childbearing potential is defined as:
–
Female who has undergone a hysterectomy, bilateral oophorectomy or bilateral tubal 
ligation 
–
Postmenopausal defined as no menses for 12 months without an alternative medical cause
–
Other medical reasons preventing childbearing potential
8.2.6
Tobacco use 
Details of tobacco use must be recorded at the first visit. Smoking is defined as smoking at least one 
cigarette or equivalent daily.
Smoking status:
!
Never smoked
!
Previous smoker
!
Current smoker
8.2.7
Fundoscopy/Fundus photography
For subjects with type 2 diabetes dilated fundoscopy/fundus photography will be performed as 
specified in section 2. Fundoscopy requires pharmacological dilation of both pupils. Results of the 
dilated fundoscopy/fundus photography will be evaluated by the investigator and the investigator 
evaluation must be documented either on the dilated fundoscopy/fundus photography result report 
or in the subject’s medical record. 
The investigator or medically qualified delegate must sign, date and interpret the dilated 
fundoscopy/fundus photography by using the following categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
If a dilated fundoscopy/fundus photography has been performed within 90 days prior to 
randomisation, the procedure does not need to be repeated, unless there has been worsening of 
visual function since the last examination. The results must be available prior to randomisation. 
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If the dilated 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.
8.3
Efficacy assessments
8.3.1
Liver biopsy
Liver biopsies must be performed according to site standard procedures.
To be randomised, subjects must have histologic evidence of NASH based on central pathologist 
evaluation of a liver biopsy. Histologic evidence of NASH can be based on a liver biopsy obtained 
up to 21 weeks prior to screening. For subjects with no historical liver biopsy within 21 weeks prior 
to screening, a liver biopsy must be performed during the screening period. The histologic evidence 
of NASH by central pathologist evaluation of the liver biopsy must be available prior to 
randomisation of the subject.
In case the liver biopsy obtained during the screening period or up to 21 weeks prior to screening
cannot be used for confirmation of NASH diagnosis due to technical issues with the biopsy sample,
the subject should be asked to have another liver biopsy performed. If the subject does not agree to 
that, the subject is a screen failure.
All randomised subjects should have a liver biopsy performed at end of treatment (if the 72 weeks
treatment period is completed) or at 72 weeks after randomisation (if trial product has been 
prematurely discontinued). In case conclusive evaluation of this biopsy is not possible due to 
technical issues with the biopsy sample, the subject should be asked to have another liver biopsy 
performed.
Handling of histology samples will be done by a central laboratory. Descriptions of laboratory 
supplies, procedures for preparation of tissue samples, handling, storage, shipments and return of 
tissue samples, will be given in the trial-specific laboratory manual provided by the central 
laboratory.
Histology results will be made available to the investigator.
Only tissue samples requested in the protocol must be sent to the central laboratory.
Tissue samples will be returned to the relevant sites no later than at finalisation of the clinical trial 
report (CTR).
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8.3.1.1
Central pathologist evaluation
The histologic evidence of NASH and histology based scores will be centrally assessed by two 
independent pathologists with expertise and experience in NASH.
The central pathologist evaluation will include the following:
!
Presence or absence of NASH
!
NAFLD Activity Score (NAS) components (steatosis, lobular inflammation and hepatocyte 
ballooning) 
!
Stage of fibrosis (according to Kleiner fibrosis classification)
The pathologists will be blinded to the subject and treatment and to each other’s assessment of the 
tissue until both have reached a final conclusion. Both pathologists have to agree on the outcome of 
the assessment. In case of misalignment of the conclusions, a consensus needs to be reached by 
discussion or joint assessment of the two pathologists. If not possible a third independent, qualified 
pathologist will make the final decision.
8.3.2
Fibroscan® measurements
At sites where Fibroscan® equipment is not available, no assessment should be done.
Liver stiffness
At sites with Fibroscan® equipment available, measurements of liver stiffness must be performed at 
the specified visits (section 2). Fibroscan measurements can be performed up to 2 weeks prior to 
each visit. A result measured in kPa must be available. The same equipment should preferably be 
used for all measurements throughout the trial.
All randomised subjects should have a liver stiffness measurement performed 72 weeks after 
randomisation regardless of whether trial product has been discontinued prematurely or not.
The liver stiffness measurements must be performed in fasting state (see section 8.1.4) and
according to site standard procedures. The result of the measurement must be documented and 
investigator evaluation of the result must be documented either on the actual report or in the 
subject´s medical record.
Liver steatosis
At sites with Fibroscan® equipment available with Controlled Attenuation Parameter (CAP) option 
available, measurements of liver steatosis must be performed at the specified visits (section 2).
Fibroscan measurements can be performed up to 2 weeks prior to each visit. A result measured in 
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dB/m must be available. The same equipment should preferably be used for all measurements 
throughout the trial.
All randomised subjects should have a liver steatosis measurement performed 72 weeks after 
randomisation regardless of whether trial product has been discontinued prematurely or not.
The liver steatosis measurements must be performed in fasting state (see section 8.1.4) and 
according to site standard procedures. The result of the measurement must be documented and 
investigator evaluation of the result must be documented either on the actual report or in the 
subject´s medical record.
8.3.3
Body measurements
8.3.3.1
Body weight
Body weight must be measured in a fasting state (except at visit 1), see flowchart (section 2) and 
will only be measured at visits where subjects are fasting due to blood sampling. 
The body weight should be measured with an empty bladder, without shoes and only wearing light 
clothing. It must be recorded with one decimal (kg or lb) and preferably using the same digital scale 
throughout the trial. The scale must be calibrated according to the directions for use.
8.3.3.2
Height
Height is measured at screening (visit 1) without shoes in centimetres or inches (one decimal).
8.3.3.3
Body mass index
Body mass index will be calculated by the eCRF from visit 1 height data and must be in accordance 
with exclusion criterion 14.
8.3.3.4
Waist circumference
The waist circumference is defined as the abdominal circumference located midway between the 
lower rib margin and the iliac crest and will be measured at the specified visits (section 2).
One waist measurement must be performed and is measured in the horizontal plane with one 
decimal using a non-stretchable measuring tape. The same measuring tape should preferably be 
used throughout the trial.
The subject should be measured in a standing position with an empty bladder and wearing light 
clothing. The subject should be standing, feet together with arms at the side and waist accessible. 
The tape should touch the skin but not compress soft tissue and twists in the tape should be avoided. 
The subject should be asked to breathe normally.
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8.3.3.5
Vital signs
Systolic and diastolic blood pressure
One measurement of blood pressure must be performed at the visits specified in section 2.
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
!
Blood pressure should be measured in a sitting position, with the legs uncrossed, the back and 
arms supported
!
The subject should be sitting for five minutes before the measurement is taken
The same arm and an appropriate cuff size should be used for blood pressure measurement at all 
visits
Pulse
Pulse (beat/min) will be recorded in a sitting position after resting for five minutes at the specified 
visits (section 2).
8.3.4
SF-36 questionnaires
The Short Form 36 (SF-36) should be completed by subjects at the visits specified in section 2.
The questionnaires must be completed by the subject and should preferably be completed after 
conclusion of all fasting-related activities, but before any other visit-related activities. Subjects must
be given the opportunity to complete the questionnaires by themselves without interruption.
SF-36 measures the individual’s overall health-related quality of life (HRQoL) on 8 domains: 
physical functioning, role functioning, bodily pain, general health, vitality, social functioning, role 
emotional and mental health.
Review of the questionnaires must be documented either on the documents and/or in the subject’s 
medical record. If clarification of entries or discrepancies in the patient reported outcomes 
questionnaires 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.
It is the responsibility of the investigator or delegated staff to review the questionnaires to report 
possible AEs immediately following completion. 
All results from the SF-36 questionnaires must be transferred into the eCRF.
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8.4
Safety assessments
8.4.1
Physical examination
Physical examination will be performed at the specified visits (section 2) according to local 
procedure. Physical examination must be recorded in the subject´s medical record and should 
include:
! General appearance 
! Thyroid gland 
! Respiratory system
! Cardiovascular system
! Gastrointestinal system including mouth
! Musculoskeletal system
! Central and peripheral nervous system
! Skin
! Lymph node palpation
! Head, ears, eyes, nose, throat and neck
Any abnormal, clinically significant findings at visit 1 must be recorded as a concomitant illness 
(see section 8.2.2).
8.4.2
Electrocardiogram
A 12-lead ECG will be performed at the visits specified in the flow chart (section 2). The 
investigator or delegate must sign, date and interpret the ECG by using the following categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
All ECGs will in addition undergo central evaluation. Sites will be informed of the central ECG 
evaluation in case this evaluation reveals an abnormal ECG reading. If the abnormality, in the 
opinion of the investigator, represents an unreported AE, such finding must be reported by the 
investigator (see section 12.2).
If the central ECG evaluation of a post-baseline ECG is suggestive of new MI, a confirmatory ECG 
should be performed. All findings suggestive of new MI detected by the central ECG reading will 
be adjudicated by the event adjudication committee (EAC) (see section 12.7.2). 
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8.4.6
Self-measured plasma glucose
At the randomisation visit (visit 2) subjects with type 2 diabetes will be provided with a blood 
glucose meter (BG-meter) including auxiliaries as well as instructions for use. The subjects will be 
instructed in how to use the device and the instruction will be repeated at regular intervals as 
needed. Subjects must be instructed to measure their blood glucose in connection with symptoms of 
hypoglycaemia.
The blood glucose meters use test strips calibrated to plasma values. Therefore, all measurements 
performed with capillary blood are automatically calibrated to plasma equivalent glucose values, 
which will be shown on the display.
Only the blood glucose meter provided by Novo Nordisk should be used for the measurements 
required in the protocol.
Subjects without type 2 diabetes at the randomisation visit will not be provided with BG-meters and 
hypoglycaemic episodes will only be identified by subjects via symptoms of hypoglycaemia.
In case a subject is diagnosed with type 2 diabetes during trial participation, the subject must be 
provided with a BG-meter and must be instructed in how to use the device and to measure their 
blood glucose in connection with symptoms of hypoglycaemia in the remaining trial period.
Subjects with type 2 diabetes should be instructed in how to record the results of the SMPG values 
in the diaries. The record of each SMPG value should include date, time and value. All data from 
the diary must be transcribed into the eCRF during or following the contact. If obtained via phone 
and a discrepancy is later detected, the values in the eCRF must be corrected.
Occasional review by the investigator of the values stored in the memory of the blood glucose meter 
and correct reporting of these in the diary is advised in order to ensure adequacy of the data reported 
in the trial database.  
8.4.7
Hypoglycaemic episodes
All subjects will at randomisation be instructed in symptom recognition and handling of 
hypoglycaemia.
All subjects will be provided with diaries for capturing information related to hypoglycaemic 
episodes throughout the trial from visit 2 to visit 19 (7 weeks after end of treatment visit (visit 18)). 
For subjects with type 2 diabetes plasma glucose should always be measured and recorded when a 
hypoglycaemic episode is suspected.
All plasma glucose values: 
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!
N 3.9 mmol/L (70 mg/dL) or 
!
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycaemic symptoms
should be reported in the diary according to the instructions below throughout the trial from visit 2 
to visit 19 (7 weeks after end of treatment visit (visit 18)).
Upon onset of a hypoglycaemic episode the subject is recommended to measure plasma glucose 
every 15 minutes until the SMPG value is >3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved in accordance to current guidelines49.
An SMPG value N 3.9 mmol/L (70 mg/dL) or hypoglycaemic symptoms must trigger a 
hypoglycaemic episode form to be completed by the subject. Repeated SMPG measurements and/or 
symptoms, occurring within a period of 60 min after onset on a hypoglycaemic episode, will by 
default be considered as one hypoglycaemic episode until a succeeding SMPG value is > 3.9 
mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycaemic episode form. SMPG measurements N 3.9 mmol/L (70 mg/dL) or hypoglycaemic 
symptoms after the 60 min period shall trigger the reporting of a new hypoglycaemia episode and 
prompt the subject to fill out a new hypoglycaemic episode form until a succeeding measurement is 
> 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.
In case of several low SMPG values within the 60 minutes interval, the lowest value is the one that 
will be reported as the SMPG value for the hypoglycaemic episode but the start time of the episode 
will remain as the time for the first SMPG value and/or symptom.
For all subjects the records on hypoglycaemic episodes should include the following information (in 
subject diaries):
!
Start date and time of the hypoglycaemic episode.
!
Stop date and time of the hypoglycaemic episode (stop time is the first time the plasma glucose 
value is > 3.9 mmol/L (70 mg/dL) (only applicable for subjects with type 2 diabetes) and/or 
symptoms have been resolved).
!
The plasma glucose level before treating the episode (if available) and any follow up 
measurements (only applicable for subjects with type 2 diabetes).
The lowest value measured during the hypoglycaemic episode will be reported as the plasma 
glucose value for the episode, the remaining values will be kept as source data in the diary.
!
Whether the episode was symptomatic (Yes/No).
A hypoglycaemic episode starting without symptoms should be updated to symptomatic if the 
subject experiences symptoms later during the episode.
!
Whether the subject was able to treat him/herself.  
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If the severity of a hypoglycaemic episode aggravates, only one hypoglycaemic episode should 
be reported, reflecting the most severe degree of hypoglycaemia.
!
Date, time and dose of last trial product administration prior to the episode.
!
Date and time of last main meal (not including snacks) prior to the episode.
!
Whether the episode occurred in relation to physical activity.
!
Change in any concomitant illness.
!
Any sign of fever and/or other acute disease.
!
Whether the subject was asleep when the episode occurred.
–
If yes, whether the symptoms of the episode woke up the subject
The answer to the question: "Was the subject able to treat him/herself?" must be answered "No" for 
an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or 
take other corrective actions. Plasma glucose concentrations may not be available during an event, 
but neurological recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration49.
Oral carbohydrates must not be given if the subject is unconscious.
If the question "Was the subject able to treat him/herself?" is answered "No", the following 
information should be recorded by the subject:
!
Who assisted in the treatment of the hypoglycaemic episode (i.e. medical person or non-medical 
person, please specify)?
!
Where the treatment was administered (in clinic/emergency room/hospital or other. If the 
subject was treated in clinic/emergency room/hospital, whether they were transported in an 
ambulance or not, please specify)
!
Type of treatment provided by another person (i.e. oral carbohydrates, glucagon, intravenous 
(IV) glucose or other, please specify)
!
Were symptoms alleviated after administration of treatment?
!
Factors contributing to the episode (i.e. physical activity, missed meal, diet change, medication 
error (i.e. overdose, mix-up between products, incorrect use of device), miscalculation of dose 
of antidiabetic medication, other factors not listed or unknown)
!
Did the subject experience seizure?
!
Was the subject unconscious/comatose?    
!
Did the subject experience any of the following symptoms50 (layman term used in the diary is 
specified in brackets if different from the protocol term)?
–
Autonomic: sweating, trembling, hunger or palpitations (rapid or irregular heart beat)
–
Neuroglycopenic: confusion, drowsiness, speech difficulty, visual disturbances, odd 
behaviour, impaired balance or incoordination (reduced ability to coordinate movement)
–
General malaise: headache or malaise (feeling discomfort/unease)
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!
Other symptoms
If the hypoglycaemic episode fulfils the criteria for an SAE then an AE form and a safety 
information form must also be filled in, see section 12.
8.4.8
Hyperglycaemic episodes
Self-measured plasma glucose values or central laboratory FPG values > 16.7 mmol/L (300 mg/dL) 
must be reported as adverse events (see section 12.2). Subjects should be instructed to contact site 
staff in case of hyperglycaemia. Applicable for subjects with type 2 diabetes only: Whenever a 
hyperglycaemic episode is suspected, plasma glucose should be measured with the BG-meter 
handed out.
8.5
Laboratory assessments
The laboratory analyses will be performed by a central laboratory except for laboratory analyses for 
pre-screening, analysis of anti-semaglutide antibodies and semaglutide plasma concentration 
analysis and some exploratory biomarkers which will be performed at specialised laboratories. The 
central laboratory may utilise subcontractors for their analyses.
Descriptions of laboratory supplies, procedures for obtaining samples, handling, storage and 
shipments of samples, will be given in the trial-specific laboratory manual provided by the central 
laboratory.
Only laboratory samples specified in the protocol must be sent to the central laboratory for analysis; 
if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be done at a local 
laboratory.
The laboratory provides results to the trial sites in the units preferred by the trial sites while the 
results that are transferred to the trial database will always be in SI units.
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 will be reported to the investigator. The investigator must review all laboratory results for 
concomitant illnesses and AEs and report these according to section 8.2.2 and section 12.
Laboratory samples may be drawn on another day than the day of the actual visit, as long as it is 
within the visit window outlined in the flow chart (see section 2). 
Laboratory results will be made available to the investigator on an on-going basis except for the 
anti-semaglutide antibody results, the results of the semaglutide plasma c oncentration analysis and 
the exploratory biomarker results. Anti-semaglutide antibody results and the results of the 
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semaglutide plasma concentration analysis will not be provided to the investigator, as these results 
will not be used for any clinical evaluation during the trial and would potentially unblind the 
treatment. Exploratory biomarker results will not be provided to the investigator, as these results 
will not be used for any clinical evaluation during the trial.
Laboratory samples, including specific safety assessments, will be destroyed no later than at 
finalisation of the clinical trial report (CTR).
Antibody samples and biosamples for future analysis will be stored as described in section 24.2.
8.5.1
Review of laboratory reports
Review of laboratory reports must be documented either on the documents and/or in the subject’s 
medical record. 
For laboratory report values outside the reference range, the investigator must specify whether the 
value is clinically significant or not. The evaluation of screening results must be documented prior 
to visit 2 (randomisation), for the subsequent visits preferably on the day of evaluation.
It is the responsibility of the investigator or delegated staff to review the laboratory reports and to 
report possible AEs immediately following completion of the review.
8.5.2
Laboratory assessments for efficacy
8.5.2.1
Biochemistry
!
ALT
!
AST
!
GGT
!
hsCRP
!
Lipids (Total cholesterol, free fatty acids, HDL cholesterol, LDL cholesterol, triglycerides, 
VLDL cholesterol)
!
Fib-4 and NFS (refer to section 17.4.1.1)
8.5.2.2
Glucose metabolism
!
FPG
!
HbA1c
!
Fasting insulin
!
Fasting glucagon
!
HOMA-IR (refer to section 17.4.1.1) 
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FPG is measured to evaluate metabolic control. The subjects must attend these visits fasting (for 
definition of fasting, see section 8.1.4). An FPG result N3.9 mmol/L (70 mg/dL) should not be 
reported as a hypoglycaemic episode but as a clinical laboratory adverse event (CLAE) at the 
discretion of the investigator (see section 12.1.1). 
8.5.2.3
Exploratory biomarkers
!
CK-18 fragments
!
ELF (refer to section 17.4.1.1)
!
miR-122
!
IL-1R antagonist
!
MCP-1
!
FGF-21
8.5.2.4
Biosamples for future analysis:
Biosamples for future analysis must be drawn/collected and shipped to the central lab at the visits 
specified in section 2. The details and instructions around these samples are described in the trial-
specific central laboratory manual. Please refer to section 24.2 for more information about the 
planned use of the samples.
8.5.3
Laboratory assessments for safety
Blood samples for haematology and biochemistry mus t be collected at the specified visits (section
2).
8.5.3.1
Biochemistry
!
Bilirubin, total
!
Bilirubin, conjugated
!
Calcium
!
Creatine phosphokinase
!
Creatinine
!
eGFR (per CKD-EPI formula)51
!
Lipase
!
Potassium
!
Sodium
!
Alkaline phosphatase
!
Amylase
!
Albumin
!
Ferritin
!
Urea
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For Austria: Urine pregnancy test must be done once a month for women of childbearing potential.
8.5.3.7
Anti-semaglutide antibodies
Blood samples will be drawn during the trial and analysed at a specialised laboratory for 
determination of serum antibodies against semaglutide, including cross reactivity to endogenous 
GLP-1 (see flow chart, section 2). 
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
has been performed at the visit. 
Samples taken at the follow-up visit (visit 19) must be taken fasting (as a minimum by only having 
consumed water for at least 2 hours). Samples taken at the follow-up visit which are positive for 
anti-semaglutide antibodies will be further characterised for in vitro neutralising effect towards 
semaglutide. In addition, samples taken at the follow-up visit which are positive for cross-reactivity 
against endogenous GLP-1 will be analysed for in vitro neutralising effect towards endogenous 
GLP-1.
8.6
Other assessments
8.6.1
Semaglutide plasma concentration
For all subjects a single blood sample for measurement of plasma semaglutide concentration will be 
drawn at selected visits (see section 2).
Subjects must be instructed to withhold their trial product dose in the morning until blood sampling 
is performed on the visit. In addition subjects must be instructed to complete their diary (see section 
8.6.2) and bring it to the visits.
8.6.2
Subject diaries
Review of subject diaries must be documented either on the documents and/or in the subject’s 
medical record. If clarification of entries or discrepancies in the diary 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.
The following information will be captured in subject diaries:
!
Information regarding first trial product dose (date, time, dose, injection site)
!
Information regarding trial product doses (prior to each visit with blood sampling for 
measurement of semaglutide plasma concentration after randomisation until the end of 
treatment visit)
!
Information regarding hypoglycaemic episodes
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Trial product dosing information
The subject must record the date, time, dose and injection site of the last trial product injection prior 
to the clinic visit. Furthermore, the subject must fill in if any trial product doses were not taken in 
the previous two weeks. This information will be collected at all visits with blood sampling for 
measurement of semaglutide plasma concentration until the end of treatment visit. The information 
will be transcribed to the eCRF by the investigator or delegate together with the exact date and time 
for blood sampling, when applicable.
Hypoglycaemic episodes
For information to be captured regarding hypoglycaemic episodes, please refer to section 8.4.7.
8.6.3
Nutritional and physical activity counselling
Subjects will receive nutritional and physical activity counselling in accordance with site practice at 
the visits specified in section 2.
8.7
Specific safety requirements
8.7.1
Suspicion of acute pancreatitis
Assessments in case of suspicion of acute pancreatitis
The diagnosis of acute pancreatitis requires two of the following three features: 
!
abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric 
pain often radiating to the back)
!
serum lipase activity (and/or amylase activity) at least three times greater than the upper limit of 
normal
!
characteristic findings of acute pancreatitis on imaging.
Abdominal pain
Most patients with acute pancreatitis experience abdominal pain that is located generally in the 
epigastrium and radiates to the back. The onset of the pain may be swift reaching maximum 
intensity within 30 minutes, it is frequently unbearable and characteristically persists for more than 
24 hours without relief. The pain is often associated with nausea and vomiting. Physical 
examination usually reveals severe upper abdominal tenderness at times associated with guarding. 
Lipase and amylase
In general, both amylase and lipase are elevated during the course of acute pancreatitis. The serum 
lipase may remain elevated slightly longer than amylase. The level of the serum amylase and/or 
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!
Bilirubin increase accompanied by signs and symptom(s) compatible with drug induced liver
injury (DILI) such as rash, eosinophilia, nausea, vomiting, or right upper quadrant pain,
regardless of the transaminase concentrations.
Event must be reported according to section8.4.5, section12and Appendix B.
For all such events repeat testing mustoccur within 48 to 72 hours and work up for competing 
etiologies must be performed53including: 
!
Complete liver profile including ALT, AST, alkaline phosphatase, total bilirubin and INR.
Hereafter, repeat testing should be done 2 to 3 times weekly. If close monitoring is not possible
the trial drug should be discontinued. The frequency of retesting can decrease to once a week or
less if abnormalities stabilise and the subject is asymptomatic.
!
A detailed history of symptoms and prior or concurrent diseases.
!
History of concomitant drug use (including non-prescription medications and herbal and dietary
supplement preparations), alcohol use, recreational drug use, and special diets.
!
Ruling out acute viral hepatitis; autoimmune or alcoholic hepatitis; hypoxic/ischemic
hepatopathy; and biliary tract disease.
!
Obtaining a history of exposure to environmental chemical agents.
Trial drug can be restarted only if an alternative etiology is definitively identified and liver blood 
parameters have returned to pre-event levels.
If an alternative etiology is not definitively defined and/or liver blood parameters have not returned 
to pre-event levels, DILI cannot be excluded and trial product must be prematurely discontinued 
(see section 6.4).
8.7.3
Training in the delivery device (NovoPen® 4)
Trial product must be dispensed to subjects at the specified visits (see section 2). At the visits 
specified in section 2 and as needed, the subjects will be instructed in the handling of trial product 
and trained in the use of NovoPen® 4 and in the administration of s.c. injection of trial product.
The subjects must be trained in how to handle the delivery device (NovoPen® 4) and in use of the 
pen-injector when handed out the first time. Training must be repeated during the trial at regular 
intervals and as needed in order to ensure correct use of the device. 
The following should be emphasised:
!
Always use a new needle for each injection as this will prevent contamination and blocked
needles
!
Priming the pen to ensure product flow
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!
The needle should be kept in the skin while counting slowly to 6 after the dose counter has 
returned to zero after injection. If the needle is removed too early then the full dose may not 
have been delivered.
8.8
Subject compliance
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. If the subject continues to be non-compliant the investigator 
may discontinue the subject from trial product (see section 6.4).
Treatment 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 trial products. The investigator must assess the amount of trial products returned compared 
to what was dispensed at the last dispensing visit and, in case of discrepancies, question the subject.
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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. 
Trial product must not be used, if it does not appear clear and colourless.
9.1
Trial products
The following trial products will be provided by Novo Nordisk A/S, Denmark:
Table 9–1
Trial products
Trial product
Strength
Dosage form
Route of 
administration
Container/delivery 
device
Semaglutide 1.0 mg/mL 
(Investigational 
medicinal product 
(IMP))
1.0 mg/mL
Solution for 
injection
Subcutaneous 
(s.c.) injection 
3 mL Cartridge 
for NovoPen® 4
Semaglutide placebo 
(Investigational 
medicinal product 
(IMP))
N/A
Semaglutide 1.0 mg/mL and semaglutide placebo are visually identical.
9.2
Labelling
The trial products will be labelled in accordance with Annex 1354, local regulations and trial 
requirements.
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis 
controlled by the IWRS.
Each dispensing unit (DU) is uniquely numbered with a Dispensing Unit Number (DUN).
NovoPen® 4 is a CE-marked, US FDA and Japan MHLW (Ministry of Health, Labour and Welfare) 
approved pen injector device for subcutaneous administration of insulin. This trial is investigating 
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an indication outside the approved intended use or indication for use and the NovoPen® 4 will 
therefore be labelled "exclusively for clinical investigations" worded in accordance with national 
legislation. A description of the device is included in the Investigator's Brochure.
The investigator must document that direction for use (DFU) is given to the subject orally and in 
writing at the first dispensing visit (visit 2). At the later dispensing visits the investigator or delegate 
should ensure that subjects comply with injection procedures and re-dispense DFU, if needed.
9.3
Storage 
Table 9–2
Storage conditions
Trial product
Storage conditions
(not-in-use)
In-use conditions
In-use timea
Semaglutide 1.0 mg/mL 
Store in a 
refrigerator 
between 2°C - 8°C 
(36°F – 46°F)
Do not freeze
Protect from light
Store below 30°C 
(86°F)
Do not refrigerate
Do not freeze
Protect from light
Use within 28 days
Semaglutide placebo 
a In-use time starts when the product is taken out of the refrigerator at subjects home
The investigator must ensure that trial product is kept under proper storage conditions and record 
and evaluate the temperature. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions (e.g. outside temperature range). Additional 
details regarding handling of temperature deviations can be found in the trial materials manual 
(TMM).
Trial product that has been stored improperly must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. The investigator must take 
appropriate action to ensure correct storage.
9.4
Drug accountability and destruction
Drug accountability of all trial products received at site is the responsibility of the investigator.
Returned trial product (used/partly used and/or unused), expired or damaged trial product can be 
stored at room temperature and must be stored separately from non-allocated trial product.
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Non-allocated trial products including expired or damaged products must be accounted as unused at 
the latest at closure of the trial site.
The trial products will be dispensed to each subject as required according to treatment group. The 
IWRS will allocate trial product to the subject at randomisation and each dispensing visit. The 
correct dispensing unit number(s) (DUN(s)) must be dispensed to the subject.
Drug accountability is performed using the IWRS drug accountability module. The trial products 
must be accounted for at pen level and either recorded as used/partly used, unused or lost. Returned 
pens must be sent for destruction, thus may not be re-allocated to new subjects. 
Subjects must be instructed to return all used, partly used and unused trial product including empty 
packaging material at each dispensing visit and at end of treatment visit.
Destruction of trial products can be performed on an on-going basis and will be done according to 
local procedures after accountability is finalised and reconciled by the monitor. Destruction of trial 
products must be documented in the IWRS.
9.5
Auxiliary supplies
The following auxiliary supplies will be provided by Novo Nordisk in accordance with the TMM:
!
Needles for NovoPen® 4 pen injector (maximum length to be used is 8 mm)
!
Direction for use for NovoPen® 4 pen injector
!
Blood glucose meters (including lancets, plasma-calibrated test strips and control solutions). 
User manual will be provided along with the blood glucose meter.
Only needles provided by Novo Nordisk must be used for administration of trial product.  
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10
Interactive voice/web response system
A trial-specific IWRS will be set up which can be accessed at any time via the internet or telephone. 
Access to the IWRS must be restricted to and controlled by authorised persons. 
In this trial, the IWRS is used for:
!
Screening
!
Screening failure
!
Randomisation
!
Medication arrival
!
Dispensing
!
Treatment discontinuation
!
Completion
!
Code break
!
Drug accountability
!
Data change
IWRS user manuals will be provided to each trial site. DUNs will be allocated using the IWRS. It is 
important to dispense the exact allocated DUNs to a subject.
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12 Adverse events, technical complaints and pregnancies
12.1
Definitions
12.1.1
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a medicinal 
product, and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a product, whether or not 
considered related to the product. 
An AE includes:
!
A clinically significant worsening of a concomitant illness.
!
A clinical laboratory adverse event (CLAE): a clinical laboratory abnormality which is 
clinically significant, i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
severity that requires active management. Active management includes active treatment or 
further investigations, for example change of medicine dose or more frequent follow -up due to 
the abnormality.
The following should not be reported as AEs:
!
Pre-existing conditions, including those found as a result of screening or other trial procedures 
performed before exposure to trial product (pre-existing conditions should be reported as 
medical history or concomitant illness).
!
Pre-planned procedures unless the condition for which the procedure was planned has worsened 
from the first trial related activity after the subject has signed the informed consent.
!
Non-serious hypoglycaemia is an AE, but is reported on a hypoglycaemic episode form instead 
of on an AE form, see section 8.4.7. 
The following three definitions are used when assessing an AE:
!
Severity 
–
Mild – no or transient symptoms, no interference with the subject’s daily activities.
–
Moderate – marked symptoms, moderate interference with the subject’s daily activities.
–
Severe – considerable interference with the subject’s daily activities; unacceptable.
!
Causality 
Relationship between an AE and the relevant trial product(s): 
–
Probable - Good reason and sufficient documentation to assume a causal relationship.
–
Possible - A causal relationship is conceivable and cannot be dismissed.
–
Unlikely - The event is most likely related to aetiology other than the trial product.
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•
Final outcome
–
Recovered/resolved - The subject has fully recovered, or by medical or surgical treatment 
the condition has returned to the level observed at the first trial-related activity after the 
subject signed the informed consent.
–
Recovering/resolving - The condition is improving and the subject is expected to recover 
from the event. This term is only applicable if the subject has completed the trial or has died 
from another AE.
–
Recovered/resolved with sequelae - The subject has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an 
SAE criterion, the AE must be reported as an SAE.
–
Not recovered/not resolved - The condition of the subject has not improved and the 
symptoms are unchanged, or the outcome is not known.
–
Fatal - This term is only applicable if the subject died from a condition related to the 
reported AE. Outcomes of other reported AEs in a subject before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae” or “not recovered/not resolved”. An AE with fatal outcome must be reported as 
an SAE.
–
Unknown - This term is only applicable if the subject is lost to follow-up.
12.1.2
Serious adverse event
A serious adverse event (SAE) 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 the definition of SAE d. 
a. The term “life threatening” in the definition of SAE refers to an event in which the subject was at 
risk of death at the time of the event. It does not refer to an event which hypothetically might have 
caused death if it was more severe.
b. The term “hospitalisation” is used when a subject: 
–
Is admitted to a hospital or in-patient, irrespective of the duration of physical stay, or 
–
Stays at the hospital for treatment or observation for more than 24 hours
Medical judgement must always be exercised, and when in doubt, the hospital contact should be 
regarded as a hospitalisation. Hospitalisations for administrative, trial related and social purposes do 
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not constitute AEs and should therefore not be reported as AEs or SAEs. Hospital admissions for 
surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
c. A substantial disruption of a subject’s ability to conduct normal life functions (e.g. following the 
event or clinical investigation the subject has significant, persistent or permanent change, 
impairment, damage or disruption in his/her body function or structure, physical activity and/or 
quality of life).
d. For example intensive treatment in an emergency room or at home of allergic bronchospasm, 
blood dyscrasia or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse.
The following adverse events must always be reported as an SAE using the important medical event 
criterion if no other seriousness criteria are applicable:
!
suspicion of transmission of infectious agents via the trial product 
!
risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law).
12.1.3
Non-serious adverse event
A non-serious AE is any AE which does not fulfil the definition of an SAE.
12.1.4
Medication errors
A medication error concerning trial products is defined as:
!
Administration of wrong drug or use of wrong device. 
Note: Use of wrong DUN is not considered a medication error.
!
Wrong route of administration, such as intramuscular instead of subcutaneous.
!
Administration of an overdose with the intention to cause harm (e.g. suicide attempt), misuse or 
abuse of trial product.
!
Accidental administration of a lower or higher dose than intended; however, the administered 
dose must deviate from the intended dose to an extent where clinical consequences for the trial 
subject were likely to happen as judged by the investigator, although they did not necessarily 
occur.
Medication errors must be reported on an AE form and a specific event form, see section 8.4.4.
12.1.5
Adverse events requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the 
evaluation of the product safety. Some events in this trial will be adjudicated by an independent 
external committee as described in section 12.7.2.
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responsibility also covers uploading of clinical data for events identified in the preferred term 
(PT) search and evaluated to be relevant to adjudication by the event adjudication supplier or 
the committee chair or appointed delegate. In case copies of source data cannot be retrieved or 
are pending for a long time, the investigator should prepare and provide a narrative describing 
the event based on the information which the investigator has access to.
12.1.6
Technical complaints
A technical complaint is any written, electronic, or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
concern the AE itself.
Examples of technical complaints:
!
The physical or chemical appearance of trial products (e.g. discoloration, particles or 
contamination)
!
All packaging material including labelling
!
Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, 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 (visit 19) or visit 19A for subjects discontinuing trial product 
prematurely. 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?”
All AEs, either observed by the investigator or subject, must be reported by the investigator and 
evaluated. 
All AEs must be recorded by the investigator 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, a safety information form 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. 
For all non-serious AEs, the applicable forms should be signed when the event is resolved or at the 
end of the trial at the latest.
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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. 
For SAEs requiring reporting on a specific event form: In addition to the above the specific 
event form within 14 calendar days from the investigator’s first knowledge of the AE.
Events for Adjudication: The adjudication form should be completed within 14 calendar days of
the investigator’s first knowledge of the AE and all relevant predefined documents provided within
4 weeks, see Section 12.7.2. 
If the eCRF is unavailable, the concerned AE information must be reported on a paper AE form and 
sent to Novo Nordisk by fax, e-mail or courier within the same timelines as stated above. When the 
eCRF becomes available again, the investigator must enter the information on the form into the 
eCRF. 
Contact details (fax, telephone, e-mail and address) are provided in the investigator trial master file. 
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Novo Nordisk products used as concomitant medication:
If an AE is considered to have a causal relationship with a Novo Nordisk marketed product used as  
concomitant medication in the trial, it is important that the suspected relationship is reported to 
Novo Nordisk, e.g. in the alternative aetiology section on the safety information form. Novo 
Nordisk may need to report this adverse event to relevant regulatory authorities.
12.3
Follow-up of adverse events
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 until the outcome of the event is “recovered/resolved”, 
“recovered/resolved with sequelae” or “fatal”, and until all queries have been resolved. Cases of 
chronic conditions, cancer or AEs ongoing at time of death (where death is due to another AE) 
may be closed with the outcome “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when the subject has completed the 
follow-up period and is expected by the investigator to recover.
The SAE follow-up information should only include new (e.g. corrections or additional) 
information and must be reported within 24 hours of the investigator’s first knowledge of the 
information. This is also the case for previously non-serious AEs which subsequently become 
SAEs. 
!
Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved” or “recovered/resolved with sequelae” or until the 
end of the follow-up period stated in the protocol, whichever comes first, and until all queries 
related to these AEs have been resolved. Cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the outcome 
of “recovering/resolving” when the subject has completed the follow-up period and is expected 
by the investigator to recover.
The investigator must ensure that the recording of the worst case severity and seriousness of an 
event is kept throughout the trial. A worsening of an unresolved AE must be reported as follow up 
with re-assessment of severity and/or seriousness of the event.
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.
SAEs after end of trial: If the investigator becomes aware of an SAE with a suspected causal 
relationship to the investigational medicinal product occurring to a subject after the subject has 
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in the shipment of the sample. If several samples are returned in one shipment, the individual 
sample and the corresponding technical complaint form must be clearly separated.
The investigator must ensure that the technical complaint sample contains the batch, code or lot 
number and, if available, the DUN. All parts of the DUN should be returned.
If the technical complaint sample is unobtainable, the investigator must specify on the technical 
complaint form why it is unobtainable. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
12.5
Pregnancies
12.5.1
Pregnancies in female subjects 
Female subjects must be instructed to notify the investigator immediately if they become pregnant 
during the trial. The investigator must report any pregnancy in subjects who have received trial 
product(s).
The investigator must follow the pregnancy until the pregnancy outcome and the newborn infant is 
one month of age.
The investigator must report information about the pregnancy, pregnancy outcome, and health of 
the newborn infant(s), as well as AEs in connection with the pregnancy, and AEs in the foetus and 
newborn infant.
The following must be collected and reported by the investigator to Novo Nordisk - electronically 
(e.g. in PDF format), or by fax or courier:
1. Reporting of pregnancy information
Information about the pregnancy and pregnancy outcome/health of the newborn infant(s) has to 
be reported on Maternal Form 1A and 1B, respectively. 
When the pregnancy outcome is abnormal (i.e. congenital anomalies, foetal death including 
spontaneous abortion and/or any anomalies of the foetus observed at gross examination or 
during autopsy), and/or when a congenital anomaly is diagnosed within the first month, further 
information has to be reported for the female subject on Maternal Form 2. In addition, 
information from the male partner has to be reported on the Paternal Form, after an informed 
consent has been obtained from the male partner. 
Initial reporting and follow-up information must be reported within 14 calendar days of the 
investigator’s first knowledge of initial or follow-up information.
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2. Reporting of AE information
The investigator has to report AEs in connection with the pregnancy as well as in the foetus and 
newborn infant(s). The SAEs that must be reported include abnormal outcome, such as foetal 
death (including spontaneous abortion), and congenital anomalies (including those observed at 
gross examination or during autopsy of the foetus), as well as other pregnancy complications 
fulfilling the criteria of an SAE.
Forms and timelines for reporting AEs:
Non-serious AEs: 
!
AE forma within 14 calendar days of the investigator’s first knowledge of the initial or follow-
up information to the non-serious AE.
SAEs: 
!
AE forma within 24 hours of the investigator’s first knowledge of the SAE.
!
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.
a 
It must be clearly stated in the AE diagnosis field on the AE form if the event occurred in 
the subject, foetus or newborn infant. If the AE occurred in the foetus or newborn infant, the AE 
can only be reported on paper AE and safety information form.
Any queries or follow-up requests from Novo Nordisk to non-serious AEs, SAEs and pregnancy 
forms must be responded to by the investigator within 14 calendar days from the date of receipt of 
the request, unless otherwise specified in the follow-up request.
12.6
Precautions and/or overdose
Limited data are available with regard to overdose and semaglutide. Expected adverse events in 
connection to an overdose of subcutaneous semaglutide are gastrointestinal AEs and hypoglycaemia 
(if combined with SU and insulin). Events of nausea, vomiting and headache have been reported in 
connection with accidental administration of up to 4 mg semaglutide. No symptoms of 
hypoglycaemia have been reported in connection with overdose of semaglutide. In the event of 
overdosage, appropriate supportive treatment should be initiated according to the subject's clinical 
signs and symptoms.
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12.7
Committees related to safety
12.7.1
Novo Nordisk safety committee
Novo Nordisk will constitute an internal semaglutide safety committee to perform ongoing safety 
surveillance. The semaglutide safety committee may recommend unblinding of any data for further 
analysis, and in this case an independent ad hoc group will be established in order to maintain the
blinding of the trial personnel.
12.7.2
Event adjudication committee
An independent external event adjudication committee is established to perform validation of 
selected AEs according to pre-defined diagnostic criteria. The validation is based on review of pre-
defined clinical source data related to the specific AE. The pre-defined clinical source data consist 
of copies of source documents collected and delivered by the investigational sites.
The EAC is composed of permanent members covering required medical specialities. The EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk.
The events are reviewed by the event adjudication committee in a blinded manner. The EAC will 
have no authorisation to impact on trial conduct, trial protocol or amendments.
The EAC works in accordance with written guidelines included in the EAC Charter describing in 
details the composition, tasks, responsibilities and work processes of the committee.
The AEs for adjudication are listed in Table 12–1. In addition, cardiovascular events are being 
adjudicated according to FDA requirements1 55.
There are different processes for capturing events for adjudication:
1. Direct reporting by investigator:
All AEs need to be assessed by the investigator if any AE category is applicable. If the AE category 
selected is in scope for adjudication, the adjudication form in the eCRF will be populated for sites to 
complete. For AEs with fatal outcome the Fatal Adjudication form will appear in the eCRF when a 
fatal outcome is selected for an AE.
2. Screening: 
All AEs will be screened by Novo Nordisk for potential missed events for adjudication and if 
needed, the investigator will be asked to provide additional information such as an alternative 
aetiology, underlying cause(s) and/or clinical details.
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All ECGs will be centrally read. If the central reading conclusion is suggestive of new MI, the ECG 
adjudication form will be populated for sites to complete for all post -baseline ECGs.
3. EAC identified events:
The EAC can decide to have an AE adjudicated even if not initially reported as an event for 
adjudication by the investigator.
Event adjudication will be performed for AEs in randomised subjects including AEs with an onset 
date during the screening period. Event adjudication will not be performed for AEs in screening 
failures. 
AEs for adjudication must be reported according to section 12.2. In addition the specific
adjudication form should be completed within 14 calendar days of the investigator’s first 
knowledge of the AE, and all relevant predefined documents provided within 4 weeks according to 
instructions in the event adjudication site manual.
The EAC will review copies in English (translated if necessary) of medical documentation received 
in the adjudication packages (e.g. x-ray, ECGs, ultrasound images, discharge summaries, pathology 
reports and death certificates). The investigator must provide medical documentation as soon as 
possible, when they receive the request from Novo Nordisk or the event adjudication vendor.
The assessment made by the event adjudication committee will be included in the clinical trial 
report as well as the assessments made by the investigator. However, the adjudication made by the 
event adjudication committee, given its independent analysis of each event, will be attributed with 
greater importance of the two. The outcome of adjudication will be kept in the clinical trial 
database.
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13 Case report forms 
For this trial a combination of electronic case report forms (eCRFs) and paper CRFs will be used.
Novo Nordisk will provide a system for the electronic case report forms (eCRF). This system and 
support services to the system will be provided by an external supplier.
Ensure that all relevant questions are answered, and that no empty data field exists. If a test or an 
assessment has not been done and will not be available, or if the question is irrelevant (e.g. is not 
applicable), indicate this according to the data entry instructions.
The following will be provided as paper CRFs:
!
Pregnancy forms
The following will be provided as paper CRFs to be used when access to the eCRF is revoked or if 
the eCRF is unavailable:
!
AE forms 
!
Safety information forms 
!
Technical complaint forms (also to be used to report complaints that are not subject related e.g. 
discovered at trial site before allocation)
On the paper CRF forms print legibly, using a ballpoint pen. Ensure that all questions are answered, 
and that no empty data blocks exist. Ensure that no information is recorded outside the data blocks. 
If a test/assessment has not been done and will not be available, indicate this by writing “ND” (not 
done) in the appropriate answer field in the CRF. If the question is irrelevant (e.g. is not applicable) 
indicate this by writing “NA” (not applicable) in the appropriate answer field. Further guidance can 
be obtained from the instructions in the CRF.
The investigator must ensure that all information is consistent with the source documentation. By 
electronically signing the 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 delegated staff. 
An audit trail will be maintained in the eCRF application containing as a minimum: the old and the 
new data, identification of the person entering the data, date and time of the entry and reason for the 
correction.
If corrections are made by the investigator’s delegated staff after the date the investigator has signed 
the case book, the case book must be signed and dated again by the investigator.
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13.2
Case report form flow 
The investigator must ensure that data is recorded in the eCRF as soon as possible, preferably 
within 5 days after the visit. Once data has been entered, it will be available to Novo Nordisk for 
data verification and validation purposes.
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.
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 at 
the trial site 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 8 weeks during recruitment and 12 
weeks after end of recruitment until LSLV at the trial site for sites with subjects between visit 1 and 
visit 19/19A.
The monitor must be given direct access to all source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are important to the evaluation of the trial. If the electronic medical record does 
not have a visible audit trail, the investigator must provide the monitor with signed and dated 
printouts. In addition the relevant trial site staff should be available for discussions at monitoring 
visits and between monitoring visits (e.g. by telephone).
All data must be verifiable in source documentation other than the eCRF.
For all data recorded the source document must be defined in a source document agreement at each 
trial site. There must only be one source defined at any time for any data element.
Source data generated by the trial site can be corrected by another person than the person entering 
the source data if accepted by local regulations; any correction must be explained, signed and dated 
by the person making the correction.
The original of the completed diaries and PROs must not be removed from the trial site.
The monitor will ensure that the eCRFs are completed and that paper CRFs are collected.
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`The following data will be source data verified for screening failures: 
!
Date for obtaining informed consent.
!
Reason for screening failure
!
Serious adverse events (if any)
Monitors will review the subject’s medical records and other source data (e.g. the diaries and PROs)
to ensure consistency and/or identify omissions compared to the eCRF. If discrepancies are found, 
the investigator must be questioned about these.
A follow-up letter (paper or electronic) will be sent to the investigator following each monitoring 
visit. They should address any action to be taken.
15 Data management
Data management is the responsibility of Novo Nordisk. Data management may be delegated under 
an agreement of transfer of responsibilities to a contract research organisation (CRO). 
Appropriate measures, including encryption of data files containing person identifiable data, will be 
used to ensure confidentiality of subject data, when they are transmitted over open networks. 
Data from central laboratories will be transferred electronically. In cases where data is transferred 
via non-secure electronic networks, data will be encrypted during transfer.
The subject and any biological material obtained from the subject will be identified by subject 
number and trial ID. Appropriate measures such as encryption or leaving out certain identifiers will 
be enforced to protect the identity of subjects in all presentations and publications as required by 
local, regional and national requirements.
16 Computerised systems
Novo Nordisk will capture and process clinical data using computerised systems that are described 
in Novo Nordisk Standard Operating Procedures and IT architecture documentation. The use and 
control of these systems are documented.
Investigators working on the trial may use their own electronic systems to capture source data.
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17 Statistical considerations
If necessary, a statistical analysis plan (SAP) may be written in addition to the protocol, including a 
more technical and detailed elaboration of the statistical analyses. The SAP will be finalised before 
database lock.
The estimand addressing the primary objective is defined as the de-facto (effectiveness) treatment 
effect on NASH resolution without worsening in fibrosis for all randomised subjects after 72 weeks. 
All post-baseline scheduled visit data will be included in the statistical analysis, including data 
collected after discontinuation of trial product. The chosen estimand assesses the difference in 
resolution of NASH in a future population that results from initiating treatment with semaglutide as 
compared to placebo. Generalisation of this estimand depends among other things on the extent to 
which treatment adherence in this trial reflects clinical practice.
If not otherwise specified, the three different placebo arms will be pooled into one placebo arm in 
the statistical analyses. The pooling is based on the assumption that there is no substantial effect of 
different placebo volumes on the efficacy and safety endpoints. The validity of this assumption will 
be checked for the primary endpoint and treatment-emergent adverse events by evaluating 
descriptive statistics where each placebo arm is presented separately. In addition, the assumption 
will be evaluated based on estimates from a supportive analysis of the primary endpoint (see section 
17.3). 
The statistical analyses will in general consist of the following three pairwise treatment 
comparisons:
!
semaglutide 0.4 mg versus placebo
!
semaglutide 0.2 mg versus placebo
!
semaglutide 0.1 mg versus placebo
The results of the comparisons will be presented as estimated treatment contrasts together with two-
sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference. The 
problem of multiple testing will be taken into account with respect to the primary endpoint (see 
section 17.3) but not for any of the secondary endpoints.
The full analysis set (FAS) will be used in the analysis of the efficacy endpoints whereas the safety 
analysis set (SAS) will be used for the safety endpoints (see the definition of the sets in section
17.2).
The baseline measurement is defined as the latest available measurement at or prior to the 
randomisation visit. An exception is made for identifying abnormal laboratory findings (including 
ALT, AST, GGT, bilirubin and INR) in which case the baseline value is defined as the mean of the 
available measurements at the screening and randomisation visits.
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Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
17.1
Sample size calculation
The sample size calculation is based on an aim to detect a difference in the probability of achieving 
NASH resolution (without worsening in fibrosis) between the highest semaglutide dose and the 
pooled placebo arm at 5% significance level, using Pearson chi-square test with normal 
approximation. The power is set to 90%.
It is expected that some subjects will respond to standard care. In the LEAN trial, 2 (9%) of 22 
placebo subjects had improvement in liver histology. In the FLINT56 and PIVENS57 trials, clearance 
of NASH was a secondary endpoint and the corresponding numbers were 13 (13%) of 98 subjects 
and 17 (21%) of 83 subjects, respectively. However, these figures also included patients that had 
worsening of fibrosis. In the more recent trials, CENTAUR58 and GOLDEN-50559, the numbers 
were 9 (7%) of 126 subjects and 11 (14%) of 77 subjects, respectively, for an endpoint that was 
defined in the same way as the primary endpoint in the present trial. As a conservative assumption, 
it is anticipated that up to 17% of the placebo completers will achieve resolution of NASH with no 
worsening of fibrosis.
It is uncertain how many subjects on semaglutide should be expected to achieve resolution of 
NASH. In the LEAN trial, an improvement was found in 9 (39%) of 23 subjects who received 
liraglutide 1.8 mg. Results from semaglutide trials in subjects with T2D and/or obesity suggest a 
greater effect of semaglutide on glycaemic control and body weight loss compared to liraglutide. In 
communication with medical advisers, a treatment difference of 20-30 percentage points was 
deemed to be a realistic target as well as clinically relevant. Therefore, it is assumed that 45% of the 
subjects who complete treatment with semaglutide 0.4 mg achieve resolution of NASH.
Based on the previous NASH trials, 15% of the randomised subjects are anticipated to prematurely 
discontinue trial product before week 72. These will be included in the main analysis either by 
using the observed outcome at week 72 (if the outcome is known) or by using imputation (if the 
outcome is not known). In either case, it is assumed that none of these subjects will achieve 
resolution of NASH.
Based on the assumptions above, the required number of randomised subjects per arm for the 3 
semaglutide arms and the pooled placebo arm is found to be 70. Since the number in the pooled 
placebo arm needs to be divisible by 3, the number of subjects in each arm is adjusted to 72. Hence, 
the total number of subjects to be randomised is 288.
In order to investigate the influence of the values of the model parameters such as treatment 
difference and rate of premature discontinuation of trial product on the calculation, sample sizes 
have been calculated for different alternative scenarios. The results can be seen in Table 17–1.
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Table 17–1
Sample size calculations for different scenarios - number of subjects per arm
Probability of achieving resolution of 
NASH
Semaglutide 
completers
Placebo completers
Rate of premature 
discontinuation
N per arm
50%
17%
10%
49
15%
53
20%
58
45%
17%
10%
65
15%
70
20%
77
40%
17%
10%
92
15%
99
30%
108
17.2
Definition of analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance60:
!
The FAS includes all randomised subjects. Subjects in the FAS will contribute to the evaluation 
“as randomised”.
!
The SAS includes all subjects receiving at least one dose of randomised treatment. 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 statistic al analysis is the joint responsibility of the 
trial statistician, the international trial manager and the medical specialist. Exclusion of data from 
analyses will be used restrictively and normally no data should be excluded from the FAS. If any 
data is excluded, the decision will be justified and documented. The subjects and observations 
excluded from analysis sets, and the reason for their exclusion, will be described in the clinical trial 
report.
Observation periods
Data will be evaluated based on different observation periods which will be derived individually for 
each subject. The following two observation periods are defined:
!
In-trial: This period starts on the date of the randomisation visit and ends on the date of the 
last trial-related procedure/assessment whether or not the subject has stopped taking trial 
product.
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!
On-treatment: For evaluation of AEs and hypoglycaemic episodes, this period starts on the 
date of first administration of trial product and ends on the date of whatever comes first of: 
a) last dose of trial product + 49 days (7 half-lives of semaglutide), b) follow-up visit (V19), 
or c) end of the in-trial period. For evaluation of all other data, the period ends at the date of 
the last dose of trial product +1 day in order to ensure specificity to reversible effects of 
treatment. 
The statistical analyses of the efficacy endpoints will primarily be based on the in-trial period. The 
on-treatment period is used for some supportive efficacy analyses and all statistical analyses of 
safety endpoints. Summary statistics will in general be presented for both observation periods.
Data collected after the observation period in question will be excluded from any summary or 
analysis based on that observation period.
Missing data
With respect to the primary analysis of the primary endpoint, missing week 72 data will be imputed 
as no resolution of NASH. Sensitivity analyses will be performed using imputation methods based 
on treatment adherence and unconditional reference, respectively (see section 17.3). For the 
secondary endpoints, the handling of missing data depends on the type of endpoint and analysis (see 
section 17.4). 
In the analyses based on the in-trial period, the proportion of missing data is expected to be 
maximum 10%. These data would be missing due to subjects withdrawing from trial or being lost to 
follow-up. In the analyses based on the on-treatment period, the proportion of missing data is 
expected to be higher (15%) since data collected after discontinuation of trial product will be 
excluded. The most common reasons for premature discontinuation of trial product are anticipated 
to be AEs, ineffective therapy, and noneligibility (subjects randomised although not fulfilling 
inclusion/exclusion criteria). AEs leading to treatment discontinuation are expected to be equally 
common across treatment arms except possibly for a higher incidence of AEs due to gastrointestinal 
side effects in the semaglutide arms. On the other hand, more subjects in the placebo arms may be 
expected to drop out due to an experienced lack of effect with respect to body weight loss. Overall, 
the proportion of missing data is expected to be similar across treatment arms.
17.3
Primary endpoint
The primary endpoint is the binary outcome NASH resolution without worsening in fibrosis after 72 
weeks (yes/no).The primary analysis will be based on the Cochran-Mantel-Haenszel (CMH) test61
which will be performed separately for the comparisons between each of the semaglutide arms and 
placebo. The test will adjust for baseline diabetes status (with or without T2D) and baseline fibrosis 
stage (F1, F2 or F3). The response data will consist of the outcomes of the week 72 biopsy 
including assessments taken after premature discontinuation of trial product. Missing response data 
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will be imputed as no resolution of NASH. This approach does not rely on an assumption of 
missing at random and should be considered conservative for estimating the treatment effect. 
The result of each comparison will be presented as the p-value for testing the null hypothesis of no 
treatment difference versus a two-sided alternative. The asymptotic p-value obtained from a chi-
square distribution will be used unless it is not considered a valid approximation based on the 
Mantel-Fleiss criterion62, in which case the exact p-value will be calculated. Besides the p-value, 
the common odds ratio will be estimated together with a 95% confidence interval using the Mantel-
Haenszel estimator associated with the CMH test.
Hierarchical testing procedure
In order to confirm the effect of semaglutide without risk of inflation of the type 1 error, the 
comparisons will be evaluated hierarchically according to descending semaglutide dose using a 
family-wise error rate of 5%. The testing procedure will start with the comparison of semaglutide 
0.4 mg versus placebo and then continue by in turn comparing semaglutide 0.2 mg versus placebo 
and semaglutide 0.1 mg versus placebo. Each test will use a local two-sided significance level of 
5%. If one of the tests fails to reject the null hypothesis, the testing procedure will stop and no 
further conclusions will be made.
Sensitivity analyses
To investigate the sensitivity of the results of the primary analysis with regard to the handling of 
missing data, the following four sensitivity analyses will be performed:
!
Analysis using imputation based on treatment adherence: An analysis based on the same type of 
non-parametric method as for the primary analysis but with missing data handled by a multiple 
imputation (MI) method which assumes that the unobserved outcomes are well described by the 
observed outcomes from subjects who at week 72 are similar in terms of treatment adherence. 
This will be done as follows:
1. Missing data are imputed by sampling with replacement from the empirical distribution of 
observed outcomes separately within the 8 groups of subjects defined by randomised treatment 
arm and whether subjects complete the 72-week treatment or not.  If a group completely lacks 
observed outcomes, missing data within this group will be imputed as no resolution of NASH. 
Multiple (1000) replicates of a complete data set are generated in this way.
2. For each complete data set, the log odds ratios are estimated using the same method as in the 
primary analysis.
3. The estimates and standard errors for the 1000 complete data sets are pooled using Rubin’s 
rule63:
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 = 1
	 
 


,
 = 1
	 
 



+ 1 + 1
	 
1
	  1 
(  )


,
where mi and SEi are the estimated log odds ratios and standard errors for the N = 1000 data 
sets, and mMI  and SEMI are the pooled estimates. From mMI and SEMI, the 95% confidence 
intervals for the odds ratios and associated p-values are calculated.
This analysis differs from the primary analysis in that it assumes that subjects with missing week 72 
data have the same chances of NASH resolution as subjects with week 72 data in the same 
treatment group, accounting for whether they completed or discontinued the randomised treatment. 
This is a less conservative assumption than the one used in the primary analysis since it includes the 
possibility that subjects with missing week 72 data may have NASH resolution. The analysis 
intends to address missing data relative to what the measurements would have been had the 
measurements been taken.
!
Analysis using imputation based on unconditional reference: An analysis based on the same 
type of non-parametric method as for the primary analysis but with missing data handled by an 
MI method which assumes that the unobserved outcomes are well described by the observed 
outcomes of the subjects in the placebo arm with similar baseline characteristics. The 
imputation will be done by random sampling of observed outcomes from subjects with the same 
baseline diabetes status and baseline fibrosis stage. 1000 replicates of a complete data set will be 
generated that will then be analysed in the same way as in the MI analysis based on treatment 
adherence. This analysis differs from the primary analysis in that it assumes that subjects with 
missing week 72 data have the same chances of NASH resolution as subjects with week 72 data 
in the placebo group. If there are more missing week 72 data in the semaglutide group than in 
the placebo group, this analysis is less conservative than the primary analysis and probably 
gives better estimate of the treatment effect. Compared to the first sensitivity analysis, this 
analysis is more conservative since it assumes that subjects with missing week 72 data in the 
semaglutide group have the same chance of NASH resolution as subjects in the placebo group.
!
Complete case in-trial analysis: The same as the primary analysis but where subjects with 
missing week 72 data are excluded from the analysis.
!
Complete case on-treatment analysis: The same as the primary analysis but where subjects with 
missing week 72 data or for whom the data were collected after the on-treatment period are 
excluded from the analysis. 
The two complete case analyses are included as benchmarks. They are not based on the 
randomisation principle and do not estimate any causal effect of semaglutide treatment. The results 
are expected to be biased in favour of semaglutide and must be interpreted with extreme caution.
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The adjustment for covariates in the primary analysis does not exactly match the stratification used 
for the randomisation. The rationale is that it will not be possible to adjust for region (Japanese or 
non-Japanese) and, at the same time, adjust for diabetes status and baseline fibrosis stage within the 
Japanese group due to small sample sizes. Adjustment for region is not expected to influence the 
overall results but is included in the stratification to facilitate an evaluation of consistency of 
treatment effect between the entire population and Japanese subjects. Region has therefore been 
excluded from the primary analysis. However, a CMH test stratified according to the five strata 
used for the randomisation will be performed as a sensitivity analysis.
Adjustment for baseline body weight as a continuous covariate may potentially give more precise 
estimates of the treatment effects. To investigate the influence of such an adjustment, a sensitivity 
analysis will be performed using a logistic regression model which includes treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline 
body weight as a covariate.
The use of vitamin E may affect the chance of NASH resolution. Therefore, a sensitivity analysis 
will be performed using a logistic regression model which includes vitamin E use at baseline 
(yes/no) as factor together with randomised treatment, baseline diabetes status, baseline fibrosis 
stage and diabetes-by-fibrosis interaction. Furthermore, a subgroup analysis will be performed 
using the same logistic regression model but with the addition of a term for the interaction betw een 
randomised treatment and vitamin E use.
Supportive analysis
As part of an evaluation of the appropriateness of pooling the three placebo arms, a supportive 
analysis will be performed using the same CMH test as in the primary analysis but without pooling 
the placebo arms. Each semaglutide arm will instead be compared with the placebo arm which 
received the same injection volume.
Exploratory analysis
The dose-response relationship with respect to the primary endpoint will be further explored by 
fitting a modified logistic regression model with baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and the log-transformed dose level and baseline body 
weight as covariates. The model may be expressed as
 =  +
(  )
 +  KLXi
where is the probability of NASH resolution for subject i, and  are the asymptotic 
probabilities of NASH resolution at zero and infinite dose levels, respectively, and KLXi is the linear 
prediction function of factors and covariates. The response in the placebo arm will be included in 
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the analysis to help estimate . If the model does not describe the dose-response relationship well 
or if there are convergence problems, a different approximation may be investigated.
17.4
Secondary endpoints
17.4.1
Supportive secondary endpoints
17.4.1.1
Efficacy endpoints
Liver-related histological parameters
The following secondary histological endpoint will be analysed:
!
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) 
The analysis of this binary endpoint will be based on a logistic regression model which includes 
treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction as 
factors and baseline body weight as a covariate. The analysis will include all assessments taken 
during the in-trial period. Missing week 72 data will be imputed as no improvement in fibrosis.
In addition, separate analyses will be performed for the change from baseline to week 72 in the 
following histological feature scores: 
!
Total NAS (0-8) and each of the components:
o
Steatosis (0-3)
o
Lobular inflammation (0-3)
o
Hepatocyte ballooning (0-2)
!
Stage of fibrosis according to the Kleiner fibrosis classification (0-4)
!
Activity component of SAF score (0-4)
The activity component of the SAF score is defined as the unweighted sum of hepatocyte 
ballooning and lobular inflammation. The definition of the lobular inflammation score is modified 
in this calculation so that the scores 2 and 3 on the original scale are merged to a score 2. The 
possible range of the sum is thus 0 to 4. For all scores, a higher value indicates a more severe state 
of disease. 
The histological feature scores will be analysed by an ordered logistic regression model (also 
known as a proportional odds model) with the score at week 72 as response; treatment, baseline 
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diabetes status, baseline fibrosis stage, diabetes-by-fibrosis interaction and corresponding baseline 
score as factors; and baseline body weight as a covariate. The analyses will be based on the in-trial 
period and missing week 72 data will be imputed as no change from baseline in agreement with the 
analyses of the binary histological endpoints. The results will be presented as an estimate of the 
cumulative odds ratio for each treatment comparison together with the associated 95% confidence 
intervals and p-values.
Biomarkers of NASH disease
Analyses will be performed for the change from baseline to week 72 in the following biomarkers 
for NASH disease:
!
Algorithms
o
Fibrosis-4 score 
o
NAFLD Fibrosis Score 
!
Blood samples
o
Liver enzymes 

ALT 

AST

GGT
o
Liver synthesis function

Albumin 

INR
o
Exploratory biomarkers

ELF 

CK-18 fragments

miR-122

IL-1R antagonist 

MCP-1

FGF-21
!
Imaging
o
Liver stiffness
o
CAP (liver steatosis)
The Fib-4 score will be derived according to the formula64: 
Fib-4 =
Age (years) × AST (U/L)
Thrombocyte count (109/L) × "ALT (U/L)
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The derivation will be performed at each visit where ALT, AST and thrombocyte count have been 
assessed. If any of the three laboratory parameters is missing at a specific visit, the Fib-4 score will 
be considered missing as well.  
The NAFLD Fibrosis Score will be derived according to the linear regression formula65:
NFS = 1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13
× Hyperglycaemia (yes/no) + 0.99 × AST/ALT  0.013
× Thrombocyte count (109/L)  0.66 × Albumin (g/dL)
Hyperglycaemia (yes/no) is a binary variable defined as 1 if FPG M 6.1 mmol/L (110 mg/dL) at the 
corresponding visit of assessment or the subject has been diagnosed with T2D at screening; 
otherwise, the variable is defined as 0. NFS will be derived at each visit where body weight, FPG, 
ALT, AST, thrombocyte count and albumin have been assessed.  
The ELF discriminant score will be derived as a log-linear combination of the markers hyaluronic 
acid (HA), amino-terminal propeptide of type III collagen (PIIINP) and tissue inhibitor of 
metalloproteinase 1 (TIMP1) according to the formula66:
ELF = 7.412 + 0.681 × ln(HA (ng/mL)) + 0.775
× ln(P3NP (ng/mL)) + 0.494 × ln(TIMP1 (ng/mL))
Analyses of liver stiffness and CAP (liver steatosis) will only be applicable to sites where these 
assessments were possible. Subjects at sites which did not have capability to assess liver stiffness or 
CAP (liver steatosis) will be excluded from the corresponding analysis.
All biomarkers except for NFS, ELF and CAP (liver steatosis) will be logarithmically transformed 
before the statistical analysis. The treatment differences will subsequently be back-transformed to 
the original scale and expressed as treatment ratios.
The main analysis of each of the biomarkers will be analysis of covariance (ANCOVA) with 
missing data handled by unconditional reference-based imputation. This will be done as follows:
1. An ANCOVA model with baseline diabetes status, baseline fibrosis stage and diabetes-by-
fibrosis interaction as factors and baseline body weight and baseline value of the corresponding 
biomarker as covariates is fitted to the change from baseline to 72 weeks for the placebo group 
only. 
2. 1000 sets of values of the model parameters are drawn from the posterior distribution. For each 
replicated set of parameter values, the model is used to generate a complete data set by imputing 
missing values at 72 weeks for subjects in all treatment groups based on their baseline diabetes 
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status, baseline fibrosis stage, baseline body weight and baseline value of the corresponding 
biomarker.
3. For each complete data set, the change from baseline to 72 weeks is analysed using an 
ANCOVA model with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-
by-fibrosis interaction as factors and baseline body weight and baseline value of the 
corresponding biomarker as covariates.
4. The estimated treatment differences and standard errors for the 1000 complete data sets are 
pooled using Rubin’s rule. From the pooled estimates and standard errors, the 95% confidence 
intervals for the treatment differences and associated p-values are calculated.
A supportive on-treatment analysis using a mixed model for repeated measurements (MMRM) will 
be performed for each of the biomarkers. In this model, all scheduled post-baseline measurements 
taken during the individual subject’s on-treatment period will enter as response; treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction will be included as 
factors; and baseline body weight and baseline value of the corresponding biomarker will be 
included as covariates. All factors and covariates will be nested within visit and an unstructured 
covariance matrix for measurements within subject will be employed. There will be no explicit 
imputation of missing values. As for the main analysis, the estimated treatment differences at week 
72 with associated 95% confidence intervals and p-values will be presented.
Whereas the main analysis attempts to estimate the de-facto treatment effect (in agreement with the 
chosen estimand for the primary objective), the supportive analysis aims to estimate the de-jure 
effect that would have been observed if all subjects had remained on treatment and completed all 
visits. The latter analysis relies on the assumption that data are missing at random, which means that 
given the observed data, the events that lead to data being missing are independent of the 
unobserved data.
Additional exploratory analyses will be conducted to evaluate the performance of the biomarkers as 
predictors of NASH (yes/no), fibrosis (stage M2, M3 and 4, respectively) and/or steatosis (score M1, 
M2 and 3, respectively) as applicable using the liver biopsy as the gold-standard reference. Separate 
analyses will be performed at baseline and week 72 for each predictor. A measurement will be 
classified as “positive” if the value of the predictor exceeds a chosen cut-point. The performance 
will be illustrated by the receiver operating characteristic (ROC) curve which describes the 
relationship of the true positive rate (sensitivity) versus the false positive r ate (1 - specificity) as one 
moves the cut-point. The area under the ROC curve will be used to summarise the overall 
performance of  a predictor and the optimal cut-point will be determined by finding the maximum 
of Youden’s index (sensitivity + specificity - 1). In addition, new algorithms may be explored by 
constructing a logistic regression model which includes a large set of potential predictors and then 
selecting the most useful ones using stepwise backward elimination. 
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Weight-related parameters
The secondary endpoints related to weight are defined as change from baseline to 72 weeks in:
!
Body weight (% and kg)
!
Waist circumference
!
BMI
These endpoints will be analysed separately using the same type of ANCOVA with MI as for the 
biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis 
interaction as factors and corresponding baseline value as a single covariate. Supportive on-
treatment analyses will be performed based on MMRM in the same way as for the biomarkers with 
factors and covariates specified as in the ANCOVA model.
In addition to the continuous endpoints, the following binary endpoints related to weight will be 
analysed separately:
!
Weight loss of M 5% of baseline body weight at 72 weeks (yes/no)
!
Weight loss of M 10% of baseline body weight at 72 weeks (yes/no)
The binary endpoints will be compared between treatment arms using an MI approach similar to the 
continuous endpoints but based on logistic regression. The 1000 data sets with imputed values for 
percent change in body weight will be reused to derive an equal number of complete data sets for 
the binary outcomes. For each data set, the binary outcomes will be analysed using a logistic 
regression model which includes treatment, diabetes status, baseline fibrosis stage and diabetes-by-
fibrosis interaction as factors and baseline body weight as a covariate. The estimated log odds ratios 
and standard errors for the 1000 complete data sets are then pooled using Rubin’s rule. From the 
pooled estimates and standard errors, the 95% confidence intervals for the odds ratios and 
associated p-values are calculated.
Glucose metabolism related parameters
The secondary endpoints related to glucose metabolism are defined as change from baseline to 72 
weeks in:
!
HbA1c
!
FPG
!
Fasting glucagon
!
HOMA-IR, derived through the approximation formula67:
HOMA -IR = FPG (mmol/L) × Fasting insulin (mmol/L) 22.5
/
These endpoints will be analysed using the same type of ANCOVA with MI as for the biomarkers. 
For each endpoint, the ANCOVA will be performed separately for subjects with and without type 2 
diabetes at screening. The model will include treatment and baseline fibrosis stage as factors and 
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corresponding baseline value as covariate. Supportive on-treatment analyses will be performed 
based on MMRM in the same way as for the biomarkers with factors and covariates specified as in 
the ANCOVA model. Fasting glucagon and HOMA-IR will be logarithmically transformed before 
analysis.
Cardiovascular risk factors
The secondary endpoints related to cardiovascular risk factors are defined as change from baseline 
to 72 weeks in: 
!
Systolic and diastolic blood pressure
!
Lipids (total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, triglycerides, 
free fatty acids)
!
hsCRP
These endpoints will be analysed separately using the same type of ANCOVA with MI as for the 
biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis 
interaction as factors and corresponding baseline value as a single covariate. Supportive on-
treatment analyses will be performed based on MMRM in the same way as for the biomarkers with 
factors and covariates specified as in the ANCOVA model. The lipids and hsCRP will be 
logarithmically transformed before analysis.
Patient reported outcomes
The results from SF-36 questionnaire will be analysed as the change from baseline to 72 weeks in 
overall mental and physical scores, respectively, as well as the change in each of the 8 domains: 
!
Physical functioning
!
Role functioning
!
Bodily pain
!
General health
!
Vitality
!
Social functioning
!
Role emotional 
!
Mental health
The change in score will be analysed as a continuous endpoint using the same type of ANCOVA 
with MI as for the biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and corresponding baseline score as a single covariate. 
Supportive on-treatment analyses will be performed based on MMRM in the same way as for the 
biomarkers with factors and covariates specified as in the ANCOVA model.
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17.4.1.2
Safety endpoints
The following secondary endpoints are used to support the safety objectives:
!
Number of treatment-emergent adverse events during the trial
!
Number of treatment-emergent hypoglycaemic episodes during the trial
!
Number of treatment-emergent severe or BG confirmed symptomatic hypoglycaemic episodes 
during the trial
!
Number of treatment-emergent severe hypoglycaemic episodes during the trial 
!
Number of subjects discontinuing treatment due to gastrointestinal adverse events
!
Change from baseline to 72 weeks in:
o
Pulse
o
ECG
o
Physical examination
o
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
o
Biochemistry (creatinine, eGFR, creatine phosphokinase, urea, bilirubin (total), alkaline 
phosphatase, ferritin, sodium, potassium, calcium (total), amylase, lipase)
o
Hormones (calcitonin)
!
Occurrence of anti-semaglutide antibodies during and after 72 weeks treatment (yes/no):
o
Anti-semaglutide binding antibodies
o
Anti-semaglutide binding antibodies with in vitro neutralising effect
o
Anti-semaglutide binding antibodies cross reacting with native GLP-1
o
Cross-reacting anti-semaglutide binding antibodies with in vitro neutralising effect to 
native GLP-1
!
Anti-semaglutide antibody binding level during and after 72 weeks treatment
Adverse events
AEs will be coded using the most recent version of the Medical Dictionary for regulatory Activities 
(MedDRA) coding. A treatment emergent adverse event (TEAE) is defined as an event that has 
onset date during the on-treatment period (see section 17.2). 
AE data will be displayed in terms of the number of subjects with at least one event, the percentage 
of subjects with at least one event, the number of events and the event rate per 100 patient years of 
exposure. The main AE summaries will only contain TEAEs. Non-treatment emergent AEs will be 
included in listings and overview summaries.
Hypoglycaemic episodes
Hypoglycaemic episodes will be classified and then summarised descriptively in terms of the 
number of subjects with at least one event, the percentage of subjects with at least one event, the 
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number of events and the event rate per 100 patient years of exposure. The summaries will be made 
separately for subjects with and without type 2 diabetes at randomisation.
For subjects with type 2 diabetes at randomisation, the severe or BG confirmed symptomatic 
hypoglycaemic episodes will be analysed using a negative binomial regression model with the 
number of treatment emergent episodes as response, the logarithmic function as link function and 
the logarithm of the time period during which episodes are considered treatment emergent as offset. 
The model will include treatment and baseline fibrosis stage as factors and baseline HbA1c as a 
covariate. The results will be described by the rate ratio for the comparison of each semaglutide 
dose versus placebo with the associated 95% confidence interval and two-sided p-value.
Classification of Hypoglycaemia:
Treatment emergent: hypoglycaemic episodes will be defined as treatment emergent if the onset of 
the episode occurs during the on-treatment period (see section 17.2). 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05.59 both inclusive.   
Hypoglycaemic episodes are classified according to the Novo Nordisk classification of 
hypoglycaemia (see Figure 17–1) and the ADA classification of hypoglycaemia (see Figure 17–2).
For subjects without type 2 diabetes, the episodes will only be classified as either severe or probable 
symptomatic according to the ADA classification. 
Novo Nordisk classification of hypoglycaemia
In normal physiology, symptoms of hypoglycaemia occur below a plasma glucose level of 3.1 
mmol/L (56 mg/dL)68. Therefore, Novo Nordisk has included hypoglycaemia with plasma glucose 
levels below this cut-off point in the definition of blood glucose (BG) confirmed hypoglycaemia.
Novo Nordisk uses the following classification (see Figure 17–1) in addition to the ADA 
classification: 
!
Severe hypoglycaemia according to the ADA classification49.
!
Symptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/L (56 mg/dL) with symptoms consistent with hypoglycaemia.
!
Asymptomatic BG confirmed hypoglycaemia: An episode that is BG confirmed by plasma 
glucose value <3.1 mmol/L (56 mg/dL) without symptoms consistent with hypoglycaemia.
!
Severe or BG confirmed symptomatic hypoglycaemia: An episode that is severe according to 
the ADA classification49 or BG confirmed by a plasma glucose value <3.1 mmol/L (56 mg/dL) 
with symptoms consistent with hypoglycaemia. 
!
BG confirmed hypoglycaemia: An episode that is BG confirmed by a plasma glucose value <3.1 
mmol/L (56 mg/dL) with or without symptoms consistent with hypoglycaemia. 
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Hypoglycaemic 
episode 
PG  3.9 mmol/L 
(70 mg/dL) 
or 
Alleviation of 
symptoms 
or
Seizure, coma or 
fatal 
SMPG
measurement
Asymptomatic 
hypoglycaemia
Documented 
symptomatic 
hypoglycaemia
Pseudo-
hypoglycaemia
Probable 
symptomatic 
hypoglycaemia
No
Yes
No measurement 
with symptoms
PG > 3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
with symptoms
PG  3.9 mmol/L 
(70 mg/dL)
without symptoms
No
Yes
Note: Glucose measurements are performed with capillary blood calibrated to plasma equivalent glucose values
PG: plasma glucose  SMPG: Self-measured plasma glucose  
Subject 
able to 
treat him/
herself
Severe 
hypoglycaemia
(ADA 2013)
Figure 17–2
ADA classification of hypoglycaemia
Pulse
Pulse will be summarised by descriptive statistics and analysed using the same type of MMRM as 
for the on-treatment analyses of the biomarkers with treatment, baseline diabetes status, baseline 
fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline pulse as a covariate.
ECG
ECG will be described by summarising the number and percentage of subjects with normal and 
abnormal readings (separated into clinically significant and not clinically significant). The 
summaries will be presented by visit and as shift tables from baseline to week 72.
Physical examination
The results of the physical examination will be summarised descriptively in the same way as ECG.
Laboratory assessments
The haematology and biochemistry parameters will be summarised and evaluated by descriptive 
statistics. 
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Amylase and lipase will be analysed separately using the same type of MMRM as for the on-
treatment analyses of the biomarkers with treatment, baseline diabetes status, baseline fibrosis stage 
and diabetes-by-fibrosis interaction as factors and the baseline value of the corresponding 
laboratory parameter as a covariate. A logarithmic transformation will be applied for both amylase 
and lipase
Calcitonin will be summarised in tables including number and percentage of observations > and N 
LLOQ, quartiles, minimum and maximum. Persistent and incidental abnormal elevation of 
calcitonin will further be displayed in terms of the number and percentage of subjects and the event 
rate per 100 patient years of exposure.
Antibodies
The occurrence of anti-semaglutide antibodies will be described by summarising the number and 
percentage of subjects with antibodies in the different treatment arms. The antibody binding level 
will be presented in listings.
In addition, a comparison of the change in HbA1c and body weight between antibody-positive and 
antibody-negative subjects will be performed using descriptive statistics and graphs. The impact of 
anti-semaglutide antibodies on safety will be similarly assessed by descriptive statistics.
17.4.1.3
Pharmacokinetic endpoints
The plasma concentrations of semaglutide will be summarised by descriptive statistics. In addition, 
the data will be used for population pharmacokinetic (PK) modelling, see section 17.6.
17.5
Interim analysis
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
17.6
Pharmacokinetic and/or pharmacodynamic modelling
Exploratory population PK and PK/PD modelling will be used to evaluate the semaglutide dose-
exposure, the effects of pre-specified covariates on the exposure and the semaglutide exposure-
response on selected efficacy and safety parameters. It will follow a modelling analysis plan that is 
to be finalised before database lock, describing criteria for inclusion of data, pre-specification of 
covariates and criteria for presentation of results. 
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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17.7
Health economics and/or patient reported outcomes
The PRO questionnaire SF-36 will be used to evaluate the effects on quality of life, see section
17.4.1.1 for the details of the statistical analysis. The results will be included in the CTR.
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18 Ethics
18.1
Benefit-risk assessment of the trial
Risks and precautions for semaglutide
The sections below describe potential risks associated with semaglutide treatment, based on 
findings with other GLP-1 RAs and observations in nonclinical and clinical trials with semaglutide 
administered s.c. once weekly. For each of these risks, mitigating actions have been implemented to 
minimise the risks for subjects enrolled in this trial.
The nonclinical safety programme of semaglutide has revealed no identified safety issues for 
humans based on conventional studies of safety pharmacology, repeat -dose toxicity or genotoxicity.
Identified risks
Diabetic retinopathy
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment 69-71. Risk factors for these events include 
long-standing poor glycaemic control and presence of proliferative retinopathy, and initial large 
improvements in blood glucose maybe an additional aggravating factor. Several studies have, 
however, documented long-term beneficial effects of intensive glycaemic treatment in reducing 
retinopathy progression72, 73 even in intensively treated patients who experienced early worsening70.  
In a cardiovascular outcomes trial with s.c. semaglutide, results indicate an increased risk of ev ents 
related to diabetic retinopathy in subjects treated with semaglutide compared to placebo. As a 
precaution in this trial, all subjects with type 2 diabetes are required to have a fundus photography 
or dilated fundoscopy performed before enrolment into the trial; moreover, subjects with 
proliferative retinopathy or maculopathy requiring acute treatment will be excluded. As part of good 
diabetes management the investigator is encouraged to ensure adequate monitoring and treatment of 
diabetic retinopathy in subjects enrolled into the trial74.
Gastrointestinal adverse events
Consistent with findings from other GLP-1 RAs, the most frequently reported AEs in the clinical 
trials with semaglutide thus far have been gastrointestinal (GI) disorders (nausea, vomiting, 
diarrhoea, dyspepsia and constipation). However, based on a completed clinical trial 
(NN9535-3819) where slower dose escalation substantially improved the GI tolerability profile, a 4-
week dose escalation regimen has been developed and is used in the ongoing clinical phase 3 
programme for semaglutide s.c. administered once weekly as well as in this trial.
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Pancreatic cancer
There is currently no support from non-clinical or clinical trials or post-marketing data that GLP-1-
based therapies increase the risk of pancreatic cancer. However, as the long-term effects of 
stimulation of f-cells and suppression of g-cells are largely unknown, pancreatic cancer is 
considered a potential risk by the European Medicine Agency (EMA).
Other safety considerations
Teratogenicity (nonclinical embryo-foetal toxicity)
Semaglutide has been concluded teratogenic in rats. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function. As 
the yolk sac does not play such a role for nutrition of the embryo in humans, this effect is unlikely 
to be relevant for humans. However, as a precaution subjects fulfilling exclusion criterion 29 will be 
excluded from trial participation. Furthermore, as specified in the flowchart, female subjects 
included in the trial will have pregnancy testing performed frequently during the entire duration of 
the trial. 
General risks and precautions
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. 
All subjects will have one or two liver biopsies performed as part of participation in the trial. Pain is 
the most common complication of percutaneous liver biopsy, occurring in up to 84% of patients, 
including those with relatively mild discomfort. The most important complication of liver biopsy is 
bleeding. Severe bleeding may require hospitalization blood transfusion, or even radiological 
intervention or surgery. Such bleeding has been estimated to occur in between 1 in 2500 to 1 in 
10,000 biopsies after an intercostal percutaneous liver biopsy. Mortality after liver biopsy is usually 
related to hemorrhage. It is very uncommon after percutaneous biopsy, but precise figures vary 
widely. The most commonly quoted mortality rate is less than or equal to 1 in 10,000 liver 
biopsies75. The risk of liver biosy is minimised by excluding patients with liver cirrhosis and 
coagulopathy, and by requiring that liver biopsy is performed according to standard practice.
Benefits
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.
In the LEAN trial significantly more patients who received liraglutide 1.8 mg/day had resolution of 
NASH compared with patients in the placebo group. Further, significantly fewer patients in the 
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liraglutide had progression of fibrosis compared to the placebo group34. Currently the standard of 
care of NASH is weight loss, and reduction of body weight was speculated to be one of the modes 
of action of liraglutide by the authors of the LEAN study 34. In a phase 2 trial (NN9535-1821), 
semaglutide resulted in a clinical meaningful and dose-dependent weight loss. Doses M 0.8 mg/week 
semaglutide provided a greater weight loss than liraglutide 1.8 mg/day. In clinical studies with 
liraglutide 3.0 mg/day, approximately 2/3 of the subjects lost more than 5% of their initial body 
weight and approximately 1/3 lost more than 10% of their initial body weight. Additionally, 
semaglutide also increase insulin, lower glucagon levels and improves insulin sensitivity and blood
lipids, all of which are beneficial in patients with NASH. Finally, semaglutide may have anti -
inflammatory effects.
Although subjects will have to spend time on site visits and procedures required by trial 
participation, it is expected that all subjects (including those subjects randomised to placebo) will 
benefit from participation through close contact with the trial site, with close follow-up of their 
NASH and general metabolic state, and a careful medical examination. Furthermore, all subjects 
will receive nutritional and physical activity counselling throughout the trial. All of which will 
probably result in a better management of their NASH.
Conclusion
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 informed 
about possible AEs and inconveniences and will be instructed to contact the investigator in case of 
any concerns regarding the trial participation.
When treatment with trial products ends, the subject and investigator will decide on the best 
available treatment.
It is concluded that the potential benefits from participating in the trial outweigh the potential risks
including the risk related to the liver biopsy. The safety profile of semaglutide generated from the 
clinical and nonclinical development programme in T2D has not revealed any safety issues that 
would prohibit administration of once weekly doses of 0.5 mg or 1.0 mg semaglutide. Based on the 
nature and frequency of the AEs in the T2D trials, it appears to be safe to investigate daily doses of 
up to 0.4 mg as in the current trial. Additional safety surveillance will be instituted in all treatment 
arms during the dose escalation period until 4 weeks after last target dose is reached (steady state). 
It is concluded that the risk to the subjects in this trial is low and acceptable in view of the potential 
benefits a long-acting GLP-1 analogue would provide subjects with NASH.
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18.2
Informed consent 
In seeking and documenting informed consent, the investigator must comply with applicable 
regulatory requirement(s) and adhere to ICH 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. This includes the use of an impartial witness where required.
The subjects must be fully informed of their rights and responsibilities while participating in the 
trial as well as possible disadvantages of being treated with the trial products.
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
A voluntary, signed and personally dated informed consent must be obtained from the subject 
before any trial-related activity.  
Separate informed consent forms for long-term storage of human biosamples and genotyping are 
available for this trial, and informed consent must be obtained before activities related to any of 
these are undertaken.
Additionally a separate informed consent form for optional pre-screening is available. This must be 
signed before any optional pre-screening activities are performed (see section 8.1.2).
The responsibility for seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. The written informed consent must be signed and personally dated by the person who 
seeks the informed consent before any trial-related activity.
If information becomes available that may be relevant to the subject’s willingness to continue 
participating in the trial, the investigator must inform the subject in a timely manner, and a revised 
written subject information must be provided and a new informed consent must be obtained.
18.3
Data handling
If the subject withdraws from the trial or is lost to follow up, then the subject’s data will be handled 
as follows:
!
Data already collected and any data collected at the end-of-trial visit including follow up visits
will be retained by Novo Nordisk, entered into the database and used for the clinical trial report. 
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!
Safety events will be reported to Novo Nordisk and regulatory authorities according to 
local/national requirements.
If data is used, it will always be in accordance with local regulations and IRBs/IECs.
18.4
Information to subjects during trial
The site will be offered a communication package to the subject during the conduct of the trial. The 
package content is issued by Novo Nordisk. The communication package will contain the letters 
intended for distribution to the subjects. The letters will be translated and adjusted to local 
requirements and distributed to the subject at the discretion of the investigator. The subject may 
receive a “welcome to the trial letter” and a “thank you for your participation letter” after 
completion of the trial. Further the subject may receive letters during the trial. 
Initiatives for subject retention will be instituted for this trial. These may include retention 
activities, materials and items, if locally acceptable. The retention items will be relevant for the 
subjects’ participation in the trial and/or their disease.
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
18.5
Premature termination of the trial and/or trial site
Novo Nordisk, the IRBs/IECs or a regulatory authority may decide to stop the trial, part of the trial 
or a trial site at any time, but agreement on procedures to be followed must be obtained.
If the trial is suspended or prematurely terminated, the investigator must inform the subjects 
promptly and ensure appropriate therapy and follow-up. The investigator and/or Novo Nordisk must 
also promptly inform the regulatory authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs in case it has an impact on the planned follow-up of subjects who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the subjects 
should be described.
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19 Protocol compliance
19.1
Protocol deviations
Deviations from the protocol should be avoided.
If deviations do occur, the investigator must inform the monitor and the implications of the 
deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
Novo Nordisk will monitor protocol deviations on an on-going basis throughout the trial followed 
by appropriate actions (e.g. re-training of site staff).
Documentation on protocol deviations must be kept in the investigator trial master file and sponsor 
trial master file.
19.2
Prevention of missing data
The importance of subject retention will be addressed by Novo Nordisk in the training and 
communication with the trial sites. 
The subjects will be carefully informed about the trial procedures before signing informed consent, 
so that they know the implications of participating in the trial. 
Close surveillance of subject retention will be performed throughout the trial by Novo Nordisk with 
focus on reasons for premature discontinuation of trial product or withdrawal of consent to secure 
early mitigations in collaboration with the trial sites. The investigator will make every effort to 
ensure that all assessments are performed and data is collected (see section 8.1.6). If missing data 
does occur the reason will be collected via the protocol deviation process described in section 19.1.
20 Audits and inspections
Any aspect of the clinical trial may be subject to audits conducted by Novo Nordisk or inspections 
from domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as Novo Nordisk staff 
have an obligation to cooperate and assist in audits and inspections. This includes giving auditors 
and inspectors direct access to all source documents and other documents at the trial site relevant to 
the clinical trial. This includes permission to examine, analyse, verify and reproduce any record(s) 
and report(s) that are relevant to the evaluation of the trial.
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21 Critical documents
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received and the following documents must be available to Novo Nordisk:
!
Regulatory approval and/or acknowledgement of notification as required 
!
Approval/favourable opinion from IRBs/IECs clearly identifying the documents reviewed as 
follows: protocol, any protocol amendments, subject information/informed consent form, any 
other written information to be provided to the subject and subject recruitment materials
!
List of IRB/IEC members and/or constitution (or a general assurance number/statement of 
compliance)
!
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed - must include 
documented GCP training or a certificate)
!
Signed receipt of Investigator’s Brochure
!
Signed and dated Agreement on Protocol
!
Signed and dated Agreement on Protocol Amendment, if applicable
!
Contract, signed by the investigator and/or appropriate parties on behalf of the investigator’s site 
and Novo Nordisk
!
Source document agreement
!
Central laboratory certification and normal ranges
!
Insurance statement, if applicable
!
Financial disclosure form from investigator and sub-investigator(s)
Only applicable for US trial sites: 
!
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 the investigator at each site
FDA form 1572:
For US sites:
!
Intended for US sites
!
Conducted under the IND
!
All US investigators, as described above, will sign FDA Form 1572
For sites outside the US:
!
Intended for participating sites outside of the US
!
Not conducted under the IND
!
All investigators outside of the US will not sign FDA form 1572
Novo Nordisk will analyse and report data from all sites together if more than one site is involved in 
the trial.
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By signing the protocol agreement, each investigator agrees to comply fully with ICH GCP1
applicable regulatory requirements and the Declaration of Helsinki2. 
By signing the protocol agreement, each investigator also agrees to allow Novo Nordisk to make 
investigator’s name and information about site name and address publically available if this is 
required by national or international regulations.
22 Responsibilities
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.
A qualified physician, who is an investigator or a sub-investigator for the trial, must be responsible 
for all trial-related medical decisions.
The investigator will follow instructions from Novo Nordisk when processing data.
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents including the subject identification 
code list must be kept in a secure locked facility, so no unauthorized persons can get access to the 
data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken.
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time.
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk. 
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s).
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23 Reports and publications
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. The information 
obtained during this trial may be made available to other physicians who are conducting other 
clinical trials with the trial product, if deemed necessary by Novo Nordisk. Provided that certain 
conditions are fulfilled, Novo Nordisk may grant access to information obtained during this trial to 
researchers who require access for research projects studying the same disease and/or trial product 
studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted clinical trial report for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the clinical trial report 
(signatory investigator) on behalf of all participating investigators. The signatory investigator will 
be appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications76.
23.1
Communication of results
Novo Nordisk commits to communicating, and otherwise making available for public disclosure, 
results of trials regardless of outcome. Public disclosure includes publication of a paper in a 
scientific journal, abstract submission with a poster or oral presentation at a scientific meeting, or 
disclosure by other means.
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations, as reflected in the Novo Nordisk Code of Conduct for 
Clinical Trial Disclosure43.
Novo Nordisk reserves the right to defer the release of data until specified milestones are reached, 
for example when the clinical trial report is available. This includes the right not to release the 
results of interim analyses, because the release of such information may influence the results of the 
entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
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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 evaluate the planned publication. In the event of any 
disagreement on the content of any publication, both the investigators’ and Novo Nordisk opinions 
will be fairly and sufficiently represented in the publication.
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Novo Nordisk maintains the right to be informed of plans by any investigator to publish and to 
review any scientific paper, presentation, communication or other information concerning the 
investigation described in this protocol. Any such communication must be submitted in writing to 
Novo Nordisk before submission for comments. Comments will be given within four weeks from 
receipt of the planned communication.
23.1.1
Authorship
Authorship of publications should be in accordance with the Uniform Requirements of the 
International Committee of Medical Journal Editors76 (sometimes referred to as the Vancouver 
Criteria).
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 of a primary publication will take 
place no later than 18 months after trial completion.
23.2
Investigator access to data and review of results
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data, and will be provided with the 
randomisation code after results are available.
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24 Retention of clinical trial documentation and human biosamples
24.1
Retention of clinical trial documentation
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
The investigator must agree to archive the documentation (this includes both electronic and paper-
based records) pertaining to the trial in an archive after completion or discontinuation of the trial if 
not otherwise notified. The investigator should not destroy any documents without prior permission 
from Novo Nordisk. If the investigator cannot archive the documents at the trial site, Novo Nordisk 
can refer the investigator to an independent archive provider that has a system in place to allow only 
the investigator to access the files.
The investigator must be able to access his/her trial documents without involving Novo Nordisk in 
any way. Site-specific CRFs and other subject data (in an electronic readable format or as paper 
copies or prints) will be provided to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. These data must be retained by the trial site. If the 
provided data (e.g. the CD-ROM) is not readable during the entire storage period, the investigator 
can request a new copy. A copy of all data will be stored by No vo Nordisk.
Novo Nordisk will maintain Novo Nordisk documentation pertaining to the trial for at least 20 years 
after discontinuation of the marketing authorisation, termination of the trial or cancellation of the 
research project whichever is longest.
The files from the trial site/institution must be retained for 15 years after end of trial as defined in 
section 7), or longer if required by local regulations or Novo Nordisk. In any case trial files cannot 
be destroyed until the trial site/institution is notified by Novo Nordisk. The deletion process must 
ensure confidentiality of data and must be done in accordance with local regulatory requirements.  
24.2
Retention of human biosamples
24.2.1
Antibody samples
Antibody samples may be retained for later analysis for further characterisation of antibody 
responses towards drug if required by health authorities or for safety reasons. The samples will not 
be used for other purposes.
The samples will be stored at a bio-repository after end of trial and until marketing authorisation 
approval or until the research project terminates, but no longer than 15 years from end of trial after 
which they will be destroyed. 
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The subject’s identity will remain confidential and the antibody samples will be identified only by 
subject number, visit number and trial identification number. No direct identification of the subject 
will be stored together with the samples. 
Only Novo Nordisk staff and bio-repository personnel will have access to the stored antibody 
samples. 
Subjects can contact the investigator if they wish to be informed about results derived from stored 
antibody samples obtained from their own body. 
24.2.2
Samples for future analysis
As new biomarkers related to the disease and/or safety, efficacy, or mechanism of action of 
semaglutide may evolve during the conduct of the trial or after end of trial, the analyses of the 
stored biosamples may also include biomarkers that are unknown at present or have not been 
included in the scientific hypotheses at initiation of the trial. Likewise if genetic high risk 
population or populations are described for NASH, Novo Nordisk may want to investigate if such
genetic predispositions are associated with different response to semaglutide.
Subjects must sign and date a separate informed consent form before biosamples to be stored for 
future analysis are drawn/collected (refer to section 8.1.1).
After trial completion the biosamples will be stored at a central storage facility contracted by Novo 
Nordisk A/S. Only Novo Nordisk and storage facility employees will be able to access the stored 
biosamples. The biosamples may be transferred to other countries for analysis and will be destroyed 
at the latest 15 years after end of trial. 
The subject may request the stored biosamples to be destroyed by withdrawing consent. The results 
obtained from any already performed analyses of the samples will still be used.
In the event that the collected biosamples (blood and urine) will be used in the future, the 
investigator will become directly informed by Novo Nordisk about the results if the findings are 
deemed clinically relevant and analytically valid and quantifiable. In such case, a written summary 
of the findings, including listings of subject specific values, will be provided once a firm conclusion 
from the results has been drawn by Novo Nordisk.
Potentially, observations of neoplastic diseases, serious hereditary diseases, other un-treatable 
diseases, or any other abnormal findings could be part of the observations. Subjects can contact the 
investigator if they wish to be informed about results derived from stored biosamples obtained from 
their own body.
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25 Institutional Review Boards/Independent Ethics Committees and 
regulatory authorities
IRB/IEC:
Written approval or favourable opinion must be obtained from IRB/IEC prior to commencement of 
the trial.
During the trial, the investigator or Novo Nordisk, as applicable, must promptly report the 
following to the IRB/IEC, in accordance with local requirements: updates to Investigator’s 
Brochure, unexpected SAEs where a causal relationship cannot be ruled out, protocol amendments 
according to local requirements, deviations to the protocol implemented to eliminate immediate 
hazards to the subjects, new information that may affect adversely the safety of the subjects or the 
conduct of the trial (including new benefit-risk analysis in case it will have an impact on the 
planned follow-up of the subjects), annually written summaries of the trial status, and other 
documents as required by the local IRB/IEC.
The investigator must ensure submission of the clinical trial report synopsis to the IRB/IEC.
Protocol amendments must not be implemented before approval or favourable opinion according to 
local regulations, unless necessary to eliminate immediate hazards to the subjects.
The investigator must maintain an accurate and complete record of all submissions made to the 
IRB/IEC. The records must be filed in the investigator trial master file and copies must be sent to 
Novo Nordisk.
Regulatory Authorities:
Regulatory authorities will receive the clinical trial application, protocol amendments, reports on 
SAEs, and the clinical trial report according to national requirements.
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26 Indemnity statement
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.
Novo Nordisk assumes no liability in the event of negligence, or any other liability of the sites or 
investigators conducting the trial, or by persons for whom the said site or investigator are 
responsible.
Novo Nordisk accepts liability in accordance with: 
For Netherlands only: Wetgeving betreffende geneesmiddelen; geneesmiddelenwet 1 juli 2007 
(Medicines Law, 1 July 2007). De Wet Medisch-wetenschappelijk Onderzoek met mensen (WMO), 
1 maart 2006 (Medical Research Involving Human Subjects Act, 1 March 2006). Besluit verplichte 
verzekering bij medisch-wetenschappelijk onderzoek met mensen 2015, 24 november 2014 (Decree 
compulsory insurance in medical research involving human subjects 2015, 24 November 2014).” 
The national protocol requirement is also here under compliance: 
http://globeshare.novonordisk.com/rd/gd/gdareas/qrd/gcc/Pages/Default.aspx
For France only: The French Public Health Code article L 1121-10 (law n° 2004-806 of 9 August 
2004 art. 88 I, IX Journal Officiel of 11 August 2004. "The sponsor is responsible for identification 
of the harmful consequences of the biomedical research for the person lending himself thereto and 
for indemnification of his beneficiaries, except in case of proof, incumbent on it, that the prejudice 
is not attributable to his fault of or the fault of any intervening party, without the sponsor's being 
entitled to call on acts by a third party or the voluntary withdrawal of the person who had initially 
consented to cooperating in the research.
For Austria only: Arzneimittelgesetz (BGBI. Nr. 185/1983) last amended with BGBI Nr. 105/2015.
For Russia only: Federal law of 12 April 2010 No. 61-FZ ‘On Medicinal Drugs’ Circulation and 
Order No. 200n dated April 01, 2016 of the Ministry of Health of the Russian Federation On 
Approval of Rules for Good Clinical Practice.
For Belgium only: Law concerning experiments on the human person of 07 May 2004 - Article 29:
§1. Even if without fault, the sponsor is liable for the damage which the subject and/or his rightful 
claimants sustain and which shows either a direct or an indirect connection with the trial.
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Semaglutide
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
Protocol - Appendix A
Status:
Final
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Appendix A
NN9931-4296
Monitoring of calcitonin
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Semaglutide
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Version:
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Table of Contents
Page
Table of Contents..............................................................................................................................................2
1
Background................................................................................................................................................3
2
Calcitonin monitoring...............................................................................................................................4
2.1
Calcitonin 5 100 ng/L....................................................................................................................4
2.2
Calcitonin 5 50 and < 100 ng/L.....................................................................................................4
2.3
Calcitonin 5 10 and <50 ng/L........................................................................................................5
3
References..................................................................................................................................................6
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1
Background
Treatment with GLP-1 receptor agonists has shown to be associated with thyroid C-cell changes in 
rodents but not in non-human primates. The human relevance of this finding is unknown. However, 
based on the findings in rodents, monitoring of serum calcitonin (a sensitive biomarker for C-cell 
activation) is currently being performed in clinical trials with semaglutide.
While there is general agreement on the clinical interpretation of substantially elevated calcitonin 
levels (greater than 100 ng/L) is likely indicative of C-cell neoplasia; the interpretation of values 
between upper normal range (5.0 and 8.4 ng/L for women and men, respectively) and 100 ng/L is 
less clear with regards to indication of the neoplasia. 
There are several known confounding factors affecting calcitonin levels, e.g.:
!
renal dysfunction
!
smoking
!
autoimmune thyroiditis
!
several drug classes (e.g. proton pump inhibitors, beta-blockers, H2-blockers and
glucocorticoids)
Physiology of C-cell activation in various clinical conditions and in different patient populations 
(i.e. with various co-morbidities) is poorly understood. There may be various clinical conditions not 
identified so far which mildly or moderately affect calcitonin secretion by C-cells.
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Semaglutide
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2016-000685-39
Page:
5 of 6
!
thyroid ultrasound examination
!
if available and there are no contraindication, a pentagastrin stimulation test. Subjects with
positive pentagastrin stimulation tests should be considered to undergo surgery
!
if pentagastrin is not available, thyroid ultrasound and fine needle aspiration biopsy may add
important clinical information about the need for surgery.
2.3
Calcitonin ' 10 and <50 ng/L
Action: The subject can continue in the trial on trial product. Continue sampling of calcitonin 
according to the protocol. 
If the subject is a screen failure, or if the value is from the last sample taken in the trial, the subject 
should be referred to a thyroid specialist for further evaluation.
Background: Calcitonin values from 20-50 ng/L were found in up to 1% of subjects of the 
population of 5817 patients with thyroid nodular disease.1 The predictive value of a C-cell anomaly 
for this calcitonin level was 8.3%. However, the likelihood of having a medullary carcinoma >1 cm 
with calcitonin in this range is extremely low. 
For calcitonin values 10-20 ng/L Costante et al1 identified 216 (3.7%) patients. One patient out of 
the 216 had a subsequent basal (unstimulated) calcitonin of 33 ng/L, and had C-cell hyperplasia at 
surgery. Two other studies used a cut-off of 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
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Semaglutide
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
Protocol - Appendix A
Status:
Final
EudraCT No.: 2016-000685-39
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):450-5.
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):243-53.
3. Verga U, Ferrero S, Vicentini L, Brambilla T, Cirello V, Muzza M, et al. Histopathological 
and molecular studies in patients with goiter and hypercalcitoninemia: reactive or neoplastic 
C-cell hyperplasia? Endocr Relat Cancer. 2007;14(2):393-403.
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Semaglutide
Date:
20 June 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
Protocol - Appendix B
Status:
Final
EudraCT No.: 2016-000685-39
Page:
1 of 8
Appendix B
NN9931-4296
Adverse events with additional data collection and adverse 
events requiring event adjudication
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1 0
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
Protocol - Appendix B
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT No.: 2016-000685-39
Version:
1.0
Page:
3 of 8
Event
Definition
Additional data collection
Event 
adjudication
surgery (CABG) related MI

Silent MI
All events with symptoms of 
myocardial ischemia must be reported.

Collection of cardiac biomarkers

Cardiac imaging

Cardiac stress testing

Angiography

Use of thrombolytic drugs
Cerebrovascular event 
(stroke or transient 
ischemic attack)
Transient ischemic attack (TIA) is 
defined as a transient (<24 hours) 
episode of focal neurological 
dysfunction caused by brain, spinal 
cord, or retinal ischemia, without 
acute infarction.1
Stroke (Ischemic, haemorrhagic, 
undetermined) is defined as an acute 
episode of neurological dysfunction 
caused by focal or global brain, spinal
cord, or retinal vascular injury as a 
result of haemorrhage or infarction.1
If a cerebrovascular event (e.g. transient ischaemic attack, 
stroke, haemorrhage) is observed during the trial the 
following additional information must be reported if 
available on the cerebrovascular event form: 

Type of event (e.g. transient ischaemic attack (TIA), 
Stroke)

Contributing condition

Neurologic signs and symptoms

History of neurologic disease

Imaging supporting the event
Yes
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Semaglutide
Protocol - Appendix B
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT No.: 2016-000685-39
Version:
1.0
Page:
4 of 8
Event
Definition
Additional data collection
Event 
adjudication

Treatment given for the event
Heart failure requiring 
hospitalisation or 
urgent unscheduled 
visit
Clinical manifestations of new episode 
or worsening of existing heart failure 
requiring hospitalisation.
If an event of heart failure requiring hospitalisation 
(admission to an in-patient unit or a visit to an emergency 
department that results in at least a 24 hour stay) is 
observed during the trial the following information must 
be reported if available on the heart failure form: 

Signs and symptoms of heart failure

New York Heart Association (NYHA) Class

Supportive imaging

Supportive laboratory measurements

Initiation or intensification of treatment for this 
condition

History of heart failure
Yes
Acute pancreatitis
Two of following diagnostic criteria 
fulfilling the diagnosis of acute 
pancreatitis:
1. severe acute abdominal pain
If an event of pancreatitis, acute or chronic is observed 
during the trial, the following information must be 
reported if available on the pancreatitis form: 

Signs, symptoms and severity of pancreatitis
Yes
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Semaglutide
Protocol - Appendix B
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT No.: 2016-000685-39
Version:
1.0
Page:
5 of 8
Event
Definition
Additional data collection
Event 
adjudication
2. amylase and/or lipase activity 
levels >3x upper normal range 
(UNR)
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

Specific laboratory test supporting a diagnosis of 
pancreatitis

Imaging performed and consistency with pancreatic 
disease

Treatment given for the event

Relevant risk factors associated with the event
Acute gallbladder 
disease
All types of acute gallbladder or acute 
biliary disorders
If an event of acute gallstone disease or clinical suspicion 
of this is observed during the trial, this must be recorded 
as an AE and on a specific acute gallstone disease event 
form in the eCRF. The following information should be 
reported if available:

Signs and symptoms of acute gallstone disease

Specific laboratory test supporting a diagnosis of 
gallstone:
o
White blood cell count (WBC)
o
C-reactive protein (CRP)
o
Direct, indirect and total bilirubin
No
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Semaglutide
Protocol - Appendix B
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT No.: 2016-000685-39
Version:
1.0
Page:
6 of 8
Event
Definition
Additional data collection
Event 
adjudication
o
ALT and AST
o
Alkaline phosphatase (ALP)
o
Amylase
o
Lipase

Imaging performed and consistency with gallstone 
disease

Treatment given for the condition

Relevant risk factors for acute gallstone disease 
including
o
History of gallstones
o
Family history of gallstones
o
Relevant surgery
Neoplasm 
All types of neoplasms must be 
reported including:

Malign neoplasm

Pre-malignant 
neoplasm/carcinoma in-situ

Benign neoplasm

Neoplasm of uncertain or 
unknown behaviour
All events of neoplasms (including thyroid neoplasms) 
must be recorded as an AE and on a specific neoplasm 
event form in the eCRF. The following information 
should be obtained if available as part of standard of care:

Type of neoplasm

Symptoms leading to identification of event

Diagnostic imaging

Pathological examination results

Treatment for the event

Participation in screening programs

Risk factors associated to the event
No
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Semaglutide
Protocol - Appendix B
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT No.: 2016-000685-39
Version:
1.0
Page:
7 of 8
Event
Definition
Additional data collection
Event 
adjudication
Hepatic event

ALT or AST > 5x UNL

ALT or AST > 3x baseline 
value

ALT or AST > 3x UNL and 
total bilirubin > 2x UNL 
(Biochemical Hy’s Law)

Total bilirubin > 1.5 mg/dL

INR > 1.3

Model For End-Stage Liver 
Disease (MELD) score G15 

Liver transplant

Ascites requiring medical 
intervention

Gastroesophageal variceal 
bleeding

Hepatic encephalopathy

Spontaneous bacterial
If one of the hepatic events is observed during the trial the 
following additional information must be reported if 
available:

Signs and symptoms associated to the event

Risk factors

Relevant laboratory test results

Liver biopsy results

Diagnostic procedures performed including 
imaging 

Treatment given for the event

Possible cause(s) of the event
No
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Semaglutide
Protocol - Appendix B
Date:
20 June 2016
Status:
Final
Novo Nordisk
Trial ID: NN9931-4296
EudraCT No.: 2016-000685-39
Version:
1.0
Page:
8 of 8
Event
Definition
Additional data collection
Event 
adjudication
peritonitis

Hepatic events leading to trial 
product discontinuation
1.
Standardized Definitions for Cardiovascular and Stroke End Point Events in Clinical Trials (DRAFT). Karen A. Hicks, H. M. James Hung, Kenneth W. Mahaffey, Roxana Mehran, Steven E. Nissen; 
Norman L. Strockbridge, Shari L. Targum, Robert Temple; on behalf of the Standardized Data Collection for Cardiovascular Trials Initiative. August 20, 2014. Or any updates here
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Protocol Amendment
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
1 of 7
Protocol Amendment
no 1
to Protocol, final version 1.0
dated 20-Jun-2016
Trial ID:NN9931-4296
Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily 
versus placebo in subjects with non-alcoholic steatohepatitis
Trial phase: Phase 2
Applicable to all countries
Amendment originator:
 Senior International Trial Manager
TrialOps 2, GLP-1 Diabetes, NADs & Complications 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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1 0
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
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
2 of 7
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
Table of Tables..................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
List of abbreviations ......................................................................................................................3
2.2
Section 2 Flowchart .......................................................................................................................3
2.3
Section 4.2.2.2 Supportive secondary safety endpoints.................................................................3
2.4
Section 6.3 Exclusion criteria ........................................................................................................4
2.5
Section 6.4 Criteria for premature discontinuation of trial product...............................................4
2.6
New section: Section 8.2.7 Fundoscopy/Fundus photography......................................................4
2.7
Section 8.5.3.1 Biochemistry.........................................................................................................4
2.8
Section 8.7.2 Assessments in case of increased levels of liver blood parameters .........................5
2.9
Section 17.4.1.2 Safety endpoints..................................................................................................6
2.10
Section 27 References....................................................................................................................6
2.11
Appendix B....................................................................................................................................7
Table of Figures   
Page
No table of figures entries found.
Table of Tables   
Page
No table of figures entries found.
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Protocol Amendment
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
3 of 7
1
Introduction including rationale for the protocol amendment
Please see below the rationales for development of this global protocol amendment:
!
Further clarification of the safety process for handling of increased levels of liver blood 
parameters.
!
For exclusion criterion 20, specification that the criterion is only applicable for patients with 
type 2 diabetes has been added. Due to the assessment requirement in the criterion,
fundoscopy/fundus photography has been added to the flowchart and a separate section for 
fundoscopy/fundus photography has been added in section 8 (8.2.7).
!
Exclusion criterion for subjects with severe renal impairment (eGFR < 30 ml/min/1.73 m2) 
has been added and also that eGFR will be monitored continuously throughout the trial.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
List of abbreviations
eGFR
estimated glomerular filtration rate
DILI
Drug induced liver injury
2.2
Section 2 Flowchart
Fundoscopy/Fundus photography
Footnote 15: Only applicable for patients with type 2 diabetes: Dilated fundoscopy/fundus
photography performed within 90 days prior to visit 2 is acceptable if results are available for 
evaluation at visit 2 and there has been no deterioration in visual function since last assessment.
Dilated fundoscopy/fundus photography can be performed between visit 1 and visit 2.
2.3
Section 4.2.2.2 Supportive secondary safety endpoints
Change from baseline to 72 weeks in:
!
Biochemistry (creatinine, estimated Glomerular Filtration Rate (eGFR), creatinine 
phosphokinase, urea, bilirubin (total), alkaline phosphatase, ferritin, sodium, potassium, calcium 
(total), amylase, lipase)
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Protocol Amendment
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
4 of 7
2.4
Section 6.3 Exclusion criteria
20. For patients with type 2 diabetes only: Proliferative retinopathy or maculopathy requiring acute 
treatment verified by fundus photography or dilated fundoscopy performed within the past 90 days 
prior to randomisation. 
32. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR 
<30 ml/min/1.73 m2 as defined by Kidney Disease: Improving Global Outcomes (KDIGO)(ref. 42).
2.5
Section 6.4 Criteria for premature discontinuation of trial product
11. Persistent abnormal liver blood parameters indicating drug induced liver injury (DILI) (see
details in section 8.7.2)    
2.6
New section: Section 8.2.7 Fundoscopy/Fundus photography
For subjects with type 2 diabetes dilated fundoscopy/fundus photography will be performed as 
specified in section 2. Results of the dilated fundoscopy/fundus photography will be evaluated by 
the investigator and the investigator evaluation must be documented either on the dilated 
fundoscopy/fundus photography result report or in the subject’s medical record.
The investigator or medically qualified delegate must sign, date and interpret the dilated 
fundoscopy/fundus photography by using the following categories:
!
Normal
!
Abnormal
o
Was the result clinically significant? (Yes/No)
If a dilated fundoscopy/fundus photography has been performed within 90 days prior to
randomisation, the procedure does not need to be repeated, unless there has been worsening of 
visual function since the last examination. The results must be available prior to randomisation. 
If the dilated 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.
2.7
Section 8.5.3.1 Biochemistry
!
eGFR (per CKD-EPI formula)(ref. 51)
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Protocol Amendment
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
5 of 7
2.8
Section 8.7.2 Assessments in case of increased levels of liver blood parameters
In case of any of the below:
!
ALT or AST > 5x UNL
!
ALT or AST > 3x baseline value
!
ALT or AST > 3x UNL and total bilirubin > 2x UNL, where no alternative aetiology exists 
(Hy’s Law)
!
Total bilirubin > 1.5 mg/dL
!
INR > 1.3
report the event according to section Error! Reference source not found. and Appendix B.
For all such events prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
For all such events prompt repeat testing (at central laboratory) including ALT, AST, alkaline 
phosphatase, total bilirubin and INR should be done and discontinuation of trial product considered. 
Thereafter, repeat testing (at central laboratory) of ALT, AST, alkaline phosphatase and total 
bilirubin should be done regularly until the abnormalities return to normal or baseline state. 
Additional clinical information should be gathered to seek a possible cause of the observed 
laboratory test abnormalities.
Temporary discontinuation of trial drug should be considered in case any of the below criteria is
met:
!
ALT or AST > 7x UNL
!
ALT or AST > 2x baseline value
!
Total bilirubin > 2.0 mg/dL
!
INR > 1.6
For definition of baseline values, see section 17.
Trial product must be temporarily discontinued in case any of the below criteria is met: 
!
ALT or AST > 3x UNL and total bilirubin > 2x UNL, where no alternative aetiology exists 
(Hy’s Law)(see section 12.1.2)
!
ALT or AST increase to >5x baseline value in subjects where the baseline ALT or AST were <2x
UNL 
!
ALT or AST increase to >3x baseline value in subjects where the baseline values were D2x UNL 
but <5x UNL.
!
ALT or AST increase to >2x baseline value AND the increase is accompanied by a concomitant 
total bilirubin increase to >2x baseline value OR concomitant INR increase by >0.2 from 
baseline.
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Protocol Amendment
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
6 of 7
!
Bilirubin increase accompanied by signs and symptom(s) compatible with drug induced liver
injury (DILI) such as rash, eosinophilia, nausea, vomiting, or right upper quadrant pain,
regardless of the transaminase concentrations.
Event must be reported according to section 8.4.5, section 12 and Appendix B.
For all such events repeat testing should occur within 48 to 72 hours and work up for competing 
etiologies must be performed (ref. 53) including: 
!
Complete liver profile including ALT, AST, alkaline phosphatase, total bilirubin and INR.
Hereafter, repeat testing should be done 2 to 3 times weekly. If close monitoring is not possible
the trial drug should be discontinued. The frequency of retesting can decrease to once a week or
less if abnormalities stabilise and the subject is asymptomatic.
!
A detailed history of symptoms and prior or concurrent diseases.
!
History of concomitant drug use (including non-prescription medications and herbal and
dietary supplement preparations), alcohol use, recreational drug use, and special diets.
!
Ruling out acute viral hepatitis; autoimmune or alcoholic hepatitis; hypoxic/ischemic
hepatopathy; and biliary tract disease.
!
Obtaining a history of exposure to environmental chemical agents.
Trial drug can be restarted only if an alternative etiology is definitively identified and liver blood 
parameters have returned to pre-event levels.
If an alternative etiology is not definitively defined and/or liver blood parameters have not returned 
to pre-event levels, DILI cannot be excluded and trial product must be prematurely discontinued 
(see section 6.4).
2.9
Section 17.4.1.2 Safety endpoints
!
Change from baseline to 72 weeks in:
o
Biochemistry (creatinine, eGFR, creatinine phosphokinase, urea, bilirubin (total),
alkaline phosphatase, ferritin, sodium, potassium, calcium (total), amylase, lipase)
2.10
Section 27 References
42.KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic
Kidney Disease. http://www.kidney-international.org 3[1]. 2013.
51.KDOQI Clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis -
2012; 60(5):850-886.
53.http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf
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Protocol Amendment
Date:
26 August 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN:U1111-1179-7464
Status:
Final
EudraCT No.:2016-000685-39
Page:
7 of 7
2.11
Appendix B
Event  
Definition
Additional data collection 
Event
adjudication
Hepatic event
!
ALT or AST > 5x UNL
!
ALT or AST > 3x baseline
value
!
ALT or AST > 3x UNL and
total bilirubin > 2x UNL 
(Biochemical Hy’s Law)
!
Total bilirubin > 1.5 mg/dL
!
INR > 1.3
!
ALT or AST > 7x UNL
!
ALT or AST > 2x baseline value
!
Total bilirubin > 2.0 mg/dL
!
INR > 1.6
!
ALT or AST > 3x UNL and total bilirubin 
> 2x UNL, where no alternative aetiology 
exists (Hy’s Law)
!
ALT or AST increase to >5x baseline 
value in subjects were the baseline ALT 
or AST were <2x UNL
!
ALT or AST increase to >3x baseline 
value in subjects were the baseline values 
were D2x UNL but <5x UNL.
!
ALT or AST increase to >2x baseline 
value AND the increase is accompanied 
by a concomitant total bilirubin increase 
to >2x baseline value OR concomitant 
INR increase by > 0.2 from baseline.
!
Bilirubin increase accompanied by signs 
and symptom(s) compatible with drug 
induced liver injury (DILI) such as rash, 
eosinophilia, nausea, vomiting, or right 
upper quadrant pain, regardless of the 
transaminase concentrations.
!
Model For End-Stage Liver
!
Disease (MELD) score F15
!
Liver transplant
!
Ascites requiring medical
!
intervention
!
Gastroesophageal variceal bleeding
!
Hepatic encephalopathy
!
Spontaneous bacterial peritonitis
!
Hepatic events leading to trial product 
discontinuation
If one of the hepatic events is 
observed during the trial the
following additional 
information must be reported 
if available:
!
Signs and symptoms 
associated to the 
event
!
Risk factors
!
Relevant laboratory 
test results
!
Liver biopsy results
!
Diagnostic 
procedures 
performed including
!
imaging
!
Treatment given for 
the event
!
Possible cause(s) of 
the event
No
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1 0


Protocol Amendment
Date:
29 November 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
1 of 7
Protocol Amendment
no 2 to 
Protocol, final version 1.0 dated 20 June 2016 and 
Global protocol amendment number 1, version 1.0, dated 26 August 2016
Trial ID: NN9931-4296
Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily
versus placebo in subjects with non-alcoholic steatohepatitis
Trial phase: Phase 2
Applicable to all countries 
Amendment originator:
Senior International Trial Manager
TrialOps 2, GLP-1 diabetes, NADs and complications
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
3URWRFRO$PHQGPHQWJORE_
_
1 0
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
Date:
29 November 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
2 of 7
Table of Contents   
Page
Table of Contents..............................................................................................................................................2
Table of Figures................................................................................................................................................2
Table of Tables..................................................................................................................................................2
1
Introduction including rationale for the protocol amendment.............................................................3
2
Changes......................................................................................................................................................3
2.1
Section 5.3 Treatment of subjects..................................................................................................3
2.2
New section: Section 5.3.2 Subjects developing type 2 diabetes...................................................4
2.3
Section 6.3 Exclusion criteria ........................................................................................................4
2.4
Section 8.2.3 Concomitant medication..........................................................................................4
2.5
Section 8.2.7 Fundoscopy/Fundus photography............................................................................4
2.6
Section 8.7.2 Assessments in case of increased levels of liver blood parameters .........................5
2.7
Section 17 Statistical considerations..............................................................................................5
2.8
Section 17.3 Primary endpoint.......................................................................................................5
2.9
Section 17.4.1.1 Efficacy endpoints ..............................................................................................6
2.10
Section 18 Ethics ...........................................................................................................................6
2.11
Section 26 Indemnity statement.....................................................................................................7
2.12
Section 27 References....................................................................................................................7
Table of Figures   
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Table of Tables   
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Protocol Amendment
Date:
29 November 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
3 of 7
1
Introduction including rationale for the protocol amendment
Please see below the rationales for development of this global protocol amendment:
!
Since the trial population is at risk of developing type 2 diabetes, the protocol is updated to 
allow antidiabetic treatment of subjects who are diagnosed with type 2 diabetes during trial 
participation.
!
Exclusion criterion 8 is updated for vitamin E and pioglitazone treatment to ensure stable 
dose for 90 days prior to screening or baseline liver biopsy. This is to ensure that the 
potential treatment effect of these compounds is stabilised prior to enrolment into the trial.  
!
Statistical section is updated to perform a supportive analysis of the primary endpoint 
without pooling the placebo arms. The supportive analysis of the primary endpoint has been 
added to further evaluate the appropriateness of pooling the placebo groups. 
Furthermore a sensitivity analysis of the primary endpoint where vitamin E use is included 
as a factor in the model has been included and additionally a subgroup analysis for subjects 
who use vitamin E versus subjects who do not use vitamin E has been included. The 
sensitivity and subgroup analyses with respect to vitamin E use have been added to assess 
the impact of vitamin E use on the primary endpoint and possible interaction with 
randomised treatment.
!
Text regarding a new safety signal on retinopathy when subjects with type 2 diabetes are 
treated with semaglutide is included in the benefit-risk section of the protocol.
Additionally there are some updates of operational character included in order to either support any
of the above or to make additional specifications.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
Section 5.3 Treatment of subjects
Throughout the trial subjects cannot initiate treatment with: 
!
Glucose lowering agents other than trial product
!
GLP-1 RAs (other than trial product), SGLT-2 inhibitors and bolus (fast-acting) insulin 
!
Vitamin E or pioglitazone
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Protocol Amendment
Date:
29 November 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
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!
Drugs with potential effect on steatosis (corticosteroids (topical and inhaled are allowed), 
methotrexate, tamoxifen, valproic acid, amiodarone or tetracycline)
!
Drugs that could promote weight loss (orlistat, zonisamide, topiramate, phentermine, 
lorcaserin, bupropion and naltrexone alone or in combination with any other medication that 
could promote weight loss).
Neither can subjects participate in any organised weight reduction programme throughout the trial.
For subjects treated with vitamin E or pioglitazone according to exclusion criterion 8, these 
medications must be kept at a stable dose throughout the trial.
2.2
New section: Section 5.3.2 Subjects developing type 2 diabetes
Subjects who are diagnosed with T2D as a result of a screening procedure or are diagnosed with 
T2D during the trial should receive diabetes treatment at the discretion of the investigator. 
However the following treatments must not be used: GLP-1 RAs (other than trial product), SGLT-2 
inhibitors and bolus (fast-acting) insulin.
The antidiabetic medication prescribed by the investigator will not be provided nor reimbursed by 
Novo Nordisk.  
5.3.2 5.3.3 Missed dose
2.3
Section 6.3 Exclusion criteria
8. Treatment with vitamin E or pioglitazone which has not been at a stable dose in the period from
28 90 days prior to screening or if recent biopsy is used from 28 90 days prior to baseline liver 
biopsy until time of screening.
2.4
Section 8.2.3 Concomitant medication
The information collected for each concomitant medication includes trade name or generic name, 
indication, start date and stop date or continuation. For vitamin E and pioglitazone the daily dose 
must be recorded as well.
2.5
Section 8.2.7 Fundoscopy/Fundus photography
For subjects with type 2 diabetes dilated fundoscopy/fundus photography will be performed as 
specified in section 2. Fundoscopy requires pharmacological dilation of both pupils. Results of the 
dilated fundoscopy/fundus photography will be evaluated by the investigator and the investigator 
evaluation must be documented either on the dilated fundoscopy/fundus photography result report 
or in the subject’s medical record. 
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Protocol Amendment
Date:
29 November 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
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2.6
Section 8.7.2 Assessments in case of increased levels of liver blood parameters
For all such events repeat testing should must occur within 48 to 72 hours and work up for 
competing etiologies must be performed53 including: 
2.7
Section 17 Statistical considerations
The three different placebo arms will be pooled into one placebo treatment arm in all planned 
analyses. This pooling assumes that there is no substantial effect of different semaglutide placebo 
volumes on the efficacy and safety endpoints. The validity of this assumption will be checked for 
the primary endpoint and treatment emergent adverse events by evaluating summaries for each 
placebo arm. Should the placebo arms demonstrate substantial differences, appropriate sensitivity 
analyses will be included.
If not otherwise specified, the three different placebo arms will be pooled into one placebo arm in 
the statistical analyses. The pooling is based on the assumption that there is no substantial effect of 
different placebo volumes on the efficacy and safety endpoints. The validity of this assumption will 
be checked for the primary endpoint and treatment-emergent adverse events by evaluating 
descriptive statistics where each placebo arm is presented separately. In addition, the assumption 
will be evaluated based on estimates from a supportive analysis of the primary endpoint (see 
section 17.3). 
The statistical analyses will in general consist of the following three pairwise treatment 
comparisons:
!
semaglutide 0.4 mg versus placebo
!
semaglutide 0.2 mg versus placebo
!
semaglutide 0.1 mg versus placebo
The results of the comparisons will be presented as estimated treatment contrasts together with two-
sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference. The 
problem of multiple testing will be taken into account with respect to the primary endpoint (see 
section17.2 17.3) but not for any of the secondary endpoints.
2.8
Section 17.3 Primary endpoint 
Adjustment for baseline body weight as a continuous covariate may potentially give more precise 
estimates of the treatment effects. To investigate the influence of such an adjustment, a sensitivity 
analysis will be performed using a logistic regression model which includes treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline 
body weight as a covariate.
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Protocol Amendment
Date:
29 November 2016
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
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The use of vitamin E may affect the chance of NASH resolution. Therefore, a sensitivity analysis 
will be performed using a logistic regression model which includes vitamin E use at baseline 
(yes/no) as factor together with randomised treatment, baseline diabetes status, baseline fibrosis 
stage and diabetes-by-fibrosis interaction. Furthermore, a subgroup analysis will be performed 
using the same logistic regression model but with the addition of a term for the interaction between 
randomised treatment and vitamin E use.
Supportive analysis
As part of an evaluation of the appropriateness of pooling the three placebo arms, a supportive 
analysis will be performed using the same CMH test as in the primary analysis but without pooling 
the placebo arms. Each semaglutide arm will instead be compared with the placebo arm which 
received the same injection volume.
Exploratory analysis
The dose-response relationship with respect to the primary endpoint will be further explored by 
fitting a modified logistic regression model with baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and the log-transformed dose level and baseline body 
weight as covariates
2.9
Section 17.4.1.1 Efficacy endpoints 
NFS = 1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13 × Hyperglycaemia (yes/no) + 0.99
× AST/ALT + 0.013 × Thrombocyte count (109/L) + 0.66 × Albumin (g/dL)
NFS = 1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13 × Hyperglycaemia (yes/no) + 0.99
× AST/ALT  0.013 × Thrombocyte count (109/L)  0.66 × Albumin (g/dL)
2.10
Section 18 Ethics
Identified risks
Diabetic retinopathy
A transient worsening of diabetic retinopathy is a recognised complication in selected patients with 
diabetes after initiation of intensive antidiabetic treatment (refs. 67-69). Risk factors for these 
events include long-standing poor glycaemic control and presence of proliferative retinopathy, and 
initial large improvements in blood glucose maybe an additional aggravating factor. Several 
studies have, however, documented long-term beneficial effects of intensive glycaemic treatment in 
reducing retinopathy progression (Refs. 70,71) even in intensively treated patients who experienced 
early worsening (Ref. 68). In a cardiovascular outcomes trial with s.c. semaglutide, results indicate 
an increased risk of events related to diabetic retinopathy in subjects treated with semaglutide 
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Protocol Amendment
Date:
29 November 2016
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Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
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compared to placebo. As a precaution in this trial, all subjects with type 2 diabetes are required to 
have a fundus photography or dilated fundoscopy performed before enrolment into the trial; 
moreover, subjects with proliferative retinopathy or maculopathy requiring acute treatment will be 
excluded. As part of good diabetes management the investigator is encouraged to ensure adequate 
monitoring and treatment of diabetic retinopathy in subjects enrolled into the trial (Ref. 72).
2.11
Section 26 Indemnity statement
For Russia only: Federal law of 12 April 2010 No. 61-FZ ‘On Medicinal Drugs’ Circulation and 
Order No. 200n dated April 01, 2016 of the Ministry of Health of the Russian Federation On 
Approval of Rules for Good Clinical Practice.
2.12
Section 27 References
67. Dahl-Jørgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O. Rapid
tightening of blood glucose control leads to transient deterioration of retinopathy in insulin
dependent diabetes mellitus: the Oslo study. Br Med J (Clin Res Ed). 1985;290(6471):811- 5.
68. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch
Ophthalmol. 1998;116(7):874-86.
69. Varadhan L, Humphreys T, Walker AB, Varughese GI. The impact of improved glycaemic
control with GLP-1 receptor agonist therapy on diabetic retinopathy. Diabetes Res Clin Pract.
2014;103(3):e37-9.
70. Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye Study
Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION)
Study Group. Persistent Effects of Intensive Glycemic Control on Retinopathy in Type 2 Diabetes in
the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Follow-On Study. Diabetes
Care. 2016;39(7):1089-100.
71. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53.
72. Diabetes Care 2016, Standards of Medical Care in Diabetes
67 73. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD, Diseases AAftSoL. Liver 
biopsy. Hepatology. 2009;49(3):1017-44.
68 74. International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org.
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
1 of 17
Protocol Amendment
no 3 to
Protocol, final version 1.0 dated 20 June 2016 and
Global protocol amendment number 1, version 1.0, dated 26 August 2016 and
Global protocol amendment number 2, version 1.0, dated 29 November 2016
Trial ID: NN9931-4296
Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily
versus placebo in subjects with non-alcoholic steatohepatitis
Trial phase: 2
Applicable to all countries
Amendment originator:
 Senior International Trial Manager
TrialOps 2, GLP-1 diabetes, NADs and complications
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
2 of 17
Table of Contents   
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................2
Table of Tables............................................................................................................................................3
1
Introduction including rationale for the protocol amendment...........................................................4
2
Changes ................................................................................................................................................6
2.1
List of abbreviations..................................................................................................................6
2.2
Section 1 Summary ...................................................................................................................6
2.3
Section 2 Flowchart...................................................................................................................7
2.4
Section 4.2.1 Primary endpoint..................................................................................................7
2.5
Section 4.2.2.2 Supportive secondary safety endpoints ..............................................................7
2.6
Section 5.1 Type of trial............................................................................................................7
2.7
Section 5.3 Treatment of subjects..............................................................................................8
2.8
Section 5.3.1 Subjects treated with basal insulin........................................................................9
2.9
New section: 5.3.2 Treatment of subjects with poorly controlled glycaemia...............................9
2.10
Section 5.3.23 Subjects developing type 2 diabetes....................................................................9
2.11
Section 6.1 Number of subjects ...............................................................................................10
2.12
Section 6.2 Inclusion criteria ...................................................................................................10
2.13
Section 6.3 Exclusion criteria ..................................................................................................10
2.14
Section 6.4 Criteria for premature discontinuation of trial product ...........................................12
2.15
Section 7 Milestones ...............................................................................................................12
2.16
Section 8.1.1 Screening, Re-screening and screen failures .......................................................13
2.17
New section: 8.1.2 Optional pre-screening..............................................................................13
2.18
Section 8.1.34 Fasting visits ....................................................................................................13
2.19
Section 8.3.1 Liver biopsy.......................................................................................................14
2.20
Section 8.3.1.1 Central pathologist evaluation .........................................................................14
2.21
Section 8.3.2 Fibroscan measurements ....................................................................................14
2.22
Section 8.3.3.3 Body mass index .............................................................................................15
2.23
Section 8.5 Laboratory assessments.........................................................................................15
2.24
Section 8.5.3.1 Biochemistry...................................................................................................15
2.25
Section 8.5.3.2 Hormones........................................................................................................15
2.26
Section 17.4.1.2 Safety endpoints............................................................................................16
2.27
Section 18.1 Benefit-risk assessment of the trial ......................................................................16
2.28
Section 18.2 Informed consent ................................................................................................16
3
References ..........................................................................................................................................17
Table of Figures   
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
3 of 17
Table of Tables   
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
4 of 17
1
Introduction including rationale for the protocol amendment
The below changes to liver biopsy assessment, bilirubin, HbA1c, BMI, thyroid stimulating hormone
and pre-screening are implemented in the trial protocol based on detailed and continuous 
monitoring of the progress of the current trial, in addition to scientific developments in the field of
non-alcoholic steatohepatitis (NASH). This combined with the continuous accumulation of 
semaglutide safety and efficacy data is the reason behind this protocol amendment. The changes are 
in accordance with advice from external NASH experts and recommendations from the Liver 
Forum (forum for collaboration between academia, industry and Health Authorities on clinical 
development in NASH). As the field of NASH is quickly evolving, including an increasing number 
of clinical trials, the described changes should also lead to an improvement in the rate of 
recruitment.
Number of subjects to be screened:
The expected screen failure rate and hence planned number of screened subjects are updated based 
on actual numbers seen in the trial. 
Eligibility criteria: 
Inclusion criterion 5: This criterion is rephrased to emphasize that eligibility is solely based on
central pathologist assessment of the baseline liver biopsy. This will not change how patients are
entering the trial and is in line with eligibility criteria for ongoing global NASH trials1, 2.
Exclusion criterion 5: Gilbert’s syndrome is a common form of unconjugated hyperbilirubinemia 
caused by an inherited deficiency in the bilirubin-conjugating enzyme. The condition is highly 
prevalent ranging from 3% to 12% of the population depending on the mode of diagnosis3. A small 
study of patients with NASH reported a prevalence of Gilbert’s syndrome of 7.5%4. Gilbert’s 
syndrome is, however, regarded a benign trait, and clinical recognition is often incidental to routine 
laboratory investigations, revealing an elevated level of total bilirubin. Thus, exclusion criterion 5 
will be changed to allow subjects into the trial with total bilirubin level >1.5 mg/dL if conjugated 
bilirubin is <1.5×upper limit of normal. 
Exclusion criterion 10 and 12: Exclusion criterion 10 is being amended to allow patients in with 
HbA1c of up to 10% to allow a slightly broader population, including more patients with type 2 
diabetes to enter the trial. Given that the current trial is placebo-controlled and of long duration, the 
responsibility of the investigator to ensure glycaemic control of the patients will be reinforced by 
adding guidance to treatment of patients with type 2 diabetes with poorly controlled glycaemia to 
the protocol. 
A significant proportion of patients with NASH and type 2 diabetes is treated with bolus insulin. To
allow for these patients to enter the trial, exclusion criterion 12 will be deleted. In order to mitigate 
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
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the risk of hypoglycaemia, the protocol is amended to instruct the total daily insulin dose to be 
reduced by 30% at baseline in subjects with HbA1c H 8.0% at the screening visit. 
Exclusion criterion 15: Exclusion criterion 15 will be amended by removing the upper limit of 
BMI in order to allow patients with a BMI I45 kg/m2 to be included in the trial.
The prevalence of non-alcoholic fatty liver disease (NAFLD) and NASH increases with increasing
body mass index (BMI). An analysis of liver histology obtained from liver donors, autopsy  
findings, and clinical liver biopsies suggests that the prevalence rates of steatosis and NASH are 
approximately 15% and 3%, 65% and 20% and 85% and 40% respectively in non-obese, BMI 30.0–
39.9 kg/m2 and BMI I40 kg/m2 subjects5. 
The recently completed semaglutide obesity trial, trial NN9536-4153, which included patients with 
a BMI > 30 kg/m2 and investigated the same dose range as the current trial (0.05-0.4 mg/day), 
reported that the semaglutide safety profile was well-tolerated, with the most common adverse 
events being gastrointestinal (GI) adverse events6. This is in line with the previous experience with 
semaglutide7. 
Exclusion criteria 16: Thyroid function disorders are not considered a safety concern for
semaglutide7 and thus exclusion criterion 16 will be removed.
Subjects can be re-screened if they have previously screen failed solely due to lab parameters
included in the eligibility criteria that are changed in this amendment (HbA1c, total bilirubin or 
TSH).
Pre-screening:
Optional pre-screening activities including blood samples and imaging methods will be 
implemented in the present protocol amendment to pre-qualify patients and thereby potentially 
minimise the number of patients having a liver biopsy performed and the number of screen failed 
subjects. These activities will require that the subject signs a separate informed consent form. 
According to the joint clinical guideline for the management of NAFLD from the European liver, 
diabetes and obesity associations, surrogate blood markers of fibrosis e.g. NAFLD Fibrosis Score 
(NFS), FIB-4 or Enhanced Liver Fibrosis (ELF) test, should be calculated for NAFLD patients in 
order to rule out significant fibrosis (IF2). If significant fibrosis cannot be ruled out, patients should 
be referred to transient elastography, and if significant fibrosis is confirmed the final diagnosis 
should be made by liver biopsy8. Similar strategies to identify and target liver biopsies to patients at 
greatest risk of having NASH with advanced fibrosis have previously been described9, 10. 
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
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Footnote to primary end-point: 
The first footnote (*) of the primary endpoint has been updated to clarify that resolution of NASH is 
defined as “no more than mild residual inflammatory cells (0 – 1) and no ballooning (0)”. This is in 
line with the Health Authority recommendation (FDA and EMA) as communicated through the 
Liver Forum11.
Other minor changes and clarifications have been included.
Since new protocol sections are added, the numbering for some protocol sections will change 
throughout the updated protocol once the amendment is implemented.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
2
Changes
2.1
List of abbreviations
TSH
thyroid stimulating hormone 
2.2
Section 1 Summary
Trial population
A total of 372 subjects are planned to be randomised. Based on an assumption of a 6550% 
screening failure rate, 1063744 subjects are planned to be screened.
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial except for protocol described pre-screening activities which require a separate 
informed consent.
!
Local histological diagnosis of NASH followed by histological confirmation of NASH 
based on central pathologist evaluation of Histologic evidence of NASH based on central 
pathologist evaluation of a liver biopsy obtained up to 21 weeks before screening.
Key exclusion criteria
•
HbA1c > 910 % at screening.
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
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•
Body Mass Index (BMI) H 25.0 or I 45.0 kg/m2 at the screening visit (visit 1).
2.3
Section 2 Flowchart
TSH
Attend visit fasting: Added x for visit 10
16) All visit 2 assessments must be carried out prior to first trial product dose
2.4
Section 4.2.1 Primary endpoint
!
NASH resolution* without worsening of fibrosis** after 72 weeks (yes/no)
*) Resolution of NASH defined by the NASH Clinical research network (CRN) as “no more than 
mild residual inflammatory cells (0 – 1) and no ballooning (0)” based on comprehensive 
interpretation by two independent pathologists (central reading) blinded to treatment allocation.
*) Resolution of NASH as defined by comprehensive interpretation by two independent 
pathologists (central reading) blinded to treatment allocation and with complete resolution captured 
by terms such as “no fatty liver disease” or “simple steatosis or isolated steatosis” and defined by 
the NASH Clinical research network (CRN) as “no more than mild residual inflammatory cells and 
no ballooning”
**) worsening defined by an increase of at least one stage of the Kleiner fibrosis classification 
2.5
Section 4.2.2.2 Supportive secondary safety endpoints
Change from baseline to 72 weeks in:
!
Pulse
!
ECG
!
Physical examination
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
!
Biochemistry (creatinine, estimated glomerular filtration rate (eGFR), creatinine 
phosphokinase, urea, bilirubin (total), alkaline phosphatase, ferritin, sodium, potassium, 
calcium (total), amylase, lipase)
!
Hormones (calcitonin)
2.6
Section 5.1 Type of trial
A planned total of 372 subjects will be randomised. Based on an assumption of a 6550% screening 
failure rate, 1063744 subjects will be screened. 
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Protocol Amendment
Date:
25 August 2017
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
8 of 17
2.7
Section 5.3 Treatment of subjects
The conversion table below shows the connection between each volume matched dose level and the 
value shown in the display on the NovoPen® 4. Subjects must be instructed to administer the value 
shown in the display.
Injections may be administered in the thigh, abdomen or upper arm, at any time of day irrespective 
of meals. The injections should be administered at approximately the same time of day during the 
trial.
Throughout the trial subjects cannot initiate treatment with: 
!
GLP-1 RAs (other than trial product), or SGLT-2 inhibitors and bolus (fast acting) insulin
!
Vitamin E or pioglitazone
!
Drugs with potential effect on steatosis (corticosteroids (topical, and inhaled and short term 
systemic use (8 14 days) are allowed), methotrexate, tamoxifen, valproic acid, amiodarone 
or tetracycline)
!
Drugs that could promote weight loss (orlistat, zonisamide, topiramate, phentermine, 
lorcaserin, bupropion and naltrexone alone or in combination with any other medication that 
could promote weight loss).
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Date:
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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2.8
Section 5.3.1 Subjects treated with basal insulin
The following basal insulins are allowed:
!
Insulin glargine
!
Insulin detemir
!
Insulin degludec
!
Neutral protamine Hagedorn (NPH) insulin
Subjects treated with basal insulin:
Throughout the trial, insulin dose should be titrated at the discretion of the investigator. For the 
individual subject, increasing the insulin dose before two weeks after the end of the final dose-
escalation should be avoided, unless required to control acute hyperglycaemia and acute diabetic 
complications. 
Subjects treated with basal insulin and with HbA1c 9 8.0 % at screening:
Subjects with HbA1c H 8.0 % at screening (visit 1) should have the total daily insulin dose reduced 
by 30 % at start of trial product treatment to limit the potential risk of hypoglycaemia induced by 
the combination of insulin and semaglutide. 
2.9
New section: 5.3.2 Treatment of subjects with poorly controlled glycaemia
Subjects with type 2 diabetes and with persistent and unacceptable hyperglycaemia should be 
offered treatment intensification. If any HbA1c value reported by central laboratory exceeds 9% 
from at least 4 weeks after end of dose escalation, the subject should be offered treatment 
intensification at the discretion of the investigator. However, the following treatment types must not 
be used: GLP-1 RAs (other than trial product) and SGLT-2 inhibitors. Subjects that are started on 
treatment intensification medication should continue to follow the protocol specified visit schedule 
and stay on trial product treatment unless the investigator judges that this will jeopardise the safety 
of the subject. 
All treatment intensification medication given should be documented in medical records and 
reported in the eCRF. Treatment intensification medication will not be provided nor reimbursed by 
Novo Nordisk.
2.10
Section 5.3.23 Subjects developing type 2 diabetes
Subjects who are diagnosed with T2D as a result of a screening procedure or are diagnosed with 
T2D during the trial should receive diabetes treatment at the discretion of the investigator. However 
the following treatments must not be used: GLP-1 RAs (other than trial product), and SGLT-2 
inhibitors and bolus (fast acting) insulin.
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5.3.34 Missed dose
5.3.45 Nutritional and physical activity counselling
2.11
Section 6.1 Number of subjects
Number of subjects planned to be screened: 744 1063.
Number of subjects planned to be randomised: 372 (50 65% screen failure rate).
2.12
Section 6.2 Inclusion criteria
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 except for protocol described pre-screening activities which require a separate informed 
consent.
5. Local histological diagnosis of NASH followed by histological confirmation of NASH based on 
central pathologist evaluation of Histologic evidence of NASH based on central pathologist 
evaluation of a liver biopsy obtained up to 21 weeks before screening.
2.13
Section 6.3 Exclusion criteria
5. Elevated total bilirubin (> 1.5 mg/dL) at screening. Total bilirubin level >1.5 mg/dL is allowed if 
conjugated bilirubin is <1.5×UNL.
6. Prothrombin time International normalized ratio (INR) of prothrombin time > 1.3 at screening.
10. HbA1c > 910 % at screening.
12. Treatment with bolus (fast acting) insulin in the period from 28 days prior to screening or if 
recent biopsy is used from 28 days prior to baseline liver biopsy until time of screening.
1312. Treatment with other glucose lowering agent(s) (apart from GLP-1 RAs or SGLT-2 inhibitors
what is listed in exclusion criterion 11 and 12) not stable in the period from 28 days prior to 
screening or if recent biopsy is used from 28 days prior to baseline liver biopsy until time of 
screening. Changes without clinical relevance in the opinion of the investigator are allowed.
1413. Diagnosis of type 1 diabetes according to medical records.
Obesity related:
1514. Body Mass Index (BMI) H 25.0 or I 45.0 kg/m2 at the screening visit (visit 1).
16. TSH > 6 mIU/L or < 0.4 mIU/L at screening.
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1715. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion and 
naltrexone alone or in combination or any other medication that could promote weight loss in the 
opinion of the investigator in the period from 28 days prior to screening or if recent biopsy is used 
from 28 days prior to baseline liver biopsy until time of screening.
1816. Participation in an organised weight reduction program (e.g. WeightWatchers®) in the period 
from 28 days prior to screening or if recent biopsy is used from 28 days prior to baseline liver 
biopsy until time of screening.
1917. Previous surgical treatment for obesity. However (1) liposuction and/or abdominoplasty if 
performed > 6 months before baseline liver biopsy is allowed or 2) lap banding where the band has 
been removed > 6 months before baseline liver biopsy is allowed 3) intragastric balloon where the 
balloon has been removed > 6 months before baseline liver biopsy is allowed.
General safety:
2018. For patients with type 2 diabetes only: Proliferative retinopathy or maculopathy requiring 
acute treatment verified by fundus photography or dilated fundoscopy performed within the past 90 
days prior to randomisation. 
2119. History or presence of pancreatitis (acute or chronic).
2220. Calcitonin I 50 ng/L at screening.
2321. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
2422. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
2523. Surgery scheduled for the trial duration period, except for minor surgical procedures, in the 
opinion of the investigator.
2624. Any condition which, in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
2725. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures.
2826. Known or suspected hypersensitivity to trial product or related products.
2927. Previous participation in this trial. Participation is defined as randomisation.
3028. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
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Version:
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3129. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as 
required by local regulation or practice).
For EU countries: The following contraceptive measures are considered adequate:
•
Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation :
o
oral
o
injectable
o
implantable
•
Placement of an 
o
intrauterine device (IUD) 
o
intrauterine hormone-releasing system ( IUS)
•
Bilateral tubal occlusion
•
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository) (not applicable for Belgium, Denmark, Finland, 
Greece, Spain, Sweden)
•
Vasectomised partner (where partner is sole partner of subject) (not applicable for 
Denmark)
•
True sexual abstinence (not applicable for Denmark). Sexual abstinence is defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.
3230. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR < 
30 ml/min/1.73 m2 as defined by Kidney Disease: Improving Global Outcomes (KDIGO).42
2.14
Section 6.4 Criteria for premature discontinuation of trial product 
10. Treatment with other GLP-1 receptor agonists or, SGLT-2 inhibitors or bolus (fast acting) 
insulin 
2.15
Section 7 Milestones
Planned duration of recruitment period: 78 51 weeks
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Version:
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UTN: U1111-1179-7464
Status:
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2.16
Section 8.1.1 Screening, Re-screening and screen failures
Informed consent must be obtained before any trial related activity, see section 18.2. Separate 
informed consent forms for long-term storage of human samples and genotyping are available and 
informed consent must be obtained before activities related to any of these are undertaken.
Additionally a separate informed consent form for optional pre-screening is available. This must be 
signed before any optional pre-screening activities are performed (see section 8.1.2).
Re-screening
Re-screening of screening failures is allowed only once within the limits of the recruitment period. 
However, re-screening is NOT allowed if the subject has failed one of the inclusion/exclusion 
criteria related to laboratory parameters (pathology and/or blood parameters histological NAS, 
NASH fibrosis stage, HBsAg, anti HIV, HCV RNA, AST, ALT, total bilirubin, INR, HbA1c, 
calcitonin or TSH). In the event of re-screening, a new informed consent must be obtained and a 
new subject number must be allocated. All assessments and laboratory samples must be repeated.
2.17
New section: 8.1.2 Optional pre-screening
The Investigator may, after obtaining separate informed consent, perform pre-screening of 
potential trial candidates. Pre-screening assessments include blood parameters and imaging
(except for imaging methods with radiation involved).The purpose of such assessments is to assess 
trial eligibility potential.
Pre-screening assessments are not defined as trial-related procedures. Results of pre-screening 
assessments will not be collected in the trial database and will not be monitored. Concerns related 
to any pre-screening assessment must not be reported as an adverse event.  
Pre-screening assessments (blood parameters and imaging) performed after signature of the 
separate informed consent can be reimbursed by Novo Nordisk A/S.
8.1.23 AUDIT questionnaire
2.18
Section 8.1.34 Fasting visits
Subjects must attend some of the most clinic visits in a fasting state (see section 2).
Fasting is defined as at least eight hours without food or liquids, except for water. Trial product and 
any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling has been performed. If the subject is not fasting as required, the subject 
must be called in for a new visit within the visit window to have the fasting procedures done. 
Fasting procedures include body weight, Fibroscan® measurements and blood sampling (FPG, 
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Trial ID: NN9931-4296
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fasting insulin, fasting glucagon, calcitonin and lipids (Total cholesterol, free fatty acids, HDL 
cholesterol, LDL cholesterol, triglycerides, VLDL cholesterol)).
Prior to Fibroscan® measurements, only two hours of fasting is required. 
At visit 19, the subject must be fasting for two hours prior to the anti-semaglutide antibody 
sampling (see section 8.5.3.7).
8.1.45 Missed visits
8.1.56 Premature discontinuation of trial product
8.1.67 Withdrawn subjects
8.1.78 Subject training
2.19
Section 8.3.1 Liver biopsy
To be randomised, subjects must have histologic evidence of NASH a local histological diagnosis of 
NASH followed by histological confirmation of NASH diagnosis based on central pathologist 
evaluation of a liver biopsy. Confirmation of Histologic evidence of NASH diagnosis can be based 
on a liver biopsy obtained up to 21 weeks prior to screening. For subjects with no historical liver 
biopsy within 21 weeks prior to screening, a liver biopsy must be performed during the screening 
period. The local NASH diagnosis and the confirmation The histologic evidence of NASH diagnosis 
by central pathologist evaluation of the liver biopsy must be available prior to randomisation of the 
subject. The local NASH diagnosis and the confirmation of NASH diagnosis by central pathologist 
evaluation can be done on the same liver biopsy sample.
2.20
Section 8.3.1.1 Central pathologist evaluation
The histologic evidence of NASH diagnosis and histology based scores will be centrally assessed by 
two independent pathologists with expertise and experience in NASH.
2.21
Section 8.3.2 Fibroscan measurements
Liver stiffness
At sites with Fibroscan® equipment available, measurements of liver stiffness must be performed at 
the specified visits (section 2). Fibroscan measurements can be performed up to 2 weeks prior to 
each visit.
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Trial ID: NN9931-4296
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Liver steatosis
At sites with Fibroscan® equipment available, measurements of liver steatosis must be performed at 
the specified visits (section 2). Fibroscan measurements can be performed up to 2 weeks prior to 
each visit.
2.22
Section 8.3.3.3 Body mass index
Body mass index will be calculated by the eCRF from visit 1 height data and must be in accordance 
with exclusion criterion 1514.
2.23
Section 8.5 Laboratory assessments
The laboratory analyses will be performed by a central laboratory except for laboratory analyses for 
pre-screening, analysis of anti-semaglutide antibodies and semaglutide plasma concentration 
analysis and some exploratory biomarkers which will be performed at specialised laboratories. 
2.24
Section 8.5.3.1 Biochemistry
!
Bilirubin, total
!
Bilirubin, conjugated
!
Calcium
!
Creatinine phosphokinase
!
Creatinine
!
eGFR (per CKD-EPI formula)
!
Lipase
!
Potassium
!
Sodium
!
Alkaline phosphatase
!
Amylase
!
Albumin
!
Ferritin
!
Urea
!
MELD score
2.25
Section 8.5.3.2 Hormones
!
Calcitonin (see Appendix A)
!
Thyroid stimulating hormone (TSH)
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Trial ID: NN9931-4296
Version:
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2.26
Section 17.4.1.2 Safety endpoints
!
Change from baseline to 72 weeks in:
o
Pulse
o
ECG
o
Physical examination
o
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
o
Biochemistry (creatinine, eGFR, creatinine phosphokinase, urea, bilirubin (total), 
alkaline phosphatase, ferritin, sodium, potassium, calcium (total), amylase, lipase)
o
Hormones (calcitonin)
2.27
Section 18.1 Benefit-risk assessment of the trial
Other safety considerations
Teratogenicity (nonclinical embryo-foetal toxicity)
Semaglutide has been concluded teratogenic in rats. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function. As 
the yolk sac does not play such a role for nutrition of the embryo in humans, this effect is unlikely 
to be relevant for humans. However, as a precaution subjects fulfilling exclusion criterion 3129 will 
be excluded from trial participation. Furthermore, as specified in the flowchart, female subjects 
included in the trial will have pregnancy testing performed frequently during the entire duration of 
the trial. 
2.28
Section 18.2 Informed consent
Separate informed consent forms for long-term storage of human samples and genotyping are 
available and informed consent must be obtained before activities related to any of these are 
undertaken.
Additionally a separate informed consent form for optional pre-screening is available. This must be 
signed before any optional pre-screening activities are performed (see section 8.1.2).
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Trial ID: NN9931-4296
Version:
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3
References
1.
Clinicaltrials.gov. Randomized Global Phase 3 Study to Evaluate the Impact on NASH With 
Fibrosis of Obeticholic Acid Treatment ( REGENERATE ) NCT02548351 [internet] 2015 
[cited 2017 10 Aug].
2.
Clinicaltrials.gov. Safety and Efficacy of Selonsertib in Adults With Nonalcoholic 
Steatohepatitis (NASH) and Bridging (F 3 ) Fibrosis ( STELLAR 3 ) 
NCT03053050 [internet] 2017 [cited 2017 10 Aug].
3.
Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert's syndrome and the risk of death: a 
population-based cohort study. J Gastroenterol Hepatol. 2013;28(10):1643-7.
4.
Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A. Unconjugated 
hyperbilirubinemia in nonalcoholic steatohepatitis--is it Gilbert's syndrome? Trop 
Gastroenterol. 2005;26(3):123-5.
5.
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, 
metabolic, and clinical implications. Hepatology. 2010;51(2):679-89.
6.
Novo Nordisk A/S. Novo Nordisk reports up to 13.8% weight loss in people with obesity 
receiving semaglutide in phase 2 trial [internet] 2017 [cited 2017 10 Aug].
7.
Novo Nordisk A/S. Investigator's Brochure for s.c. Semaglutide (NN9535, NN9931, 
NN9536), Edition 12. 2017.
8.
(EASL) EAftSotL, (EASD) EAftSoD, (EASO) EAftSoO. EASL-EASD-EASO Clinical 
Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 
2016;59(6):1121-40.
9.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and 
management of non-alcoholic fatty liver disease: practice Guideline by the American 
Association for the Study of Liver Diseases, American College of Gastroenterology, and the 
American Gastroenterological Association. Hepatology. 2012;55(6):2005-23.
10.
Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of 
non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 
2011;33(5):525-40.
11.
Forum L. Liver Forum meeting 6, 18 Apr 2017 [internet] 2017 [cited 2017 10 Aug].
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Protocol Amendment no 4
Date:
01 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT no.: 2016-000685-39
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Protocol Amendment
no 4 to
Protocol, final version 1.0 dated 20 June 2016 and
Global protocol amendment number 1, version 1.0, dated 26 August 2016 and
Global protocol amendment number 2, version 1.0, dated 29 November 2016 and
Global protocol amendment number 3, version 1.0, dated 25 August 2017 and
Local protocol amendment number 5 in Sweden, version 1.0, dated 09 January 2018
Trial ID:NN9931-4296
Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily
versus placebo in subjects with non-alcoholic steatohepatitis
Trial phase: 2
Applicable to all countries
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 4
Date:
01 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT no.: 2016-000685-39
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2 of 10
Table of Contents
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................6
2.1
Section 1 Summary ...................................................................................................................6
2.2
Section 5.1 Type of trial............................................................................................................6
2.3
Section 5.2 Rationale for trial design.........................................................................................6
2.4
Section 6.1 Number of subjects .................................................................................................6
2.5
Section 6.2 Inclusion criteria .....................................................................................................7
2.6
Section 6.3 Exclusion criteria ....................................................................................................7
2.7
Section 6.7 Rationale for trial population...................................................................................7
2.8
Section 7 Milestones .................................................................................................................7
2.9
Section 8.1.1 Screening, re-screening and screen failures...........................................................7
2.10
Section 11 Randomisation procedure and breaking of blinded codes..........................................7
2.11
Section 17.1 Sample size calculation .........................................................................................8
2.12
Section 17.3 Primary endpoint...................................................................................................9
2.13
Section 27 References ...............................................................................................................9
3
References ..........................................................................................................................................10
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Protocol Amendment no 4
Date:
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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1
Introduction including rationale for the protocol amendment
This amendment introduces a change to the sample size and a broadening of the patient inclusion 
criterion to include subjects with liver fibrosis stage 1 (F1). The sample size reduction is based on 
new data from trials in non-alcoholic steatohepatitis (NASH), which collectively suggest a lower 
placebo response rate than was assumed when this study was designed. The inclusion of patients 
with F1 reflects the view that some patients may be so-called “fast progressors” who could benefit 
from pharmacological treatment.
A change to allow re-test of INR is implemented based on an evaluation of the causes behind 
prolonged INR observed in the current trial. 
Sample size reduction:
The planned sample size in this clinical trial is being reduced due to emerging placebo response 
data from competitor NASH trials in subjects with NASH as well as semaglutide data from a Novo 
Nordisk trial in subjects with obesity.
CENTAUR1 was a 2-year, randomised, double-blind, placebo-controlled phase 2b trial to evaluate 
the effect of cenicriviroc in subjects with NASH and liver fibrosis. Resolution of NASH with no 
worsening of liver fibrosis at year 1 was a secondary endpoint in the trial and of 126 subjects 
receiving placebo treatment with evaluable biopsies at both baseline and after 1 year, only 9 (7%) 
subjects met this endpoint.
GOLDEN-5052 was a 52-week, randomised, double-blind, placebo-controlled phase 2 trial to 
evaluate the effect of elafibranor in subjects with NASH. The primary endpoint was resolution of 
NASH with no worsening of fibrosis at 1 year, using protocol-defined and modified definitions. The 
modified definition is recommended by regulatory agencies and is the one used in the current trial. 
Out of 77 subjects receiving placebo treatment with evaluable biopsies at both baseline and end of 
trial, only 11 (14%) subjects met this modified endpoint.
Based on the results from the CENTAUR1 and GOLDEN-5052 trials, the assumed proportion of 
completers meeting the primary endpoint with placebo has been reduced from 20% to 17% in the 
sample size calculation for the current trial.
The effect of semaglutide in subjects with obesity has been investigated in a phase 2 dose finding 
trial (NN9536-4153)3. The trial was a 52-week, randomised, double-blind, placebo- and active-
controlled trial in which 957 adults with obesity but without type 2 diabetes received once-daily s.c. 
injection of semaglutide in one of five different doses (0.05 mg/day to 0.4 mg/day), once-daily 
injection of liraglutide (3.0 mg/day) or once-daily placebo as add on to lifestyle counselling. The 
estimated mean body weight loss at 52 weeks was up to 13.8% with semaglutide compared to 7.8% 
with liraglutide and 2.3% with placebo. The LEAN4 trial investigated overweight subjects with 
biopsy-confirmed NASH and showed that statistically significantly more subjects treated with 
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Protocol Amendment no 4
Date:
01 March 2018
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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liraglutide (1.8 mg/day) compared to subjects treated with placebo obtained resolution of NASH 
with no worsening of fibrosis after 48 weeks of treatment. In the LEAN trial, subjects treated with 
liraglutide had a mean weight loss of 5.5% compared to 0.7% in subjects treated with placebo. 
The observed effect on weight loss with higher doses of semaglutide suggests that semaglutide 
putatively has a greater effect on resolution of NASH than previously anticipated. This is supported 
by data showing that a greater extent of weight loss is associated with improvement in histologic 
features of NASH.5 To be conservative, the assumed proportion of completers meeting the primary 
endpoint with semaglutide 0.4 mg/day remains unchanged in the sample size calculation, but with 
the adjusted placebo effect from 20% to 17% this will imply an increase of the assumed treatment 
difference from 25 to 28 percentage points.
Eligibility criteria:
Inclusion criterion 7: The patient inclusion criteria have been broadened to include subjects with 
F1. Some patients with F1 may be “fast progressors”, who may benefit from pharmacological 
treatment. Although the presence of increasing number of metabolic disorders such as insulin 
resistance, type 2 diabetes, hypertension, dyslipidemia, and visceral obesity seems to increase the 
risk of progression6, the current understanding is incomplete. 
Indeed, the broadening of the patient population in the current trial is in line with other phase 2 
NASH trials, for which most have included patients with fibrosis stage 0-32, 7 or 1-31. Further, a 
subset of F1 patients may be included in phase 3, as seen in other development programmes8, 9, and 
as such it is important to understand the effect of semaglutide in these subjects.
A review of published data from other trials in NASH including LEAN4, FLINT7, GOLDEN-5052
and CENTAUR1, which involved a range of different drug classes, gives no clear indication of a 
differential treatment effect according to baseline fibrosis stage. Therefore, the inclusion of subjects 
with F1 at baseline is not anticipated to impact on the power of achieving the main trial objectives 
of NN9931-4296.
As stated above sufficient data across fibrosis stages are needed, therefore the aim is to randomise a 
maximum of approximately 35% subjects with F1.
Exclusion criterion 6: This trial specifically excludes subjects with advanced liver disease i.e. liver 
cirrhosis as based on liver histology and clinical/biochemical parameters including international 
normalized ratio (INR) >1.3 (exclusion criterion 6).
INR is the ratio of measured prothrombin time over normal prothrombin time and it evaluates the 
extrinsic coagulation pathway (vitamin K dependent clotting factors II; V, VII, IX and X). These 
clotting factors are synthesised in the liver, thus INR is used as a marker of liver synthesis 
function.10
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Protocol Amendment no 4
Date:
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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INR can be prolonged due to factors other than decreased liver synthetic function including vitamin 
K deficiency as seen in the setting of dietary restrictions or malabsorption.10 Furthermore, INR may 
be prolonged due to pre-analytical events associated with sample collection and processing. INR 
analysis is sensitive to under-filling of the collection tube as this cause an increase in the anti-
coagulant (in the tube) to blood ratio, which results in a falsely prolonged INR. In addition, INR 
may be prolonged if centrifugation of the sample is delayed or is too vigorous.11
Serum albumin is also a protein that is produced in the liver and therefore serum albumin 
concentration is also a marker of liver synthesis function. Conjugation of bilirubin takes place in the 
liver and therefore bilirubin is also a marker of liver function.10
To ensure patient safety whilst at the same time avoiding exclusion of subjects that may otherwise 
be eligible for experimental treatment of a disease with currently no approved treatment options, re-
testing of INR is allowed. INR re-testing is allowed once in patients with a normal screening 
albumin within central laboratory reference range and screening bilirubin below the concentration 
described in exclusion criterion 5.
Exclusion criterion 9: This is rephrased to emphasize that medication known to affect steatosis is 
exclusionary. However, allows for short term treatment not evaluated to impact steatosis.
Subjects can be re-screened once within the recruitment period if they have screen failed prior to 
approval of this global protocol amendment 4 due to: INR eligibility criterion only and/or F1 only. 
Other minor changes and clarifications have been included.
Since new references are added, the numbering for references will change throughout the updated 
protocol once the amendment is implemented.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
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Protocol Amendment no 4
Date:
01 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT no.: 2016-000685-39
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2
Changes
2.1
Section 1 Summary
Randomisation will be stratified in five strata based on region (Japanese or non-Japanese) and, 
within the non-Japanse group, based on diabetes status at screening (with or without type 2 
diabetes) and fibrosis stage for baseline liver biopsy (F1/F2 or F3 ).
Trial population
A total of 288372 subjects are planned to be randomised. Based on an assumption of a 65% 
screening failure rate, 8231063 subjects are planned to be screened.
Key inclusion criteria
!
NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on 
central pathologist evaluation.
2.2
Section 5.1 Type of trial
A planned total of 288372 subjects will be randomised. Based on an assumption of a 65% screening 
failure rate, 8231063 subjects will be screened. 
2.3
Section 5.2 Rationale for trial design
Randomisation will be stratified in five strata based on region (Japanese or non-Japanese) and, 
within the non-Japanese group, based on diabetes status at screening (with or without type 2 
diabetes) and fibrosis stage for baseline liver biopsy (F1/F2 or F3). 
2.4
Section 6.1 Number of subjects
Number of subjects planned to be screened: 8231063.
Number of subjects planned to be randomised: 288372 (65% screen failure rate).
Number of subjects expected to complete the trial on or off trial product: 259335 (10% trial 
withdrawal rate).
Number of subjects expected to complete the trial on trial product: 245316 (15% total trial product 
discontinuation rate).
The aim is that between 30 and 70% of subjects should have NASH and type 2 diabetes.
To ensure that a sufficient number of subjects with F2 and F3 are included in the trial the aim is to 
randomise a maximum of approximately 35% subjects with F1.
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Date:
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Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
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2.5
Section 6.2 Inclusion criteria
7. NASH fibrosis stage 1, 2 or 3 according to the NASH CRN fibrosis staging system based on 
central pathologist evaluation
2.6
Section 6.3 Exclusion criteria
9. Treatment with drugs with potential or anticipated initiation (for more than 14 consecutive days) 
of medications known to have an effect on steatosis; (e.g. treatment with Corticosteroids (topical 
and inhaled are allowed), Methotrexate, Tamoxifen, Valproic acid, Amiodarone or Tetracycline) in 
the period from 28 days prior to screening or if recent biopsy is used from 28 days prior to baseline 
liver biopsy until time of screening.
2.7
Section 6.7 Rationale for trial population
The trial population will consist of patients with NASH and a fibrosis stage of F1F2-F3. Patients 
with F0 and F1 will be excluded as they do not have fibrosis (F0) or are less progressed in the 
disease spectrum, why less benefit may be achieved on fibrosis (F1). Furthermore, subjects with 
fibrosis stage 4 (cirrhosis) will be excluded from the trial as an important endpoint addressing 
worsening in fibrosis cannot be addressed in this population (the Kleiner classification has a 
maximum score of 4). 
2.8
Section 7 Milestones
Planned duration of recruitment period: 10378 weeks 
2.9
Section 8.1.1 Screening, re-screening and screen failures
Re-screening
Re-screening of screening failures is allowed only once within the limits of the recruitment period. 
However, re-screening is NOT allowed if the subject has failed one of the inclusion/exclusion 
criteria related to laboratory parameters (pathology and/or blood parameters). In the event of re-
screening, a new informed consent must be obtained and a new subject number must be allocated. 
All assessments and laboratory samples must be repeated.
For subjects meeting exclusion criterion number 6, re-test of INR is allowed once within the limits 
of the screening period for that subject. To be eligible for INR re-test the subject must have a 
screening albumin within central laboratory reference range. Re-test of INR does not require a new 
informed consent or new subject number.
2.10
Section 11 Randomisation procedure and breaking of blinded codes
Randomisation will be controlled by the IWRS and stratified in five strata defined by region, 
diabetes status and fibrosis stage for baseline liver biopsy according to the criteria below:
!
Japanese
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Date:
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Trial ID: NN9931-4296
Version:
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!
Non-Japanese, with type 2 diabetes, fibrosis stage 1/2
!
Non-Japanese, with type 2 diabetes, fibrosis stage 3
!
Non-Japanese, without type 2 diabetes, fibrosis stage 1/2
!
Non-Japanese, without type 2 diabetes, fibrosis stage 3
2.11
Section 17.1 Sample size calculation
The sample size calculation is based on an aim to detect a difference in the probability of achieving 
NASH resolution (without worsening in fibrosis) between the highest semaglutide dose and the 
pooled placebo arm at 5% significance level, using Pearson chi-square test with normal 
approximation. The power is set to 90%.
It is expected that some subjects will respond to standard care. In the LEAN trial, 2 (9%) of 22 
placebo subjects had improvement in liver histology. In the FLINT56 and PIVENS57 trials, clearance 
of NASH was a secondary endpoint and the corresponding numbers were 13 (13%) of 98 subjects 
and 17 (21%) of 83 subjects, respectively. However, these figures also included patients that had 
worsening of fibrosis. In the more recent trials, CENTAUR58 and GOLDEN-50559 , the numbers 
were 9 (7%) of 126 subjects and 11 (14%) of 77 subjects, respectively, for an endpoint that was 
defined in the same way as the primary endpoint in the present trial. As a conservative assumption, 
it is anticipated that up to 1720% of the placebo completers will achieve resolution of NASH with 
no worsening of fibrosis.
It is uncertain how many subjects on semaglutide should be expected to achieve resolution of 
NASH. In the LEAN trial, an improvement was found in 9 (39%) of 23 subjects who received 
liraglutide 1.8 mg. Results from semaglutide trials in subjects with T2D and/or obesity suggest a 
greater effect of semaglutide on glycaemic control and body weight loss compared to liraglutide. In 
communication with medical advisers, a treatment difference of 20-30 percentage points was 
deemed to be a realistic target as well as clinically relevant. Therefore, it is assumed that 45% of the 
subjects who complete treatment with semaglutide 0.4 mg achieve resolution of NASH.
Based on the previous NASH trials, 15% of the randomised subjects are anticipated to prematurely 
discontinue trial product before week 72. These will be included in the main analysis either by 
using the observed outcome at week 72 (if the outcome is known) or by using imputation (if the 
outcome is not known). In either case, it is assumed that none of these subjects will achieve 
resolution of NASH.
Based on the assumptions above, the required number of randomised subjects per arm for the 3 
semaglutide arms and the pooled placebo arm is found to be 7091. Since the number in the pooled 
placebo arm needs to be divisible by 3, the number of subjects in each arm is adjusted to 7293. 
Hence, the total number of subjects to be randomised is 288372.
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Protocol Amendment no 4
Date:
01 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT no.: 2016-000685-39
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In order to investigate the influence of the values of the model parameters such as treatment 
difference and rate of premature discontinuation of trial product on the calculation, sample sizes 
have been calculated for different alternative scenarios. The results can be seen in Table 17-1.
Table 17-1
Sample size calculations for different scenarios - number of subjects per arm
Probability of achieving resolution of 
NASH
Semaglutide 
completers
Placebo completers
Rate of premature 
discontinuation
N per arm
50%
1720%
10%
4961
15%
5366
20%
5872
45%
1720%
10%
6584
15%
7091
20%
7799
40%
1720%
10%
92126
15%
99137
30%
108176
2.12
Section 17.3 Primary endpoint
The primary endpoint is the binary outcome NASH resolution without worsening in fibrosis after 72 
weeks (yes/no).The primary analysis will be based on the Cochran-Mantel-Haenszel (CMH) test59
which will be performed separately for the comparisons between each of the semaglutide arms and 
placebo. The test will adjust for baseline diabetes status (with or without T2D) and baseline fibrosis 
stage (F1, F2 or F3).
2.13
Section 27 References
58
Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A 
randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic 
steatohepatitis with fibrosis. Hepatology. 2018.
59
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an 
Agonist of the Peroxisome Proliferator-Activated Receptor-C and -D, Induces Resolution of 
Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 
2016;150(5):1147-59.e5
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Protocol Amendment no 4
Date:
01 March 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT no.: 2016-000685-39
Page:
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3
References
1.
Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A 
randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic 
steatohepatitis with fibrosis. Hepatology. 2018.
2.
Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an 
Agonist of the Peroxisome Proliferator-Activated Receptor-K and -L, Induces Resolution of 
Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology. 
2016;150(5):1147-59.e5.
3.
Novo Nordisk A/S. Company Announcement, Novo Nordisk reports up to 13.8% weight 
loss in people with obesity receiving semaglutide in phase 2 trial 2017 [cited 2018 02-16].
4.
Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and 
efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, 
randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-90.
5.
Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, 
Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly 
Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-78.
6.
Chalasani N, IN IUSoMI, Younossi Z, VA IFHCfLDaDoMFC, Lavine JE, NY CUNY, et al. 
The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from 
the American Association for the Study of Liver Diseases. Hepatology. 2017;67(1):328-57.
7.
Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek 
MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-
alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. 
Lancet. 2015;385(9972):956-65.
8.
Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients 
With Nonalcoholic Steatohepatitis (NASH) (RESOLVE-IT) [Internet]. ClinicalTrials.gov. 
Available from: https://clinicaltrials.gov/ct2/show/NCT02704403.
9.
Randomized Global Phase 3 Study to Evaluate the Impact on NASH With Fibrosis of 
Obeticholic Acid Treatment [Internet]. ClinicalTrials.gov.  [cited 2018-02-07]. Available 
from: https://clinicaltrials.gov/ct2/show/NCT02548351.
10.
Newsome PN, Cramb R, Davison SM, Dillon JF, Foulerton M, Godfrey EM, et al. 
Guidelines on the management of abnormal liver blood tests. 2017.
11.
Favaloro EJ, (Adcock) Funk DM, Lippi G. Pre-analytical Variables in Coagulation Testing 
Associated With Diagnostic Errors in Hemostasis. Laboratory Medicine. 2012;43(2):1-10.
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Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
1 of 17
Protocol Amendment
no 5 to
Protocol, final version 1.0 dated 20 June 2016 and
Global protocol amendment number 1, version 1.0, dated 26 August 2016 and
Global protocol amendment number 2, version 1.0, dated 29 November 2016
Trial ID: NN9931-4296
Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily
versus placebo in subjects with non-alcoholic steatohepatitis
Trial phase: 2
Applicable to Sweden
Amendment originator:
 Local Trial Manager
Novo Nordisk Scandinavia AB, Sweden
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
2 of 17
Table of Contents   
Page
Table of Contents........................................................................................................................................2
Table of Figures ..........................................................................................................................................2
Table of Tables............................................................................................................................................3
1
Introduction including rationale for the protocol amendment...........................................................4
2
Changes ................................................................................................................................................6
2.1
List of abbreviations..................................................................................................................6
2.2
Section 1 Summary ...................................................................................................................6
2.3
Section 2 Flowchart...................................................................................................................6
2.4
Section 4.2.1 Primary endpoint..................................................................................................6
2.5
Section 4.2.2.2 Supportive secondary safety endpoints ..............................................................7
2.6
Section 5.1 Type of trial............................................................................................................7
2.7
Section 5.3 Treatment of subjects..............................................................................................7
2.8
Section 5.3.1 Subjects treated with basal insulin........................................................................8
2.9
New section: 5.3.2 Treatment of subjects with poorly controlled glycaemia...............................8
2.10
Section 5.3.23 Subjects developing type 2 diabetes....................................................................9
2.11
Section 6.1 Number of subjects .................................................................................................9
2.12
Section 6.2 Inclusion criteria .....................................................................................................9
2.13
Section 6.3 Exclusion criteria ....................................................................................................9
2.14
Section 6.4 Criteria for premature discontinuation of trial product ...........................................12
2.15
Section 7 Milestones ...............................................................................................................12
2.16
Section 8.1.1 Screening, Re-screening and screen failures .......................................................12
2.17
New section: 8.1.2 Optional pre-screening (Not applicable for Sweden)..................................12
2.18
Section 8.1.34 Fasting visits ....................................................................................................13
2.19
Section 8.3.1 Liver biopsy.......................................................................................................13
2.20
Section 8.3.1.1 Central pathologist evaluation .........................................................................14
2.21
Section 8.3.2 Fibroscan measurements ....................................................................................14
2.22
Section 8.3.3.3 Body mass index .............................................................................................14
2.23
Section 8.5 Laboratory assessments.........................................................................................14
2.24
Section 8.5.3.1 Biochemistry...................................................................................................14
2.25
Section 8.5.3.2 Hormones........................................................................................................15
2.26
Section 17.4.1.2 Safety endpoints............................................................................................15
2.27
Section 18.1 Benefit-risk assessment of the trial ......................................................................15
2.28
Section 18.2 Informed consent ................................................................................................16
3
References ..........................................................................................................................................17
Table of Figures   
Page
No table of figures entries found.
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Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
3 of 17
Table of Tables   
Page
No table of figures entries found.
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Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
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1
Introduction including rationale for the protocol amendment
The below changes to liver biopsy assessment, bilirubin, HbA1c and BMI are implemented in the 
trial protocol based on detailed and continuous monitoring of the progress of the current trial, in 
addition to scientific developments in the field of non-alcoholic steatohepatitis (NASH). This 
combined with the continuous accumulation of semaglutide safety and efficacy data is the reason 
behind this protocol amendment. The changes are in accordance with advice from external NASH 
experts and recommendations from the Liver Forum (forum for collaboration between academia, 
industry and Health Authorities on clinical development in NASH). As the field of NASH is 
quickly evolving, including an increasing number of clinical trials, the described changes should 
also lead to an improvement in the rate of recruitment.
This local Swedish protocol amendment is following the global protocol amendment that was 
submitted to the authorities in Sweden earlier. Medical Product Agency did not agree with two of 
changes (TSH in screening and pre-screening process) and the amendment was rejected. These 
changes are changed back to their original now in this amendment. The other changes that were not 
reason for rejection by the Medical Product Agency are included as it was submitted earlier.
Number of subjects to be screened:
The expected screen failure rate and hence planned number of screened subjects are updated based 
on actual numbers seen in the trial. 
Eligibility criteria: 
Inclusion criterion 5: This criterion is rephrased to emphasize that eligibility is solely based on
central pathologist assessment of the baseline liver biopsy. This will not change how patients are
entering the trial and is in line with eligibility criteria for ongoing global NASH trials1, 2.
Exclusion criterion 5: Gilbert’s syndrome is a common form of unconjugated hyperbilirubinemia 
caused by an inherited deficiency in the bilirubin-conjugating enzyme. The condition is highly 
prevalent ranging from 3% to 12% of the population depending on the mode of diagnosis3. A small 
study of patients with NASH reported a prevalence of Gilbert’s syndrome of 7.5%4. Gilbert’s 
syndrome is, however, regarded a benign trait, and clinical recognition is often incidental to routine 
laboratory investigations, revealing an elevated level of total bilirubin. Thus, exclusion criterion 5 
will be changed to allow subjects into the trial with total bilirubin level >1.5 mg/dL if conjugated 
bilirubin is <1.5×upper limit of normal. 
Exclusion criterion 10 and 12: Exclusion criterion 10 is being amended to allow patients in with 
HbA1c of up to 10% to allow a slightly broader population, including more patients with type 2 
diabetes to enter the trial. Given that the current trial is placebo-controlled and of long duration, the 
responsibility of the investigator to ensure glycaemic control of the patients will be reinforced by 
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Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
5 of 17
adding guidance to treatment of patients with type 2 diabetes with poorly controlled glycaemia to 
the protocol. 
A significant proportion of patients with NASH and type 2 diabetes is treated with bolus insulin. To
allow for these patients to enter the trial, exclusion criterion 12 will be deleted. In order to mitigate 
the risk of hypoglycaemia, the protocol is amended to instruct the total daily insulin dose to be 
reduced by 30% at baseline in subjects with HbA1c I 8.0% at the screening visit. 
Exclusion criterion 15: Exclusion criterion 15 will be amended by removing the upper limit of 
BMI in order to allow patients with a BMI J45 kg/m2 to be included in the trial.
The prevalence of non-alcoholic fatty liver disease (NAFLD) and NASH increases with increasing
body mass index (BMI). An analysis of liver histology obtained from liver donors, autopsy  
findings, and clinical liver biopsies suggests that the prevalence rates of steatosis and NASH are 
approximately 15% and 3%, 65% and 20% and 85% and 40% respectively in non-obese, BMI 30.0–
39.9 kg/m2 and BMI J40 kg/m2 subjects5. 
The recently completed semaglutide obesity trial, trial NN9536-4153, which included patients with 
a BMI > 30 kg/m2 and investigated the same dose range as the current trial (0.05-0.4 mg/day), 
reported that the semaglutide safety profile was well-tolerated, with the most common adverse 
events being gastrointestinal (GI) adverse events6. This is in line with the previous experience with 
semaglutide7. 
Subjects can be re-screened if they have previously screen failed solely due to lab parameters
included in the eligibility criteria that are changed in this amendment (HbA1c, total bilirubin).
Footnote to primary end-point: 
The first footnote (*) of the primary endpoint has been updated to clarify that resolution of NASH is 
defined as “no more than mild residual inflammatory cells (0 – 1) and no ballooning (0)”. This is in 
line with the Health Authority recommendation (FDA and EMA) as communicated through the 
Liver Forum11.
Other minor changes and clarifications have been included.
Since new protocol sections are added, the numbering for some protocol sections will change 
throughout the updated protocol once the amendment is implemented.
In this protocol amendment:
!
Any new text is written in italics.
!
Any text deleted from the protocol is written using strike through.
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Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
Page:
6 of 17
2
Changes
2.1
List of abbreviations
TSH (Applicable for Sweden)
thyroid-stimulating hormone 
2.2
Section 1 Summary
Trial population
A total of 372 subjects are planned to be randomised. Based on an assumption of a 6550% 
screening failure rate, 1063744 subjects are planned to be screened.
Key inclusion criteria
!
Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability
for the trial except for protocol described pre-screening activities which require a separate 
informed consent.
Applicable for Sweden: 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.
!
Local histological diagnosis of NASH followed by histological confirmation of NASH 
based on central pathologist evaluation of Histologic evidence of NASH based on central 
pathologist evaluation of a liver biopsy obtained up to 21 weeks before screening.
Key exclusion criteria
•
HbA1c > 910 % at screening.
•
Body Mass Index (BMI) I 25.0 or J 45.0 kg/m2 at the screening visit (visit 1).
2.3
Section 2 Flowchart
TSH (Sweden only)
Attend visit fasting: Added x for visit 10
16) All visit 2 assessments must be carried out prior to first trial product dose
2.4
Section 4.2.1 Primary endpoint
!
NASH resolution* without worsening of fibrosis** after 72 weeks (yes/no)
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Local Protocol Amendment_SE
Date:
09 January 2018
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No.: 2016-000685-39
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*) Resolution of NASH defined by the NASH Clinical research network (CRN) as “no more than 
mild residual inflammatory cells (0 – 1) and no ballooning (0)” based on comprehensive 
interpretation by two independent pathologists (central reading) blinded to treatment allocation.
*) Resolution of NASH as defined by comprehensive interpretation by two independent 
pathologists (central reading) blinded to treatment allocation and with complete resolution captured 
by terms such as “no fatty liver disease” or “simple steatosis or isolated steatosis” and defined by 
the NASH Clinical research network (CRN) as “no more than mild residual inflammatory cells and 
no ballooning”
**) worsening defined by an increase of at least one stage of the Kleiner fibrosis classification 
2.5
Section 4.2.2.2 Supportive secondary safety endpoints
Change from baseline to 72 weeks in:
!
Pulse
!
ECG
!
Physical examination
!
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
!
Biochemistry (creatinine, estimated glomerular filtration rate (eGFR), creatinine 
phosphokinase, urea, bilirubin (total), alkaline phosphatase, ferritin, sodium, potassium, 
calcium (total), amylase, lipase)
!
Hormones (calcitonin)
2.6
Section 5.1 Type of trial
A planned total of 372 subjects will be randomised. Based on an assumption of a 6550% screening 
failure rate, 1063744 subjects will be screened. 
2.7
Section 5.3 Treatment of subjects
The conversion table below shows the connection between each volume matched dose level and the 
value shown in the display on the NovoPen® 4. Subjects must be instructed to administer the value 
shown in the display.
Injections may be administered in the thigh, abdomen or upper arm, at any time of day irrespective 
of meals. The injections should be administered at approximately the same time of day during the 
trial.
Throughout the trial subjects cannot initiate treatment with: 
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!
GLP-1 RAs (other than trial product), or SGLT-2 inhibitors and bolus (fast acting) insulin
!
Vitamin E or pioglitazone
!
Drugs with potential effect on steatosis (corticosteroids (topical, and inhaled and short term 
systemic use (8 14 days) are allowed), methotrexate, tamoxifen, valproic acid, amiodarone 
or tetracycline)
!
Drugs that could promote weight loss (orlistat, zonisamide, topiramate, phentermine, 
lorcaserin, bupropion and naltrexone alone or in combination with any other medication that 
could promote weight loss).
2.8
Section 5.3.1 Subjects treated with basal insulin
The following basal insulins are allowed:
!
Insulin glargine
!
Insulin detemir
!
Insulin degludec
!
Neutral protamine Hagedorn (NPH) insulin
Subjects treated with basal insulin:
Throughout the trial, insulin dose should be titrated at the discretion of the investigator. For the 
individual subject, increasing the insulin dose before two weeks after the end of the final dose-
escalation should be avoided, unless required to control acute hyperglycaemia and acute diabetic 
complications. 
Subjects treated with basal insulin and with HbA1c 9 8.0 % at screening:
Subjects with HbA1c I 8.0 % at screening (visit 1) should have the total daily insulin dose reduced 
by 30 % at start of trial product treatment to limit the potential risk of hypoglycaemia induced by 
the combination of insulin and semaglutide. 
2.9
New section: 5.3.2 Treatment of subjects with poorly controlled glycaemia
Subjects with type 2 diabetes and with persistent and unacceptable hyperglycaemia should be 
offered treatment intensification. If any HbA1c value reported by central laboratory exceeds 9% 
from at least 4 weeks after end of dose escalation, the subject should be offered treatment 
intensification at the discretion of the investigator. However, the following treatment types must not 
be used: GLP-1 RAs (other than trial product) and SGLT-2 inhibitors. Subjects that are started on 
treatment intensification medication should continue to follow the protocol specified visit schedule 
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and stay on trial product treatment unless the investigator judges that this will jeopardise the safety 
of the subject. 
All treatment intensification medication given should be documented in medical records and 
reported in the eCRF. Treatment intensification medication will not be provided nor reimbursed by 
Novo Nordisk.
2.10
Section 5.3.23 Subjects developing type 2 diabetes
Subjects who are diagnosed with T2D as a result of a screening procedure or are diagnosed with 
T2D during the trial should receive diabetes treatment at the discretion of the investigator. However 
the following treatments must not be used: GLP-1 RAs (other than trial product), and SGLT-2 
inhibitors and bolus (fast acting) insulin.
5.3.34 Missed dose
5.3.45 Nutritional and physical activity counselling
2.11
Section 6.1 Number of subjects
Number of subjects planned to be screened: 744 1063.
Number of subjects planned to be randomised: 372 (50 65% screen failure rate).
2.12
Section 6.2 Inclusion criteria
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 except for protocol described pre-screening activities which require a separate informed 
consent.
Applicable for Sweden: 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.
5. Local histological diagnosis of NASH followed by histological confirmation of NASH based on 
central pathologist evaluation of Histologic evidence of NASH based on central pathologist 
evaluation of a liver biopsy obtained up to 21 weeks before screening.
2.13
Section 6.3 Exclusion criteria
5. Elevated total bilirubin (> 1.5 mg/dL) at screening. Total bilirubin level >1.5 mg/dL is allowed if 
conjugated bilirubin is <1.5×UNL.
6. Prothrombin time International normalized ratio (INR) of prothrombin time > 1.3 at screening.
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10. HbA1c > 910 % at screening.
12. Treatment with bolus (fast acting) insulin in the period from 28 days prior to screening or if 
recent biopsy is used from 28 days prior to baseline liver biopsy until time of screening.
1312. Treatment with other glucose lowering agent(s) (apart from GLP-1 RAs or SGLT-2 inhibitors
what is listed in exclusion criterion 11 and 12) not stable in the period from 28 days prior to 
screening or if recent biopsy is used from 28 days prior to baseline liver biopsy until time of 
screening. Changes without clinical relevance in the opinion of the investigator are allowed.
1413. Diagnosis of type 1 diabetes according to medical records.
Obesity related:
1514. Body Mass Index (BMI) I 25.0 or J 45.0 kg/m2 at the screening visit (visit 1).
16. TSH > 6 mIU/L or < 0.4 mIU/L at screening.
1715. Treatment with orlistat, zonisamide, topiramate, phentermine, lorcaserin, bupropion and 
naltrexone alone or in combination or any other medication that could promote weight loss in the 
opinion of the investigator in the period from 28 days prior to screening or if recent biopsy is used 
from 28 days prior to baseline liver biopsy until time of screening.
1816. Participation in an organised weight reduction program (e.g. WeightWatchers®) in the period 
from 28 days prior to screening or if recent biopsy is used from 28 days prior to baseline liver 
biopsy until time of screening.
1917. Previous surgical treatment for obesity. However (1) liposuction and/or abdominoplasty if 
performed > 6 months before baseline liver biopsy is allowed or 2) lap banding where the band has 
been removed > 6 months before baseline liver biopsy is allowed 3) intragastric balloon where the 
balloon has been removed > 6 months before baseline liver biopsy is allowed.
General safety:
2018. For patients with type 2 diabetes only: Proliferative retinopathy or maculopathy requiring 
acute treatment verified by fundus photography or dilated fundoscopy performed within the past 90 
days prior to randomisation. 
2119. History or presence of pancreatitis (acute or chronic).
2220. Calcitonin J 50 ng/L at screening.
2321. Family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid 
carcinoma. Family is defined as a first degree relative.
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2422. Presence or history of malignant neoplasms within the past 5 years prior to the day of 
screening. Basal and squamous cell skin cancer and any carcinoma in-situ are allowed.
2523. Surgery scheduled for the trial duration period, except for minor surgical procedures, in the 
opinion of the investigator.
2624. Any condition which, in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol.
2725. Language barrier, mental incapacity, unwillingness or inability to adequately understand or 
comply with study procedures.
2826. Known or suspected hypersensitivity to trial product or related products.
2927. Previous participation in this trial. Participation is defined as randomisation.
3028. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening.
3129. Female who is pregnant, breast-feeding or intends to become pregnant or is of childbearing 
potential and not using an adequate contraceptive method (adequate contraceptive measures as
required by local regulation or practice).
For EU countries: The following contraceptive measures are considered adequate:
•
Combined estrogen and progestogen containing hormonal contraception associated with 
inhibition of ovulation:
o
oral
o
intravaginal
o
transdermal
•
Progestogen-only hormonal contraception associated with inhibition of ovulation :
o
oral
o
injectable
o
implantable
•
Placement of an 
o
intrauterine device (IUD) 
o
intrauterine hormone-releasing system ( IUS)
•
Bilateral tubal occlusion
•
Barrier methods of contraception (condom or occlusive cap with spermicidal 
foam/gel/film/cream/suppository) (not applicable for Belgium, Denmark, Finland, 
Greece, Spain, Sweden)
•
Vasectomised partner (where partner is sole partner of subject) (not applicable for 
Denmark)
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•
True sexual abstinence (not applicable for Denmark). Sexual abstinence is defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the subject.
3230. Renal impairment measured as estimated Glomerular Filtration Rate (eGFR) value of eGFR < 
30 ml/min/1.73 m2 as defined by Kidney Disease: Improving Global Outcomes (KDIGO).42
31. Applicable for Sweden: TSH > 6 mIU/L or < 0.4 mIU/L at screening.
2.14
Section 6.4 Criteria for premature discontinuation of trial product 
10. Treatment with other GLP-1 receptor agonists or, SGLT-2 inhibitors or bolus (fast acting) 
insulin 
2.15
Section 7 Milestones
Planned duration of recruitment period: 78 51 weeks
2.16
Section 8.1.1 Screening, Re-screening and screen failures
Informed consent must be obtained before any trial related activity, see section 18.2. Separate 
informed consent forms for long-term storage of human samples and genotyping are available and 
informed consent must be obtained before activities related to any of these are undertaken.
Additionally a separate informed consent form for optional pre-screening is available. This must be 
signed before any optional pre-screening activities are performed (see section 8.1.2).
Re-screening
Re-screening of screening failures is allowed only once within the limits of the recruitment period. 
However, re-screening is NOT allowed if the subject has failed one of the inclusion/exclusion 
criteria related to laboratory parameters (pathology and/or blood parameters histological NAS, 
NASH fibrosis stage, HBsAg, anti-HIV, HCV-RNA, AST, ALT, total bilirubin, INR, HbA1c, 
calcitonin or TSH). In the event of re-screening, a new informed consent must be obtained and a 
new subject number must be allocated. All assessments and laboratory samples must be repeated.
2.17
New section: 8.1.2 Optional pre-screening (Not applicable for Sweden)
The Investigator may, after obtaining separate informed consent, perform pre-screening of 
potential trial candidates. Pre-screening assessments include blood parameters and imaging
(except for imaging methods with radiation involved).The purpose of such assessments is to assess 
trial eligibility potential.
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Pre-screening assessments are not defined as trial-related procedures. Results of pre-screening 
assessments will not be collected in the trial database and will not be monitored. Concerns related 
to any pre-screening assessment must not be reported as an adverse event.  
Pre-screening assessments (blood parameters and imaging) performed after signature of the 
separate informed consent can be reimbursed by Novo Nordisk A/S.
8.1.23 AUDIT questionnaire
2.18
Section 8.1.34 Fasting visits
Subjects must attend some of the most clinic visits in a fasting state (see section 2).
Fasting is defined as at least eight hours without food or liquids, except for water. Trial product and 
any medication which should be taken with or after a meal should be withheld on the day of the 
visit until blood sampling has been performed. If the subject is not fasting as required, the subject 
must be called in for a new visit within the visit window to have the fasting procedures done. 
Fasting procedures include body weight, Fibroscan® measurements and blood sampling (FPG, 
fasting insulin, fasting glucagon, calcitonin and lipids (Total cholesterol, free fatty acids, HDL 
cholesterol, LDL cholesterol, triglycerides, VLDL cholesterol)).
Prior to Fibroscan® measurements, only two hours of fasting is required. 
At visit 19, the subject must be fasting for two hours prior to the anti-semaglutide antibody 
sampling (see section 8.5.3.7).
8.1.45 Missed visits
8.1.56 Premature discontinuation of trial product
8.1.67 Withdrawn subjects
8.1.78 Subject training
2.19
Section 8.3.1 Liver biopsy
To be randomised, subjects must have histologic evidence of NASH a local histological diagnosis of 
NASH followed by histological confirmation of NASH diagnosis based on central pathologist 
evaluation of a liver biopsy. Confirmation of Histologic evidence of NASH diagnosis can be based 
on a liver biopsy obtained up to 21 weeks prior to screening. For subjects with no historical liver 
biopsy within 21 weeks prior to screening, a liver biopsy must be performed during the screening 
period. The local NASH diagnosis and the confirmation The histologic evidence of NASH diagnosis 
by central pathologist evaluation of the liver biopsy must be available prior to randomisation of the 
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subject. The local NASH diagnosis and the confirmation of NASH diagnosis by central pathologist 
evaluation can be done on the same liver biopsy sample.
2.20
Section 8.3.1.1 Central pathologist evaluation
The histologic evidence of NASH diagnosis and histology based scores will be centrally assessed by 
two independent pathologists with expertise and experience in NASH.
2.21
Section 8.3.2 Fibroscan measurements
Liver stiffness
At sites with Fibroscan® equipment available, measurements of liver stiffness must be performed at 
the specified visits (section 2). Fibroscan measurements can be performed up to 2 weeks prior to 
each visit.
Liver steatosis
At sites with Fibroscan® equipment available, measurements of liver steatosis must be performed at 
the specified visits (section 2). Fibroscan measurements can be performed up to 2 weeks prior to 
each visit.
2.22
Section 8.3.3.3 Body mass index
Body mass index will be calculated by the eCRF from visit 1 height data and must be in accordance 
with exclusion criterion 1514.
2.23
Section 8.5 Laboratory assessments
The laboratory analyses will be performed by a central laboratory except for laboratory analyses for 
pre-screening, analysis of anti-semaglutide antibodies and semaglutide plasma concentration 
analysis and some exploratory biomarkers which will be performed at specialised laboratories. 
2.24
Section 8.5.3.1 Biochemistry
!
Bilirubin, total
!
Bilirubin, conjugated
!
Calcium
!
Creatinine phosphokinase
!
Creatinine
!
eGFR (per CKD-EPI formula)
!
Lipase
!
Potassium
!
Sodium
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!
Alkaline phosphatase
!
Amylase
!
Albumin
!
Ferritin
!
Urea
!
MELD score
2.25
Section 8.5.3.2 Hormones
!
Calcitonin (see Appendix A)
!
For Sweden: Thyroid-stimulating hormone (TSH)
2.26
Section 17.4.1.2 Safety endpoints
!
Change from baseline to 72 weeks in:
o
Pulse
o
ECG
o
Physical examination
o
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
o
Biochemistry (creatinine, eGFR, creatinine phosphokinase, urea, bilirubin (total), 
alkaline phosphatase, ferritin, sodium, potassium, calcium (total), amylase, lipase)
o
Hormones (calcitonin)
2.27
Section 18.1 Benefit-risk assessment of the trial
Other safety considerations
Teratogenicity (nonclinical embryo-foetal toxicity)
Semaglutide has been concluded teratogenic in rats. This effect is regarded to be caused by 
impairment of nutrient supply to the embryo across the inverted yolk sac with placental function. As 
the yolk sac does not play such a role for nutrition of the embryo in humans, this effect is unlikely 
to be relevant for humans. However, as a precaution subjects fulfilling exclusion criterion 3129 will 
be excluded from trial participation. Furthermore, as specified in the flowchart, female subjects 
included in the trial will have pregnancy testing performed frequently during the entire duration of 
the trial. 
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2.28
Section 18.2 Informed consent
Separate informed consent forms for long-term storage of human samples and genotyping are 
available and informed consent must be obtained before activities related to any of these are 
undertaken.
Additionally a separate informed consent form for optional pre-screening is available. This must be 
signed before any optional pre-screening activities are performed (see section 8.1.2).
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3
References
1.
Clinicaltrials.gov. Randomized Global Phase 3 Study to Evaluate the Impact on NASH With 
Fibrosis of Obeticholic Acid Treatment ( REGENERATE ) NCT02548351 [internet] 2015 
[cited 2017 10 Aug].
2.
Clinicaltrials.gov. Safety and Efficacy of Selonsertib in Adults With Nonalcoholic 
Steatohepatitis (NASH) and Bridging (F 3 ) Fibrosis ( STELLAR 3 ) 
NCT03053050 [internet] 2017 [cited 2017 10 Aug].
3.
Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert's syndrome and the risk of death: a 
population-based cohort study. J Gastroenterol Hepatol. 2013;28(10):1643-7.
4.
Duseja A, Das A, Das R, Dhiman RK, Chawla Y, Bhansali A. Unconjugated 
hyperbilirubinemia in nonalcoholic steatohepatitis--is it Gilbert's syndrome? Trop 
Gastroenterol. 2005;26(3):123-5.
5.
Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, 
metabolic, and clinical implications. Hepatology. 2010;51(2):679-89.
6.
Novo Nordisk A/S. Novo Nordisk reports up to 13.8% weight loss in people with obesity 
receiving semaglutide in phase 2 trial [internet] 2017 [cited 2017 10 Aug].
7.
Novo Nordisk A/S. Investigator's Brochure for s.c. Semaglutide (NN9535, NN9931, 
NN9536), Edition 12. 2017.
8.
(EASL) EAftSotL, (EASD) EAftSoD, (EASO) EAftSoO. EASL-EASD-EASO Clinical 
Practice Guidelines for the management of non-alcoholic fatty liver disease. Diabetologia. 
2016;59(6):1121-40.
9.
Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and 
management of non-alcoholic fatty liver disease: practice Guideline by the American 
Association for the Study of Liver Diseases, American College of Gastroenterology, and the 
American Gastroenterological Association. Hepatology. 2012;55(6):2005-23.
10.
Dowman JK, Tomlinson JW, Newsome PN. Systematic review: the diagnosis and staging of 
non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 
2011;33(5):525-40.
11.
Forum L. Liver Forum meeting 6, 18 Apr 2017 [internet] 2017 [cited 2017 10 Aug].
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SAP_001.pdf: 
Cover Page for Statistical Analysis Plan 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT02970942 
Sponsor trial ID: 
NN9931-4296 
Official title of study: 
Investigation of efficacy and safety of three dose levels of 
subcutaneous semaglutide once daily versus placebo in 
subjects with non-alcoholic steatohepatitis  
Document date: 
27 February 2020 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Semaglutide s.c.
Trial ID: NN9931 4296
Clinical Trial Report
Appendix 16.1.9
17 July 2020
1.0
Final
16.1.9 Documentation of statistical methods
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Statistical Analysis Plan
Date:
27 February 2020
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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Statistical Analysis Plan
NN9931-4296
Statistical Analysis Plan
Name: 
Department: Biostatistics Obesity & Metabolism 
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Redacted VWDWLVWLFDODQDO\VLVSODQ 
Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
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Table of contents   
Page
Table of contents.........................................................................................................................................2
Table of figures ...........................................................................................................................................3
Table of tables.............................................................................................................................................3
Version history............................................................................................................................................4
1
Introduction .........................................................................................................................................5
1.1
Objectives and endpoints...........................................................................................................5
1.1.1
Objectives................................................................................................................5
1.1.2
Endpoints.................................................................................................................5
1.2
Trial design...............................................................................................................................6
2
Statistical hypotheses ...........................................................................................................................8
3
Sample size determination.................................................................................................................10
4
Analysis sets .......................................................................................................................................10
5
Statistical analyses .............................................................................................................................11
5.1
General considerations ............................................................................................................11
5.2
Subject disposition..................................................................................................................12
5.3
Primary endpoint analyses.......................................................................................................12
5.3.1
Definition of endpoint............................................................................................12
5.3.2
Main analytical approach .......................................................................................12
5.3.3
Sensitivity analyses................................................................................................12
5.3.4
Supplementary analyses.........................................................................................14
5.4
Secondary endpoint analysis....................................................................................................15
5.4.1
Confirmatory secondary endpoint...........................................................................15
5.4.1.1
Definition of endpoint ......................................................................15
5.4.1.2
Main analytical approach..................................................................15
5.4.1.3
Sensitivity analysis...........................................................................15
5.4.1.4
Supplementary analysis....................................................................15
5.4.2
Supportive secondary endpoints.............................................................................15
5.4.2.1
Efficacy endpoints............................................................................15
5.4.2.2
Safety endpoints...............................................................................20
5.4.2.3
Pharmacokinetic endpoints...............................................................23
5.5
Exploratory endpoint analysis .................................................................................................23
5.6
Other safety analyses...............................................................................................................23
5.7
Other analyses.........................................................................................................................23
5.8
Interim analyses ......................................................................................................................23
6
Supporting documentation ................................................................................................................24
6.1
Appendix 1: List of abbreviations............................................................................................24
6.2
Appendix 2: Changes to protocol-planned analyses .................................................................26
7
References ..........................................................................................................................................28
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Statistical Analysis Plan
Date:
27 February 2020
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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Table of figures
Page
Figure 1–1 Trial design..............................................................................................................................7
Figure 2–1 Graph of test procedure..........................................................................................................9
Table of tables
Page
Table 1
SAP Version History Summary.................................................................................................4
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Statistical Analysis Plan
Date:
27 February 2020
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Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
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Version history
This Statistical Analysis Plan (SAP) for trial NN9931-4296 is based on the protocol version 5.0 
dated 09 March 2018. 
Table 1
SAP Version History Summary
SAP 
Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version
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Statistical Analysis Plan
Date:
27 February 2020
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Trial ID: NN9931-4296
Version:
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UTN: U1111-1179-7464
Status:
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1
Introduction
This SAP elaborates on the statistical analyses described in the protocol section 17. Changes to the  
protocol-planned analyses are documented in section 6.2, appendix 2. 
1.1
Objectives and endpoints
1.1.1
Objectives
Primary objective
To compare the effect of semaglutide subcutaneous (s.c.) once daily versus placebo on histological 
resolution of non-alcoholic steatohepatitis (NASH).
Secondary efficacy objectives
To investigate the dose-response relationship of three dose levels of semaglutide s.c. once daily (0.1 
mg/day, 0.2 mg/day and 0.4 mg/day) on histological resolution of NASH.
To compare the effects of semaglutide s.c. once daily to placebo on liver-related histological 
parameters and biomarkers of NASH disease.
To investigate the effects of semaglutide s.c. once daily versus placebo in subjects with NASH on:
1. Weight-related parameters
2. Glucose metabolism related parameters
3. Cardiovascular risk factors
4. Patient reported outcomes
Secondary safety objectives
To evaluate the safety and tolerability of three dose levels of semaglutide s.c. once daily in subjects 
with NASH.
1.1.2
Endpoints
Primary endpoint
NASH resolution* without worsening of fibrosis** after 72 weeks (yes/no)
*) Resolution of NASH defined by the NASH Clinical research network (CRN) as “no more than mild residual 
inflammatory cells (0 – 1) and no ballooning (0)” based on comprehensive interpretation by two independent 
pathologists (central reading) blinded to treatment allocation.
**) worsening defined by an increase of at least one stage of the Kleiner fibrosis classification 
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Statistical Analysis Plan
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Secondary endpoints
Confirmatory secondary endpoint
At least one stage of liver fibrosis improvement with no worsening of NASH after 72 weeks 
(yes/no) (worsening defined as an increase of at least one stage of either lobular inflammation or 
hepatocyte ballooning according to NASH CRN criteria).
Supportive secondary endpoints
See section 5.4.2.
1.2
Trial design
This is a 72-week, randomised, double-blind, placebo-controlled, six-armed, parallel group, multi-
centre, multi-national trial comparing once daily administration of semaglutide s.c. in three different 
doses (0.1 mg, 0.2 mg and 0.4 mg) with placebo in subjects with NASH.
A planned total of 288 subjects will be randomised. Based on an assumption of a 65% screening 
failure rate, 823 subjects will be screened. Subjects will be randomised in a 3:3:3:1:1:1 manner to 
receive daily dosing of semaglutide s.c. 0.1 mg, 0.2 mg, 0.4 mg or corresponding injection volumes 
of placebo once daily (for details see Figure 1–1). To avoid bias in the assessment of the different 
semaglutide doses, the trial will be double-blinded within dose levels. The dose levels will not be 
blinded between each other because of different dose escalations and different target doses and 
volumes required.  It is expected that 15% of subjects will withdraw from the trial or prematurely 
discontinue treatment with trial product. 
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Statistical Analysis Plan
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Figure 1–1
Trial design
Subjects in all treatment groups including placebo will receive nutritional and physical activity 
counselling by a member of the study team according to local site practice. 
The randomisation of subjects to treatment will be stratified in five groups as described in protocol 
section 5.2 and protocol section 11. 
The diagnosis of NASH as well as the histology based scores will be subject to central pathologist 
evaluation.
Subjects who prematurely discontinue the trial product treatment should continue with the 
originally scheduled site visits/contacts including a liver biopsy and final assessments 72 weeks 
after randomisation (visit 19A). However the following should not be done after visit 19 for 
subjects prematurely discontinuing trial product: Semaglutide plasma concentration, anti-
semaglutide antibody assessment, hypo reporting and handing out subject diaries.
Subjects who prematurely discontinue trial product treatment will continue to receive nutritional 
and physical exercise counselling throughout their trial participation.
The total trial duration for the individual subject will be up to 85 weeks (maximum).
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2
Statistical hypotheses
For the primary endpoint, NASH resolution without worsening in fibrosis after 72 weeks (yes/no), 
three confirmatory tests are planned to compare each dose level of semaglutide with placebo. Each 
comparison will test for superiority of semaglutide versus placebo, i.e. the null hypothesis of equal 
responder proportions will be tested against the alternative hypothesis of a higher proportion with 
semaglutide. Likewise, three confirmatory tests (one for each dose level of semaglutide vs. placebo) 
are planned for the confirmatory secondary histological endpoint, at least one stage of liver fibrosis 
improvement with no worsening of NASH after 72 weeks (yes/no). All six confirmatory tests will 
be performed on the subpopulation of subjects with fibrosis stage 2 or 3 at baseline, i.e. excluding 
subjects with fibrosis stage 1.
In order to control the family-wise type 1 error rate at 2.5% (for one-sided testing), the six 
confirmatory tests will be performed hierarchically in accordance to the graph in Figure 2–1. The 
graph defines a closed test procedure as described in Bretz et al 20091. The test procedure will start 
with the comparison of semaglutide 0.4 mg versus placebo on NASH resolution without worsening 
in fibrosis. If the test confirms superiority, the comparison of semaglutide 0.4 mg versus placebo 
will be performed on fibrosis improvement with no worsening of NASH. If this test confirms 
superiority, the comparison of semaglutide 0.2 mg versus placebo will be performed on NASH 
resolution without worsening in fibrosis. The procedure will continue by descending dose 
alternating between the two endpoints. In each case, the null hypothesis will be tested using a local 
one-sided significance level of 2.5% (equivalent of a two-sided level of 5%). If one of the tests fails 
to reject the null hypothesis, the test procedure will stop and no further conclusions will be made.
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Figure 2–1
Graph of test procedure
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3
Sample size determination
The sample size calculation is based on an aim to detect a difference in the primary endpoint 
between the highest semaglutide dose and the pooled placebo arm, using all subjects irrespective of 
baseline fibrosis stage (1-3). See protocol section 17.1 for details.
4
Analysis sets
The following analysis sets are defined in accordance with the ICH-E9 guidance2:
!
The full analysis set (FAS) includes all randomised subjects. Subjects in the FAS will 
contribute to the evaluation “as randomised”.
!
The safety analysis set (SAS) includes all subjects receiving at least one dose of randomised 
treatment. Subjects in the SAS will contribute to the evaluation “as treated”.
Observation periods
Data will be evaluated based on different observation periods which will be derived individually for 
each subject. The following two observation periods are defined:
!
In-trial: This period starts on the date of the randomisation visit and ends on the first of the 
following dates (both inclusive):
a) follow-up visit (end-of-trial visit)
b) withdrawal of consent
c) last contact with subject (for subjects lost to follow-up)
d) death
!
On-treatment: For evaluation of adverse events (AEs) and hypoglycaemic episodes, this 
period starts on the date of first administration of trial product and ends on the date of 
whatever comes first of: a) last dose of trial product + 49 days (7 half-lives of semaglutide)
or b) end of the in-trial period. For evaluation of all other data, the period ends at the date of 
the last dose of trial product +7 days. 
The statistical analyses of the efficacy endpoints will primarily be based on the in-trial period. The 
on-treatment period is used for some supportive efficacy analyses and all statistical analyses of 
safety endpoints. Summary statistics will in general be presented for both observation periods.
Data collected after the observation period in question will be excluded from any summary or 
analysis based on that observation period.
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Statistical Analysis Plan
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Version:
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5
Statistical analyses
5.1
General considerations
The FAS will be used in the analysis of the efficacy endpoints whereas the SAS will be used for the 
safety endpoints (see the definition of the sets in section 4). If not otherwise specified, analyses for 
the primary and confirmatory secondary endpoints will be made on the subpopulation of subjects 
with fibrosis stage 2 or 3 at baseline, whereas analyses for the supportive secondary endpoints will 
be made on all subjects in the analysis sets.
The estimand addressing the primary objective is defined as the de-facto (effectiveness) treatment 
effect on NASH resolution without worsening in fibrosis for all randomised subjects after 72 weeks. 
All post-baseline scheduled visit data will be included in the statistical analysis, including data 
collected after discontinuation of trial product. The chosen estimand assesses the difference in 
resolution of NASH in a future population that results from initiating treatment with semaglutide as 
compared to placebo. Generalisation of this estimand depends among other things on the extent to 
which treatment adherence in this trial reflects clinical practice.
If not otherwise specified, the three different placebo arms will be pooled into one placebo arm in 
the statistical analyses. The pooling is based on the assumption that there is no substantial effect of 
different placebo volumes on the efficacy and safety endpoints. The validity of this assumption will 
be checked for the primary endpoint and treatment-emergent adverse events by evaluating 
descriptive statistics where each placebo arm is presented separately. In addition, the assumption 
will be evaluated based on estimates from a supportive analysis of the primary endpoint (see section 
5.3.4). 
The statistical analyses will in general consist of the following three pairwise treatment 
comparisons:
!
semaglutide 0.4 mg versus placebo
!
semaglutide 0.2 mg versus placebo
!
semaglutide 0.1 mg versus placebo
The results of the comparisons will be presented as estimated treatment contrasts together with two-
sided 95% confidence intervals and p-values corresponding to two-sided tests of no difference. For 
confirmatory tests of superiority, one-sided p-values will be used. The issue of multiple testing will 
be addressed for the primary and confirmatory secondary endpoints (see section 2) but not for any 
of the supportive secondary endpoints.
The baseline measurement is defined as the latest available measurement at or prior to the 
randomisation visit. An exception is made for identifying abnormal laboratory findings (including 
ALT, AST, GGT, bilirubin and INR) in which case the baseline value is defined as the mean of the 
available measurements at the screening and randomisation visits.
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Statistical Analysis Plan
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Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
5.2
Subject disposition
The number of subjects in the analysis sets will be displayed as well as number of subjects in 
categories defined by end of treatment status (completed treatment or prematurely discontinued 
treatment, primary reason for discontinuation) and end of trial status (completed trial or was 
withdrawn from trial, primary reason for withdrawal, presence of biopsy).
5.3
Primary endpoint analyses
5.3.1
Definition of endpoint
The primary endpoint is the binary outcome NASH resolution without worsening in fibrosis after 
72 weeks (yes/no). NASH resolution is derived from the scores given by the pathologists and is 
defined as lobular inflammation score M1 and hepatocyte ballooning score 0. Worsening in fibrosis 
is defined as an increase of at least one stage of the Kleiner fibrosis classification.
5.3.2
Main analytical approach
The primary analysis will be based on the Cochran-Mantel-Haenszel (CMH) test3 which will be 
performed separately for the comparisons between each of the semaglutide arms and placebo. The 
test will adjust for baseline diabetes status (with or without T2D) and baseline fibrosis stage (F2 or 
F3). The response data will consist of the outcomes of the week 72 biopsy including assessments 
taken after premature discontinuation of trial product. Missing response data will be imputed as no 
resolution of NASH. This approach does not rely on an assumption of missing at random and 
should be considered conservative for estimating the treatment effect. 
The exact one-sided p-value will be calculated for testing superiority. The two-sided p-value will be 
calculated as two times the one-sided p-value. Besides the p-values, the common odds ratio will be 
estimated together with an exact 95% confidence interval using the Mantel-Haenszel estimator 
associated with the CMH test.
5.3.3
Sensitivity analyses
To investigate the sensitivity of the results of the primary analysis with regard to the handling of 
missing data, the following four sensitivity analyses will be performed:
!
Analysis using imputation based on treatment adherence: An analysis based on the same 
type of non-parametric method as for the primary analysis but with missing data handled by 
a multiple imputation (MI) method which assumes that the unobserved outcomes are well 
described by the observed outcomes from subjects who at week 72 are similar in terms of 
treatment adherence. This will be done as follows:
1. Missing data are imputed by sampling with replacement from the empirical 
distribution of observed outcomes separately within the 8 groups of subjects defined 
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by randomised treatment arm and whether subjects complete the 72-week treatment 
or not.  If a group completely lacks observed outcomes, missing data within this 
group will be imputed as no resolution of NASH. Multiple (1000) replicates of a 
complete data set are generated in this way.
2. For each complete data set, the log odds ratios are estimated using the same method 
as in the primary analysis together with the asymptotic standard errors.
3. The estimates and standard errors for the 1000 complete data sets are pooled using 
Rubin’s rule4:
 = 1
	 
 


,
 = 1
	 
 



+ 1 + 1
	 
1
	  1 
(  )


,
where mi and SEi are the estimated log odds ratios and standard errors for the N = 
1000 data sets, and mMI  and SEMI are the pooled estimates. From mMI and SEMI, the 
95% confidence intervals for the odds ratios and associated p-values are calculated.
This analysis differs from the primary analysis in that it assumes that subjects with missing 
week 72 data have the same chances of NASH resolution as subjects with week 72 data in 
the same treatment group, accounting for whether they completed or discontinued the 
randomised treatment. This is a less conservative assumption than the one used in the 
primary analysis since it includes the possibility that subjects with missing week 72 data 
may have NASH resolution. The analysis intends to address missing data relative to what 
the measurements would have been had the measurements been taken.
!
Analysis using imputation based on unconditional reference: An analysis based on the same 
type of non-parametric method as for the primary analysis but with missing data handled by 
an MI method which assumes that the unobserved outcomes are well described by the 
observed outcomes of the subjects in the placebo arm with similar baseline characteristics. 
The imputation will be done by random sampling of observed outcomes from subjects with 
the same baseline diabetes status and baseline fibrosis stage. 1000 replicates of a complete 
data set will be generated that will then be analysed in the same way as in the MI analysis 
based on treatment adherence. This analysis differs from the primary analysis in that it 
assumes that subjects with missing week 72 data have the same chances of NASH resolution 
as subjects with week 72 data in the placebo group. If there are more missing week 72 data 
in the semaglutide group than in the placebo group, this analysis is less conservative than 
the primary analysis and probably gives better estimate of the treatment effect. Compared to 
the first sensitivity analysis, this analysis is more conservative since it assumes that subjects 
with missing week 72 data in the semaglutide group have the same chance of NASH 
resolution as subjects in the placebo group.
!
Complete case in-trial analysis: The same as the primary analysis but where subjects with 
missing week 72 data are excluded from the analysis.
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!
Complete case on-treatment analysis: The same as the primary analysis but where subjects 
with missing week 72 data or for whom the data were collected after the on-treatment period 
are excluded from the analysis. 
The two complete case analyses are included as benchmarks. They are not based on the 
randomisation principle and do not estimate any causal effect of semaglutide treatment. The results 
are expected to be biased in favour of semaglutide and must be interpreted with extreme caution.
The adjustment for covariates in the primary analysis does not exactly match the stratification used 
for the randomisation. The rationale is that it will not be possible to adjust for region (Japanese or 
non-Japanese) and, at the same time, adjust for diabetes status and baseline fibrosis stage within the 
Japanese group due to small sample sizes. Adjustment for region is not expected to influence the 
overall results but is included in the stratification to facilitate an evaluation of consistency of 
treatment effect between the entire population and Japanese subjects. Region has therefore been 
excluded from the primary analysis. However, a CMH test stratified according to the five strata 
used for the randomisation will be performed as a sensitivity analysis.
Adjustment for baseline body weight as a continuous covariate may potentially give more precise 
estimates of the treatment effects. To investigate the influence of such an adjustment, a sensitivity 
analysis will be performed using a logistic regression model which includes treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline 
body weight as a covariate.
5.3.4
Supplementary analyses
Supportive analyses
As a supportive analysis, the main analytical approach will be repeated including all subjects 
irrespective of baseline fibrosis stage. The test will adjust for baseline diabetes status and baseline 
fibrosis stage as a three-level factor (F1, F2 or F3).
As part of an evaluation of the appropriateness of pooling the three placebo arms, a supportive 
analysis will be performed using the same CMH test as in the primary analysis but without pooling 
the placebo arms. Each semaglutide arm will instead be compared with the placebo arm which 
received the same injection volume. All subjects irrespective of baseline fibrosis stage will be 
included in this analysis.
Exploratory analysis
The dose-response relationship with respect to the primary endpoint will be further explored by 
fitting a modified logistic regression model with baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and the log-transformed dose level and baseline body 
weight as covariates. The model may be expressed as
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 =  +
(  )
 +  89Xi
where is the probability of NASH resolution for subject i, and  are the asymptotic 
probabilities of NASH resolution at zero and infinite dose levels, respectively, and 89Xi is the linear 
prediction function of factors and covariates. The response in the placebo arm will be included in 
the analysis to help estimate . If the model does not describe the dose-response relationship well 
or if there are convergence problems, a different approximation may be investigated. All subjects 
irrespective of baseline fibrosis stage will be included in this analysis.
5.4
Secondary endpoint analysis
5.4.1
Confirmatory secondary endpoint
5.4.1.1
Definition of endpoint
The secondary confirmatory endpoint is a binary outcome defined as at least one stage of liver 
fibrosis improvement with no worsening of NASH after 72 weeks (yes/no). Worsening of NASH is 
defined as an increase of at least one point in either lobular inflammation score or hepatocyte 
ballooning score. 
5.4.1.2
Main analytical approach
The main analysis will be the same as for the primary endpoint, i.e. a CMH test adjusted for 
baseline diabetes status and baseline fibrosis stage. Missing week 72 data will be imputed as no 
improvement in fibrosis.
5.4.1.3
Sensitivity analysis
The analysis using imputation based on unconditional reference will be performed in the same way 
as for the primary endpoint.
5.4.1.4
Supplementary analysis
The main analytical approach will be repeated including all subjects irrespective of baseline fibrosis 
stage.
5.4.2
Supportive secondary endpoints
5.4.2.1
Efficacy endpoints
Analyses will be performed for the change from baseline to week 72 in the following histological 
feature scores: 
!
Total NAS (0-8) and each of the components:
o
Steatosis (0-3)
o
Lobular inflammation (0-3)
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Statistical Analysis Plan
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o
Hepatocyte ballooning (0-2)
!
Stage of fibrosis according to the Kleiner fibrosis classification (0-4)
!
Activity component of SAF score (0-4)
The activity component of the SAF score is defined as the unweighted sum of hepatocyte 
ballooning and lobular inflammation. The definition of the lobular inflammation score is modified 
in this calculation so that the scores 2 and 3 on the original scale are merged to a score 2. The 
possible range of the sum is thus 0 to 4. For all scores, a higher value indicates a more severe state 
of disease. 
The histological feature scores will be analysed by an ordered logistic regression model (also 
known as a proportional odds model) with the score at week 72 as response; treatment, baseline 
diabetes status, baseline fibrosis stage, diabetes-by-fibrosis interaction and corresponding baseline 
score as factors; and baseline body weight as a covariate. The analyses will be based on the in-trial 
period and missing week 72 data will be imputed as no change from baseline in agreement with the 
analyses of the binary histological endpoints. The results will be presented as an estimate of the 
cumulative odds ratio for each treatment comparison together with the associated 95% confidence 
intervals and p-values.
Biomarkers of NASH disease
Analyses will be performed for the change from baseline to week 72 in the following biomarkers 
for NASH disease:
!
Algorithms
o
Fibrosis-4 (Fib-4) score 
o
NAFLD Fibrosis Score (NFS)
!
Blood samples
o
Liver enzymes 

Alanine aminotransferase (ALT)

Aspartate aminotransferase (AST)

Gamma glutamyltransferase (GGT)
o
Liver synthesis function

Albumin 

International normalized ratio (INR)
o
Exploratory biomarkers

Enhanced liver fibrosis (ELF) test

Cytokeratin 18 (CK-18) fragments (M30 and M65 assays)

microRNA 122 (miR-122)

Interleukin-1 receptor (IL-1R) antagonist 

Monocyte chemoattractant protein 1 (MCP-1)

Fibroblast growth factor 21 (FGF-21)
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!
Imaging
o
Liver stiffness
o
Controlled attenuation parameter (CAP) (liver steatosis)
The Fib-4 score will be derived according to the formula5: 
Fib-4 =
Age (years) × AST (U/L)
Thrombocyte count (109/L) × "ALT (U/L)
The derivation will be performed at each visit where ALT, AST and thrombocyte count have been 
assessed. If any of the three laboratory parameters is missing at a specific visit, the Fib-4 score will 
be considered missing as well.  
The NAFLD Fibrosis Score will be derived according to the linear regression formula6:
NFS = 1.675 + 0.037 × Age (years) + 0.094 × BMI (kg/m2) + 1.13
× Hyperglycaemia (yes/no) + 0.99 × AST/ALT  0.013
× Thrombocyte count (109/L)  0.66 × Albumin (g/dL)
Hyperglycaemia (yes/no) is a binary variable defined as 1 if FPG R 6.1 mmol/L (110 mg/dL) at the 
corresponding visit of assessment or the subject has been diagnosed with T2D at screening; 
otherwise, the variable is defined as 0. NFS will be derived at each visit where body weight, FPG, 
ALT, AST, thrombocyte count and albumin have been assessed.  
The ELF discriminant score will be derived as a log-linear combination of the markers hyaluronic 
acid (HA), amino-terminal propeptide of type III collagen (PIIINP) and tissue inhibitor of 
metalloproteinase 1 (TIMP1). The derivation will be performed at the central laboratory according 
to the instructions of the equipment manufacturer.
Analyses of liver stiffness and CAP (liver steatosis) will only be applicable to sites where these 
assessments were possible. Subjects at sites which did not have capability to assess liver stiffness or 
CAP (liver steatosis) will be excluded from the corresponding analysis.
All biomarkers except for NFS, ELF and CAP (liver steatosis) will be logarithmically transformed 
before the statistical analysis. The treatment differences will subsequently be back-transformed to 
the original scale and expressed as treatment ratios.
The main analysis of each of the biomarkers will be analysis of covariance (ANCOVA) with 
missing data handled by unconditional reference-based imputation. This will be done as follows:
1. An ANCOVA model with baseline diabetes status, baseline fibrosis stage and diabetes-by-
fibrosis interaction as factors and baseline body weight and baseline value of the 
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Statistical Analysis Plan
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corresponding biomarker as covariates is fitted to the change from baseline to 72 weeks for 
the placebo group only. 
2. 1000 sets of values of the model parameters are drawn from the posterior distribution. For 
each replicated set of parameter values, the model is used to generate a complete data set by 
imputing missing values at 72 weeks for subjects in all treatment groups based on their 
baseline diabetes status, baseline fibrosis stage, baseline body weight and baseline value of 
the corresponding biomarker.
3. For each complete data set, the change from baseline to 72 weeks is analysed using an
ANCOVA model with treatment, baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and baseline body weight and baseline value of 
the corresponding biomarker as covariates.
4. The estimated treatment differences and standard errors for the 1000 complete data sets are 
pooled using Rubin’s rule. From the pooled estimates and standard errors, the 95% 
confidence intervals for the treatment differences and associated p-values are calculated.
A supportive on-treatment analysis using a mixed model for repeated measurements (MMRM) will 
be performed for each of the biomarkers. In this model, all scheduled post-baseline measurements 
taken during the individual subject’s on-treatment period will enter as response; treatment, baseline 
diabetes status, baseline fibrosis stage and diabetes-by-fibrosis interaction will be included as 
factors; and baseline body weight and baseline value of the corresponding biomarker will be 
included as covariates. All factors and covariates will be nested within visit and an unstructured 
covariance matrix for measurements within subject will be employed. There will be no explicit 
imputation of missing values. As for the main analysis, the estimated treatment differences at week 
72 with associated 95% confidence intervals and p-values will be presented.
Whereas the main analysis attempts to estimate the de-facto treatment effect (in agreement with the 
chosen estimand for the primary objective), the supportive analysis aims to estimate the de-jure 
effect that would have been observed if all subjects had remained on treatment and completed all 
visits. The latter analysis relies on the assumption that data are missing at random, which means 
that given the observed data, the events that lead to data being missing are independent of the 
unobserved data.
Additional exploratory analyses will be conducted to evaluate the performance of the biomarkers as 
predictors of NASH (yes/no), fibrosis (stage R2, R3 and 4, respectively) and/or steatosis (score R1, 
R2 and 3, respectively) as applicable using the liver biopsy as the gold-standard reference. The 
results will be reported separately from the clinical trial report. 
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Statistical Analysis Plan
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27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
19 of 28
Weight-related parameters
The secondary endpoints related to weight are defined as change from baseline to 72 weeks in:
!
Body weight (% and kg)
!
Waist circumference
!
Body mass index (BMI)
These endpoints will be analysed separately using the same type of ANCOVA with MI as for the 
biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis 
interaction as factors and corresponding baseline value as a single covariate. Supportive on-
treatment analyses will be performed based on MMRM in the same way as for the biomarkers with 
factors and covariates specified as in the ANCOVA model.
In addition to the continuous endpoints, the following binary endpoints related to weight will be 
analysed separately:
!
Weight loss of R 5% of baseline body weight at 72 weeks (yes/no)
!
Weight loss of R 10% of baseline body weight at 72 weeks (yes/no)
The binary endpoints will be compared between treatment arms using an MI approach similar to the 
continuous endpoints but based on logistic regression. The 1000 data sets with imputed values for 
percent change in body weight will be reused to derive an equal number of complete data sets for 
the binary outcomes. For each data set, the binary outcomes will be analysed using a logistic 
regression model which includes treatment, diabetes status, baseline fibrosis stage and diabetes-by-
fibrosis interaction as factors and baseline body weight as a covariate. The estimated log odds ratios 
and standard errors for the 1000 complete data sets are then pooled using Rubin’s rule. From the 
pooled estimates and standard errors, the 95% confidence intervals for the odds ratios and 
associated p-values are calculated.
Glucose metabolism related parameters
The secondary endpoints related to glucose metabolism are defined as change from baseline to 72 
weeks in:
!
Glycosylated haemoglobin A1c (HbA1c)
!
Fasting plasma glucose (FPG)
!
Fasting glucagon
!
Homeostatic model assessment - insulin resistance (HOMA-IR), derived through the 
approximation formula7:
HOMA-IR = FPG (mmol/L) × Fasting insulin (mIU/L) 22.5
1
These endpoints will be analysed using the same type of ANCOVA with MI as for the biomarkers. 
For each endpoint, the ANCOVA will be performed separately for subjects with and without type 2 
diabetes at screening. The model will include treatment and baseline fibrosis stage as factors and 
corresponding baseline value as covariate. Supportive on-treatment analyses will be performed 
based on MMRM in the same way as for the biomarkers with factors and covariates specified as in 
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
20 of 28
the ANCOVA model. Fasting glucagon and HOMA-IR will be logarithmically transformed before 
analysis.
Cardiovascular risk factors
The secondary endpoints related to cardiovascular risk factors are defined as change from baseline 
to 72 weeks in: 
!
Systolic and diastolic blood pressure
!
Lipids (total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein
cholesterol, very low-density lipoprotein cholesterol, triglycerides, free fatty acids)
!
High-sensitivity C-reactive protein (hsCRP)
These endpoints will be analysed separately using the same type of ANCOVA with MI as for the 
biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and diabetes-by-fibrosis 
interaction as factors and corresponding baseline value as a single covariate. Supportive on-
treatment analyses will be performed based on MMRM in the same way as for the biomarkers with 
factors and covariates specified as in the ANCOVA model. The lipids and hsCRP will be 
logarithmically transformed before analysis.
Patient reported outcomes
The results from the short form 36 (SF-36) questionnaire will be analysed as the change from 
baseline to 72 weeks in overall mental and physical scores, respectively, as well as the change in 
each of the 8 domains: 
!
Physical functioning
!
Role functioning
!
Bodily pain
!
General health
!
Vitality
!
Social functioning
!
Role emotional 
!
Mental health
The change in score will be analysed as a continuous endpoint using the same type of ANCOVA 
with MI as for the biomarkers with treatment, baseline diabetes status, baseline fibrosis stage and 
diabetes-by-fibrosis interaction as factors and corresponding baseline score as a single covariate. 
Supportive on-treatment analyses will be performed based on MMRM in the same way as for the 
biomarkers with factors and covariates specified as in the ANCOVA model.
5.4.2.2
Safety endpoints
The following secondary endpoints are used to support the safety objectives:
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
21 of 28
!
Number of treatment-emergent adverse events during the trial
!
Number of treatment-emergent hypoglycaemic episodes during the trial
!
Number of treatment-emergent severe or blood glucose (BG) confirmed symptomatic 
hypoglycaemic episodes during the trial
!
Number of treatment-emergent severe hypoglycaemic episodes during the trial 
!
Number of subjects discontinuing treatment due to gastrointestinal adverse events
!
Change from baseline to 72 weeks in:
o
Pulse
o
Electrocardiogram (ECG)
o
Physical examination
o
Haematology (haemoglobin, haematocrit, thrombocytes, erythrocytes, leucocytes, 
differential count)
o
Biochemistry (creatinine, eGFR, creatine phosphokinase, urea, bilirubin (total), 
alkaline phosphatase, ferritin, sodium, potassium, calcium (total), amylase, lipase)
o
Hormones (calcitonin)
!
Occurrence of anti-semaglutide antibodies during and after 72 weeks treatment (yes/no):
o
Anti-semaglutide binding antibodies
o
Anti-semaglutide binding antibodies with in vitro neutralising effect
o
Anti-semaglutide binding antibodies cross reacting with native GLP-1
o
Cross-reacting anti-semaglutide binding antibodies with in vitro neutralising effect to 
native GLP-1
!
Anti-semaglutide antibody binding level during and after 72 weeks treatment
Adverse events
AEs will be coded using version 22.1 of the Medical Dictionary for regulatory Activities 
(MedDRA) coding. A treatment emergent adverse event (TEAE) is defined as an event that has 
onset date during the on-treatment period (see section 4). 
AE data will be displayed in terms of the number of subjects with at least one event, the percentage 
of subjects with at least one event, the number of events and the event rate per 100 patient years of 
exposure. The main AE summaries will only contain TEAEs. Non-treatment emergent AEs will be 
included in listings and overview summaries.
Additional summaries will be made for select AEs based on predefined MedDRA searches.  A list 
of MedDRA search terms will be specified and documented before database lock.
Hypoglycaemic episodes
Hypoglycaemic episodes will be classified and then summarised descriptively in terms of the 
number of subjects with at least one event, the percentage of subjects with at least one event, the 
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
22 of 28
number of events and the event rate per 100 patient years of exposure. The summaries will be made 
separately for subjects with and without type 2 diabetes at randomisation.
For subjects with type 2 diabetes at randomisation, the severe or BG confirmed symptomatic 
hypoglycaemic episodes will be analysed as a binary outcome using Fisher's exact test, which will 
be performed separately for the comparisons between each of the semaglutide arms and placebo. 
The results will be presented as two-sided p-values. 
For details on the classification of hypoglycaemia, see protocol section 17.4.1.2.
Pulse
Pulse will be summarised by descriptive statistics and analysed using the same type of MMRM as 
for the on-treatment analyses of the biomarkers with treatment, baseline diabetes status, baseline 
fibrosis stage and diabetes-by-fibrosis interaction as factors and baseline pulse as a covariate.
ECG
ECG will be described by summarising the number and percentage of subjects with normal and 
abnormal readings (separated into clinically significant and not clinically significant). The 
summaries will be presented by visit and as shift tables from baseline to week 72.
Physical examination
The results of the physical examination will be summarised descriptively in the same way as ECG.
Laboratory assessments
The haematology and biochemistry parameters will be summarised and evaluated by descriptive 
statistics. 
Amylase and lipase will be analysed separately using the same type of MMRM as for the on-
treatment analyses of the biomarkers with treatment, baseline diabetes status, baseline fibrosis stage 
and diabetes-by-fibrosis interaction as factors and the baseline value of the corresponding 
laboratory parameter as a covariate. A logarithmic transformation will be applied for both amylase 
and lipase
Calcitonin will be summarised in tables including number and percentage of observations > and M 
LLOQ, quartiles, minimum and maximum. Abnormal elevations of calcitonin will further be 
explored by a shift plot showing the maximum post-baseline observation against baseline for each 
subject.
Antibodies
The occurrence of anti-semaglutide antibodies will be described by summarising the number and 
percentage of subjects with antibodies in the different treatment arms. 
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
23 of 28
5.4.2.3
Pharmacokinetic endpoints
The plasma concentrations of semaglutide will be summarised by descriptive statistics. In addition, 
the data will be used for population pharmacokinetic (PK) modelling, see section 17.6 in the 
protocol.
5.5
Exploratory endpoint analysis
Not applicable for this trial.
5.6
Other safety analyses
Not applicable for this trial.
5.7
Other analyses
Not applicable for this trial.
5.8
Interim analyses
No interim analyses or other analyses of unblinded data will be performed before the database is 
locked.
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
24 of 28
6
Supporting documentation
6.1
Appendix 1: List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BG
blood glucose
BMI
body mass index
CAP
controlled attenuation parameter
CK-18
cytokeratin 18
CMH
Cochran-Mantel-Haenszel
ECG
electrocardiogram
eCRF
electronic case report form
ELF
enhanced liver fibrosis
FAS
full analysis set
FGF-21
fibroblast growth factor 21
Fib-4
fibrosis 4
FPG
fasting plasma glucose
GGT
gamma glutamyltransferase
HbA1c
glycosylated haemoglobin A1c
HOMA-IR
homeostatic model assessment - insulin resistance 
hsCRP
high-sensitivity C-reactive protein
ICH
International Council on Harmonization
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
25 of 28
IL-1R
interleukin-1 receptor 
INR
international normalized ratio 
LLOQ
lower limit of quantification
MCP-1
monocyte chemoattractant protein 1
MedDRA
medical dictionary for regulatory activities
MI
multiple imputation
miR-122
microRNA 122
MMRM
mixed model for repeated measurements
NAFLD
non-alcoholic fatty liver disease
NAS
NAFLD activity score 
NASH
non-alcoholic steatohepatitis
NFS
NAFLD fibrosis score 
SAP
statistical analysis plan
SAS
safety analysis set
s.c.
subcutaneous
SF-36
short form 36
T2D
type 2 diabetes
TEAE
treatment emergent adverse event
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
26 of 28
6.2
Appendix 2: Changes to protocol-planned analyses
Statistical hypotheses
The secondary endpoint fibrosis improvement with no worsening of NASH was added to the 
confirmatory test procedure. In addition, the population for the confirmatory tests was changed to 
only consist of subjects with fibrosis stage 2 or 3 at baseline based on national scientific advice held 
with DKMA (DK), MEB (NL), and BfArM (DE) in 2019.
Observation periods
The definition of the in-trial period was clarified. In addition, the end of the on-treatment period 
was extended from last dose of trial product +1 day to +7 days, in order to match the visit window 
in the protocol flow chart.
Primary endpoint analyses
As a consequence of the change in the population for the confirmatory tests, the main analysis and 
the sensitivity analyses will only include subjects with fibrosis stage 2 or 3 at baseline. A supportive 
analysis was added repeating the main analytical approach including all subjects irrespective of 
baseline fibrosis stage.
The exact p-value and confidence interval will be used for the confirmatory tests instead of the 
asymptotic p-value for best accuracy.
The sensitivity analysis including baseline vitamin E use as factor was removed due to an observed 
low number of subjects using vitamin E.
Confirmatory secondary endpoint
The supportive secondary endpoint fibrosis improvement with no worsening of NASH was changed 
to a confirmatory endpoint to reflect its inclusion in the confirmatory test procedure. The main 
analysis was changed from logistic regression to a CMH test and a sensitivity analysis was added 
with respect to handling of missing data.
As for the primary endpoint, the main analysis and the sensitivity analyses will only include 
subjects with fibrosis stage 2 or 3 at baseline. A supportive analysis was added repeating the main 
analytical approach including all subjects irrespective of baseline fibrosis stage.
Supportive secondary endpoints
Biomarkers of NASH disease
For ELF, the value reported by the central laboratory will be used instead of a value derived by 
Biostatistics in order to use the correct derivation for the specific equipment.
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
27 of 28
Exploratory analyses to evaluate the performance of the biomarkers as predictors of NASH, fibrosis 
and/or steatosis have been moved out of the clinical trial report since they do not concern the trial 
objectives.
HOMA-IR
The unit for fasting insulin was corrected in the derivation formula.
Hypoglycaemic episodes
Due to few observed events, the analysis of severe or BG confirmed symptomatic hypoglycaemic 
episodes was changed from negative binomial regression to Fisher's exact test.
Calcitonin
Summary tables of abnormal elevations of calcitonin were replaced by a shift plot.
Antibodies
Listings of antibody binding levels and descriptive statistics comparing efficacy and safety between 
antibody-positive and antibody-negative subjects were removed. An exploratory investigation will 
instead be data-driven with a consideration of the number of antibody-positive subjects, and will 
only be presented if informative.
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CONFIDENTIAL


Statistical Analysis Plan
Date:
27 February 2020
Novo Nordisk
Trial ID: NN9931-4296
Version:
1.0
UTN: U1111-1179-7464
Status:
Final
EudraCT No: 2016-000685-39
Page:
28 of 28
7
References
1. Bretz F, Maurer W, Brannath W, Posch M. A Graphical Approach to Sequentially Rejective 
Multiple Test Procedures. Statistics in Medicine. 2009;28:586–604.
2. Group IEEW. Statistical principles for Clinical Trials: ICH Harmonised Tripartite Guideline. 
Statistics in Medicine. 1999. p. 1905-42.
3. Agresti A. Categorical Data Analysis. 2nd ed. New York ed: John Wiley & Sons; 2002.
4. Little RJA, Rubin DB. Statistical analysis with missing data: New York: John Wiley & Sons. 
1987.
5. Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, et al. Development of a 
simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. 
Hepatology. 2006;43(6):1317-25.
6. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis 
score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 
2007;45(4):846-54.
7. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis 
model assessment: insulin resistance and beta-cell function from fasting plasma glucose and 
insulin concentrations in man. Diabetologia. 1985;28(7):412-9.
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