Clinical trial NCT03856047
Conditions: Overweight Obesity
Sponsor: Novo Nordisk A/S
Start date: 2019-03-01; Completion date: 2021-03-25
Enrollment: 706 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will look at the change in body weight in people taking NNC0174-0833, liraglutide and "dummy" medicine, from the start to the end of the study. As well as taking the medicine, participants will have talks with study staff about healthy food choices, how to be more physically active and what participants can do to lose weight. Participants will either take NNC0174-0833, liraglutide or "dummy" medicine - which treatment participants get is decided by chance. Participants will need to take one injection once a week or once a day, depending on the treatment. The study medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm. The study will last for about 8 months. Participants will have 12 clinic visits with the study doctor.

Detailed description:

Arms: arm 1: Patients will receive 4.5 mg of NNC0174-0833 once a week as injections for 26 weeks. arm 2: Patients will receive 2.4 mg of NNC0174-0833 once a week as injections for 26 weeks. arm 3: Patients will receive 1.2 mg of NNC0174-0833 once a week as injections for 26 weeks. arm 4: Patients will receive 0.6 mg of NNC0174-0833 once a week as injections for 26 weeks. arm 5: Patients will receive 0.3 mg of NNC0174-0833 once a week as injections for 26 weeks. arm 6: Patients will receive 2.4 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. arm 7: Patients will receive 4.5 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. arm 8: Patients will receive 1.2 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. arm 9: Patients will receive 0.6 mg of placebo (NNC0174-0833) once a week as injections for 26 weeks. arm 10: Patients will receive 0.3 mg of NNC0174-0833 once a week as injections for 26 weeks. arm 11: Patients will receive 3.0 mg of liraglutide once daily as injections for 26 weeks. arm 12: Patients will receive placebo 3.0 mg(liraglutide) once daily as injections for 26 weeks.
Interventions: intervention 1: NNC0174-0833 intervention 2: Placebo (NNC0174-0833) intervention 3: Liraglutide 3.0 mg intervention 4: Placebo (Liraglutide 3.0 mg)
Intervention descriptions: intervention 1: Participants will get one dose of NNC0174-0833 once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks. intervention 2: Participants will get one dose of Placebo (NNC0174-0833) once weekly. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using NovoPen® 4. Participants will gradually increase the dose until they reach the target dose, and will continue on the this dose once weekly up to 26 weeks. intervention 3: Participants will get one dose of liraglutide 3.0 mg once daily. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using pre-filled PDS290 pen-injector. Participants will gradually increase their dose every week until they reach the target dose of 3.0 mg daily. The participants will continue on 3.0 mg of liraglutide, once daily up to 26 weeks. intervention 4: Participants will get one dose of Placebo (liraglutide 3.0 mg) once daily. The medicine is injected with a thin needle in a skin fold in the stomach, thigh or upper arm using pre-filled PDS290 pen-injector. Participants will gradually increase their dose every week until they reach the target dose of 3.0 mg. The participants will continue on Placebo (liraglutide 3.0 mg), once daily up to 26 weeks.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03856047 
Sponsor trial ID: 
NN9838-4433  
Official title of study: 
Investigation of safety and efficacy of NNC0174-0833 for 
weight management – a dose finding trial 
Document date: 
18 September 2020 
 


Link
Link
Link
Link
List of contents
Protocol ...............................................................................................................................................
Attachment I and II............................................................................................................................
Protocol amendment 1 .......................................................................................................................
Protocol amendment 2 .......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Cagrilintide
Trial ID: NN9838-4433
Clinical Trial Report
Appendix 16.1.1
18 September 2020
1.0
Final
16.1.1 Protocol and protocol amendments
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Protocol
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Trial ID: NN9838-4433
Version:
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Protocol
Protocol title: Investigation of safety and efficacy of NNC0174-0833 for weight management –
a dose finding trial
Substance number: NNC0174-0833
Universal Trial Number: U1111-1214-0429 
EUdraCT Number: 2018-001945-14
Trial phase: 2
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”.
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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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
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Table of Contents   
Page
Table of Contents........................................................................................................................................2
1
Synopsis................................................................................................................................................5
2
Flowchart .............................................................................................................................................8
3
Introduction .......................................................................................................................................10
3.1
Trial rationale..........................................................................................................................10
3.2
Background.............................................................................................................................11
3.2.1
NNC0174-0833 .....................................................................................................11
3.2.2
Trial population .....................................................................................................11
3.3
Benefit-risk assessment ...........................................................................................................12
3.3.1
Benefits .................................................................................................................12
3.3.2
Identified risks for NNC0174-0833........................................................................12
3.3.3
Potential risks for NNC0174-0833 .........................................................................13
3.3.4
Identified risks for liraglutide 3.0 mg .....................................................................14
4
Objectives and endpoints...................................................................................................................15
4.1
Primary, secondary and exploratory objective(s)......................................................................15
4.1.1
Primary objective...................................................................................................15
4.1.2
Secondary objectives .............................................................................................15
4.1.3
Exploratory objectives ...........................................................................................15
4.2
Primary and secondary estimand .............................................................................................15
4.2.1
Primary estimand...................................................................................................15
4.2.2
Secondary estimand ...............................................................................................15
4.3
Primary endpoint and secondary endpoint(s) ...........................................................................16
4.3.1
Primary endpoint ...................................................................................................16
4.3.2
Secondary endpoints ..............................................................................................16
4.3.2.1
Supportive secondary endpoints .......................................................16
4.3.3
Exploratory endpoints............................................................................................17
5
Trial design ........................................................................................................................................18
5.1
Overall design.........................................................................................................................18
5.2
Subject and trial completion....................................................................................................19
5.3
End of trial definition..............................................................................................................20
5.4
Scientific rationale for trial design...........................................................................................20
5.5
Justification for dose ...............................................................................................................20
6
Trial population .................................................................................................................................22
6.1
Inclusion criteria .....................................................................................................................22
6.2
Exclusion criteria ....................................................................................................................22
6.3
Lifestyle restrictions................................................................................................................24
6.3.1
Meals and dietary restrictions.................................................................................24
6.3.2
Caffeine and tobacco..............................................................................................24
6.3.3
Physical activity.....................................................................................................24
6.4
Screen/randomisation failures..................................................................................................24
6.5
Randomisation criteria ............................................................................................................25
7
Treatments .........................................................................................................................................26
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7.1
Treatments administered .........................................................................................................26
7.1.1
Medical devices .....................................................................................................28
7.1.2
Diet and physical activity counselling ....................................................................28
7.2
Dose modification...................................................................................................................29
7.3
Method of treatment assignment..............................................................................................29
7.4
Blinding..................................................................................................................................29
7.5
Preparation/Handling/Storage/Accountability..........................................................................30
7.6
Treatment compliance.............................................................................................................31
7.7
Concomitant medication..........................................................................................................32
7.8
Treatment after the end of the trial...........................................................................................32
8
Discontinuation/Withdrawal criteria ................................................................................................33
8.1
Discontinuation of trial product ...............................................................................................33
8.1.1
Temporary discontinuation of trial product.............................................................34
8.2
Withdrawal from the trial ........................................................................................................34
8.2.1
Replacement of subjects.........................................................................................34
8.3
Lost to follow-up.....................................................................................................................35
9
Trial assessments and procedures .....................................................................................................36
9.1
Efficacy assessments...............................................................................................................37
9.1.1
Body measurements...............................................................................................37
9.1.2
Clinical efficacy laboratory assessments.................................................................37
9.1.3
Efficacy clinical outcome assessments ...................................................................37
9.2
Adverse events........................................................................................................................38
9.2.1
Time period and frequency for collecting AE and SAE information........................38
9.2.2
Method of detecting AEs and SAEs .......................................................................39
9.2.3
Follow-up on AEs and SAEs..................................................................................40
9.2.4
Regulatory reporting requirements for SAEs ..........................................................40
9.2.5
Cardiovascular and death events.............................................................................40
9.2.6
Disease related events and/or disease related outcomes not qualifying as an AE 
or SAE...................................................................................................................40
9.2.7
Pregnancies and associated adverse events .............................................................40
9.2.8
Medical device incidents (including malfunctions).................................................42
9.2.9
Technical complaints .............................................................................................42
9.3
Treatment of overdose.............................................................................................................42
9.4
Safety assessments ..................................................................................................................43
9.4.1
Physical examinations............................................................................................43
9.4.2
Vital signs..............................................................................................................43
9.4.3
Electrocardiograms ................................................................................................44
9.4.4
Clinical safety laboratory assessments....................................................................44
9.4.5
Immunogenicity assessments .................................................................................44
9.4.6
Hypersensitivity.....................................................................................................45
9.4.7
Safety clinical outcome assessments.......................................................................45
9.4.8
Ambulatory blood pressure monitoring ..................................................................46
9.5
Pharmacokinetics ....................................................................................................................47
9.6
Pharmacodynamics .................................................................................................................47
9.7
Genetics..................................................................................................................................47
9.8
Biomarkers .............................................................................................................................48
9.9
Biosamples for future analysis.................................................................................................48
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10
Statistical considerations ...................................................................................................................49
10.1
Sample size determination.......................................................................................................50
10.2
Definition of analysis sets........................................................................................................52
10.2.1
Observation periods ...............................................................................................52
10.3
Statistical analyses ..................................................................................................................53
10.3.1
Primary endpoint ...................................................................................................53
10.3.1.1
Analyses addressing the primary estimand........................................54
10.3.1.2
Analyses addressing the secondary estimand ....................................57
10.3.2
Secondary endpoints ..............................................................................................59
10.3.2.1
Supportive secondary endpoints .......................................................59
10.3.3
Exploratory endpoints............................................................................................62
10.3.4
Explorative statistical analysis for pharmacogenetics and biomarkers.....................63
10.3.5
Other analyses .......................................................................................................63
10.4
Pharmacokinetic and/or pharmacodynamic modelling .............................................................63
11
Appendices .........................................................................................................................................64
Abbreviations and Trademarks.......................................................................................64
Appendix 1
Clinical laboratory tests ...................................................................................................68
Appendix 2
Trial governance considerations......................................................................................72
Appendix 3
Adverse events: definitions and procedures for recording, evaluation, follow-up, 
Appendix 4
and reporting .....................................................................................................................................81
Contraceptive guidance and collection of pregnancy information .................................86
Appendix 5
Technical complaints: Definition and procedures for recording, evaluation, follow-
Appendix 6
up and reporting ................................................................................................................................88
Retention of human biosamples.......................................................................................90
Appendix 7
Country-specific requirements ........................................................................................92
Appendix 8
12
References ..........................................................................................................................................93
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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1
Synopsis
Rationale:
The prevalence of obesity has been increasing during the last 30 years1 and globally, more than 600 
million people have obesity2. Obesity is associated with an increased risk of developing a variety of 
comorbidities, reduced quality of life including physical function3-5 and increased mortality6, 7.
Pharmacotherapy may serve as a valuable adjunct to lifestyle intervention for individuals with 
obesity in order to achieve and sustain a clinically relevant weight loss, to improve comorbid 
conditions and to facilitate a healthier lifestyle. Few weight management medications are currently 
available and there is a need for more safe and effective therapeutic options for the treatment of 
obesity, especially treatments that also target weight maintenance and the treatment and prevention 
of comorbidities8-14.
NNC0174-0833 is a long-acting amylin analogue designed for weight management treatment.
The present trial is designed to determine the dose of NNC0174-0833, which is optimal for weight 
management. Different doses of NNC0174-0833 will be compared against placebo and liraglutide 
3.0 mg. Liraglutide 3.0 mg is included to enable comparisons of NNC0174-0833 with a weight 
management product (Saxenda®) that is approved in several countries.
Objectives and endpoints:
Primary objective
To compare the dose-response of increasing doses of NNC0174-0833 once weekly (OW) versus 
placebo and versus liraglutide 3.0 mg once daily (OD) on body weight, in subjects with overweight 
or obesity, when added as an adjunct to a reduced-calorie diet and increased physical activity.
Secondary objectives
To compare the effect of NNC0174-0833 OW versus placebo and versus liraglutide 3.0 mg OD, 
when added as an adjunct to a reduced-calorie diet and increased physical activity, on:
!
Change in waist circumference 
!
Change in glycaemic parameters
!
Safety and tolerability
Primary estimand
The estimand will quantify the average treatment effect of NNC0174-0833 relative to placebo and 
liraglutide 3.0 mg after 26 weeks, as an adjunct to a reduced-calorie diet and increased physical 
activity, in all randomised subjects had they remained on their randomised treatment for the entire 
planned duration of the trial and not started any other weight loss intervention 
(‘efficacy’/’hypothetical’ estimand).
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Primary endpoint
Change from randomisation at week 0 to week 26 in body weight (%).
Key supportive secondary endpoints
!
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 5% from randomisation
!
Change from randomisation at week 0 to week 26 in:
o
Glycated haemoglobin (HbA1c) (%-point, mmol/mol)
!
Number of treatment emergent adverse events (TEAEs) from randomisation at week 0 to week 
32 (‘end of trial’)
Overall design:
This is a 26-week, randomised, double blind placebo-controlled, twelve-armed, parallel group, 
multi-centre, multi-national dose finding trial comparing five doses (0.3, 0.6, 1.2, 2.4 and 4.5 mg 
OW) of NNC0174-0833 with placebo and liraglutide 3.0 mg OD when added as an adjunct to 
reduced-calorie diet and increased physical activity in subjects with overweight or obesity. 
Key inclusion criteria
!
≥ 18 years at the time of signing the informed consent 
!
Female subject of non-childbearing potential1
or 
Male subject who is surgically sterilised (vasectomy) or who is willing to use adequate 
contraceptive methods (as required by local regulation or practice) throughout the trial (until 
‘end of trial’)
!
Body mass index (BMI) ≥ 30.0 kg/m2 or BMI ≥ 27.0 kg/m2 with the presence of at least one of 
the following weight-related comorbidities (treated or untreated): hypertension or dyslipidaemia 
(to be assessed at the investigator’s discretion)
Key exclusion criteria
!
HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening 
!
A self-reported change in body weight > 5 kg (11 lbs) within 90 days prior to screening 
irrespective of medical records
1 (see Appendix 5 for the definition of a woman of childbearing potential (WOCBP))
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Number of subjects:
Approximately 933 subjects will be screened to achieve a planned 700 subjects randomly assigned 
to trial product.
Treatment groups and duration:
Eligible subjects will, at visit 2, be randomised to one of the five NNC0174-0833 treatment arms 
(0.3, 0.6, 1.2, 2.4 and 4.5 mg), to the liraglutide 3.0 mg treatment arm or to one of the volume 
matched placebo arms. Subjects will be randomised 6:1 between the active treatment arms and the 
placebo arms. 
The trial includes a screening visit to assess subject’s eligibility. At visit 2 (randomisation) eligible 
subjects will enter an up to 6-week dose escalation period, depending on which arm the subject is 
randomised to, followed by a maintenance period until end of treatment (week 26). To assess 
subject safety after the trial product has been washed out a follow-up visit (‘end of trial’) is 
scheduled 6 weeks after end of treatment. The total duration for each subject will be approximately 
33 weeks. 
The following trial products are supplied by Novo Nordisk A/S:
!
NNC0174-0833 A, 10 mg/ml, solution for injection, NovoPen® 4
!
Placebo NNC0174-0833 A, solution for injection, NovoPen® 4
!
Liraglutide 6 mg/ml, solution for injection, 3 ml PDS290 pen-injector
!
Liraglutide placebo, solution for injection, 3 ml PDS290 pen-injector
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2
Flowchart 
Scree-
ning
Rando-
misation
Dose 
escalation/
maintenance
Maintenance
End of
treatment
End 
of 
trial
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Timing of Visit (Weeks)
-1
0
2
4
6
8
10
14
18
22
26
32
Visit Window (Days)
-7
±0
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
Attend visit fasting
X
X
X
X
Informed consent and demographya (Appendix 
3)
X
Barriers and motivation interview  (9)
X
Inclusion, exclusion and randomisation criteria 
(6)
X
X
Medical history/concomitant illness (9.4)
X
Weight history (9)
X
Concomitant medication (7.7)
X
X
X
X
X
X
X
X
X
X
X
X
Tobacco useb (9.4)
X
Height (9.1.1)
X
Body weight (9.1.1)
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference (9.1.1)
X
X
X
X
X
X
Laboratory assessments (Appendix 2)
X
Xc
Xc
Xc
Xc
X
Xc
Xc,d
Urine pregnancy test (9.4.4, Appendix 2)e
X
X
X
X
X
X
X
X
X
X
Physical examination (9.4.1)
X
X
Vital signs (9.4.2)
X
X
X
X
X
X
X
X
X
X
X
X
ECG (9.4.3)
X
X
Ambulatory blood pressure monitoring (9.4.8)
X
X
Clinical outcome assessments (9.1.3, 9.4.7)
X
X
X
X
X
X
X
Criteria for discontinuation of trial product (8.1)
X
X
X
X
X
X
X
X
Breast/colon neoplasms follow-up (9.4)
X
X
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Scree-
ning
Rando-
misation
Dose 
escalation/
maintenance
Maintenance
End of
treatment
End 
of 
trial
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9 V10
V11
V12
Timing of Visit (Weeks)
-1
0
2
4
6
8
10
14
18
22
26
32
Visit Window (Days)
-7
±0
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
Attend visit fasting
X
X
X
X
REMINDERS
Adverse event incl. technical complaints (9.2, 
Appendix 4, Appendix 6)
X
X
X
X
X
X
X
X
X
X
X
X
Hand out and instruct in diet and physical 
activity diary (7.1.2)
X
X
X
X
X
X
X
X
X
Diet and physical activity counselling (7.1.2)
X
X
X
X
X
X
X
X
Hand out instructions for ambulatory blood 
pressure monitoring device (9.4.8)
X
X 
Collect ambulatory blood pressure monitoring 
device (9.4.8)
X
X
Hand out directions for use (7.1.1)
X
Training in trial product, pen-handling (7.1.1)
X
X
X
X
Hand out and instruct in dosing diary (7.1,  9)
X
X
X
X
X
X
X
X
X
Collect, review and  transcribe dosing diary
(7.1, 9)
X
X
X
X
X
X
X
X
X
Hand out urine collection cup (9.4.4)
X
X
X
X
X
Collect urine collection cup (9.4.4)
X
X
X
X
X
Hand out ID card 
X
IWRS subject status session 
X
X
X
Dispensing of trial product
X
X
X
X
Drug accountability (7.5)
X
X
X
X
X
a) Demography consists of date of birth, sex, ethnicity, and race (according to local regulation).
b) Smoking is defined as smoking at least one cigarette or equivalent daily.
c) Blood sample for measurement of NNC0174-0833 plasma concentration and antibodies against NNC0174-0833 must be drawn 
before dosing of trial product. Long venous stasis time should be avoided when sampling for measurement of NNC0174-0833 
plasma concentration. 
d) Subjects who have tested positive for antibodies against NNC0174-0833 at visit 12 will be requested to have a follow-up analysis 
performed 6 months after visit 12 and if the analysis is positive an additional follow-up analysis will be performed 12 months after 
visit 12. 
e) Only for postmenopausal female subjects who have stopped menstruating within the last 5 years and for female subjects with 
bilateral tubal ligation.
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3
Introduction
3.1
Trial rationale
The prevalence of obesity has been increasing during the last 30 years1 and globally, more than 600 
million people have obesity2. Obesity is associated with an increased risk of developing type 2 
diabetes (T2D)15, 16, dyslipidaemia, hypertension17, cardiovascular disease, obstructive sleep 
apnoea18, non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH)19, urinary 
incontinence20, several types of cancers21, and increased mortality6, 7. In addition to these 
pathophysiologic changes, individuals with obesity experience reduced health-related quality of life 
including physical function3-5. In recognition of the seriousness of obesity, several professional 
associations and organisations worldwide9, 22-25 now classify obesity as a disease.
The risk of obesity-related complications and comorbidities increases with increasing body mass 
index (BMI). A weight loss of 5–10% has been shown to have significant health benefits in 
individuals with obesity in terms of decreasing the risk of progressing to T2D26, improving 
hypertension27, dyslipidaemia28 and NAFLD/NASH29. In addition, improvements in patient-
reported health-related quality of life including physical function have been demonstrated with 
weight loss30. Therefore, achieving and maintaining weight loss in individuals with obesity is 
crucial. Current standard of care consists of lifestyle counselling including reduced-calorie diets and 
increased physical activity. However, with this first line treatment for obesity only one in five 
individuals successfully achieve a significant long-term weight loss31. 
Pharmacotherapy may therefore serve as a valuable adjunct to lifestyle intervention for individuals 
with obesity in order to achieve and sustain a clinically relevant weight loss, to improve comorbid 
conditions and to facilitate a healthier lifestyle. Few weight management medications are currently 
available and there is a need for more effective and safe therapeutic options for the treatment of 
obesity, especially treatments that also target weight maintenance, and the treatment and prevention 
of comorbidities8-14.
To assess whether patient response to NNC0174-0833 therapy can be predicted, various biomarker 
assessments as well deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing will be 
included in the trial.
The present trial is designed to determine the dose of NNC0174-0833, which is optimal for weight 
management. Different doses of NNC0174-0833 will be compared against placebo and liraglutide 
3.0 mg. Liraglutide 3.0 mg is included to enable comparisons of NNC0174-0833 with a weight 
management product (Saxenda®) that is approved in several countries.
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3.2
Background
3.2.1
NNC0174-0833
NNC0174-0833 is currently under development by Novo Nordisk for weight management (project 
NN9838). 
Endogenous amylin is a 37-amino acid neuroendocrine peptide hormone that is co-secreted with 
insulin by pancreatic beta-cells in response to meals. It affects a number of gastrointestinal (GI) 
processes including delay of gastric emptying and suppression of post-prandial glucagon release32. 
In addition to this, studies indicate that amylin is also involved in the central regulation of food 
intake and body weight33.
NNC0174-0833 is a long-acting amylin analogue designed for weight management treatment.  
Amino acid substitutions as well as acylation of native amylin were introduced in order to achieve a 
chemically and physically stable molecule with prolonged action and maintained biological activity. 
NNC0174-0833 has agonistic effects on both the amylin receptors and the calcitonin receptor (CtR). 
NNC0174-0833 potently and dose-dependently reduces food intake in lean rats, dogs, and monkeys. 
In diet-induced obese rats, NNC0174-0833 efficiently reduces food intake and body weight in a 
dose-dependent manner.
NNC0174-0833 has been tested in two clinical trials: the first-in-human, single dose trial NN9838-
3993 and the multiple-ascending dose trial NN9838-4021. The multiple-ascending dose trial tested 
daily subcutaneous (s.c.) administration of NNC0174-0833 for 8 weeks and concluded that 
NNC0174-0833 was considered safe and well tolerated up to 800 μg/day. Decreased appetite, 
nausea and vomiting were the most frequent adverse events (AEs) seen. The renin-angiotensin-
aldosterone system (RAAS) seemed to be activated, apparently related to dose, but the effect was 
transient and declined after 2 - 4 weeks. Importantly, no increase in heart rate or blood pressure was 
observed. No effect on ionised or total calcium was observed and there were no symptoms of 
hypocalcaemia. Pharmacokinetic (PK) data indicated a half-life of approximately 180 hours, 
supporting once weekly (OW) dosing. Furthermore, the anticipated weight loss was confirmed by 
dose dependent weight loss around 6 - 8% compared to placebo after 8 weeks of treatment. No 
clinically relevant effects on glucose metabolism were observed in this non-diabetic population. 
A comprehensive review of results from the non-clinical and clinical studies of NNC0174-0833 can 
be found in the current edition of the investigator’s brochure (IB)34 and any updates hereof.
3.2.2
Trial population 
The trial population will consist of subjects with obesity or overweight with weight-related 
comorbidities. These subjects represent a clinically relevant population for pharmacotherapeutic 
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weight management as they are at significant risk for weight-related morbidities and mortality, and 
are likely to benefit from weight reduction. 
Subjects with T2D are excluded from the trial. Since some antidiabetic medications influence 
weight, it is expected that inclusion of subjects with T2D will complicate the assessment of the 
effect of NNC0174-0833 on weight. Furthermore, weight loss may lead to individual and 
potentially NNC0174-0833 dose-related adjustment of the concomitant antidiabetic medication, 
because weight loss may reduce the need for antidiabetic medication. It is planned to study subjects 
with T2D at a later point in the clinical development program. 
Reproductive toxicity studies conducted in rats and mice showed that NNC0174-0833 induced 
major foetal malformations at human relevant exposures. However, these findings were not seen in 
rabbits despite a significantly higher exposure level. Mechanistic studies are ongoing which focus 
on the involvement of rodent specific calcium regulation, however, the mode of action behind the 
embryo-foetal toxicity in rodents has thus far not been identified. Hence, at present it cannot be 
excluded that the rodent findings are of human relevance and therefore women of childbearing 
potential will be excluded from this trial. 
3.3
Benefit-risk assessment
3.3.1
Benefits
Subjects will be treated with a regimen anticipated to be better than or equal to the weight 
management they receive at the time of entry into the trial. It is expected that all subjects (including 
those randomised to placebo) will benefit from participation in this trial through close contact with 
the trial site and counselling by a dietician or a similarly qualified healthcare professional, all of 
which will likely result in improved lifestyle and weight management. 
Subjects randomised to treatment with NNC0174-0833 may experience a greater weight loss. 
Results from the 8-week long phase 1 multiple dose trial (NN9838-4021) demonstrated that 
treatment with NNC0174-0833, on average, resulted in a clinically relevant weight loss. Subjects 
randomised to liraglutide 3.0 mg can also expect a clinically relevant weight loss.
3.3.2
Identified risks for NNC0174-0833 
These risks are based on data from the two completed phase 1 trials, NN9838-3993 and NN9838-
4021.
Gastrointestinal side effects
The most frequently reported side effects in trials NN9838-3993 and NN9838-4021 were decreased 
appetite, followed by GI side effects like nausea, vomiting and diarrhoea. The frequency and 
severity of GI AEs were reduced when the target dose level was reached via stepwise escalations of 
the dose.
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3.3.3
Potential risks for NNC0174-0833 
These risks are based on the suspicion of an association with NNC0174-0833, however, the 
relationship has not been confirmed in humans.
Hypocalcaemia
NNC0174-0833 activates the CtR and nonclinical data indicate that hypocalcaemia is a potential 
risk. Hypocalcaemia has neither been observed in the NN9838-3993 trial nor in the NN9838-4021 
trial and no changes to ionised (free) calcium or total calcium were observed in these trials. 
Increased urinary volume and electrolyte excretion
Increased urinary volume and excretion of salts have been observed in animals. However, no effect 
on urinary volume, electrolytes or blood pressure has been observed in the two clinical trials 
NN9838-3993 and NN9338-4021.
Activation of the renin-angiotensin-aldosterone system 
In animal studies, treatment with NNC0174-0833 was associated with increased renin activity and 
aldosterone. Similar findings have been observed in human studies, although only temporarily in 
the multiple dose study NN9838-4021 and without any stimulatory effect on blood pressure.
Decreased heart rate
Studies in dogs have shown decreases in heart rate. No signs or symptoms of decreased heart rate 
were observed in the two clinical trials.
Injection site reaction
Injection site reactions are always a risk when investigating the safety of injectable protein 
molecules. Only one injection site reaction was reported in NN9838-3993. In NN9838-4021 the 
number of injection site reactions did not differ between active and placebo arms.
Development of antibodies
NNC0174-0833 has a high homology to native amylin. In trial NN9838-3993, anti-NNC0174-0833 
antibodies were detected in two subjects. One subject tested positive for pre-existing antibodies. 
The other subject was tested positive for anti-NNC0174-0833 antibodies at the follow-up visit, and 
this was considered treatment related. In vitro neutralising effect against NNC0174-0833 was 
negative. In the multiple dose trial NN9838-4021, 17 of 72 subjects tested positive for anti-
NNC0174-0833 antibodies after initiation of treatment, with no clear dose dependency. One case of 
in vitro neutralising antibodies was detected at the follow-up visit (day 99).
Cancer (signal observed with salmon calcitonin)
NNC0174-0833 activates both the calcitonin and the amylin receptors. A meta-analysis of salmon 
calcitonin trials has shown a small increase in overall cancer risk35.
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Teratogenicity
Embryo-foetal development data indicate that NNC0174-0833 has teratogenic effects in rats and 
mice. However, teratogenic effects have not been observed in rabbits. There are no data from the 
use of NNC0174-0833 in pregnant women.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of NNC0174-0833 can be found in the current edition of the IB34 and any updates 
hereof.
3.3.4
Identified risks for liraglutide 3.0 mg
Detailed information about the known and expected benefits and risks and reasonably expected AEs 
of liraglutide 3.0 mg (Saxenda®) can be found in the current edition of the IB36 and any updates 
hereof.
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4
Objectives and endpoints
4.1
Primary, secondary and exploratory objective(s)  
4.1.1
Primary objective
To compare the dose-response of increasing doses of NNC0174-0833 OW versus placebo and 
versus liraglutide 3.0 mg once daily (OD) on body weight, in subjects with overweight or obesity, 
when added as an adjunct to a reduced-calorie diet and increased physical activity.
4.1.2
Secondary objectives
To compare the effect of NNC0174-0833 OW versus placebo and versus liraglutide 3.0 mg OD, 
when added as an adjunct to a reduced-calorie diet and increased physical activity, on:
!
Change in waist circumference 
!
Change in glycaemic parameters
!
Safety and tolerability
4.1.3
Exploratory objectives
To compare the effect of NNC0174-0833 OW versus placebo and versus liraglutide 3.0 mg OD, 
when added as an adjunct to a reduced-calorie diet and increased physical activity, on:
!
Biomarkers
!
Health-related quality of life
4.2
Primary and secondary estimand
4.2.1
Primary estimand
The estimand will quantify the average treatment effect of NNC0174-0833 relative to placebo and 
liraglutide 3.0 mg after 26 weeks, as an adjunct to a reduced-calorie diet and increased physical 
activity, in all randomised subjects had they remained on their randomised treatment for the entire 
planned duration of the trial and not started any other weight loss intervention 
(‘efficacy’/‘hypothetical’ estimand).
4.2.2
Secondary estimand
The estimand will quantify the average treatment effect of NNC0174-0833 relative to placebo and 
liraglutide 3.0 mg after 26 weeks, as an adjunct to a reduced-calorie diet and increased physical 
activity, in all randomised subjects regardless of adherence to treatment and regardless of starting 
any other weight loss intervention (‘effectiveness’/‘treatment policy’ estimand).
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4.3
Primary endpoint and secondary endpoint(s)
4.3.1
Primary endpoint
Change from randomisation at week 0 to week 26 in body weight (%).
4.3.2
Secondary endpoints
4.3.2.1
Supportive secondary endpoints
Efficacy endpoints
!
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 5% from randomisation
o
Body weight reduction ≥ 10% from randomisation
!
Change from randomisation at week 0 to week 26 in:
o
Body weight (kg)
o
Waist circumference (cm)
o
Fasting lipids (mg/dL)

Total cholesterol

High density lipoprotein (HDL) cholesterol

Low density lipoprotein (LDL) cholesterol

Very low density lipoprotein (VLDL) cholesterol

Triglycerides
o
Glycated haemoglobin (HbA1c) (%-point, mmol/mol)
o
Fasting plasma glucose (FPG) (mg/dL)
o
Fasting insulin (μIU/mL)
o
Homeostatic model assessment of insulin resistance (HOMA-IR) (%-point)
o
Homeostatic model assessment of β-cell function (HOMA-β) (%-point)
Safety endpoints
!
Number of treatment emergent adverse events (TEAEs) from randomisation at week 0 to week 
32 (‘end of trial’)
!
Number of treatment emergent serious adverse events (SAEs) from randomisation at week 0 to 
week 32 (‘end of trial’)
!
Occurrence (yes/no) of anti-drug antibodies towards NNC0174-0833 from randomisation at 
week 0 to week 32 (‘end of trial’)
!
Change from randomisation at week 0 to week 26 in:
o
Systolic blood pressure (mmHg) 
o
Diastolic blood pressure (mmHg)
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o
Mean 24-hour systolic blood pressure (mmHg)  
o
Mean 24-hour diastolic blood pressure (mmHg)
o
Pulse (bpm)
o
High sensitivity C-Reactive Protein (hsCRP) (mg/L)
o
Plasminogen Activator Inhibitor-1 (PAI-1) activity (mg/L)
o
Renin activity (ng/mL/h)
o
Aldosterone (ng/dL)
4.3.3
Exploratory endpoints
!
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 15% from randomisation
o
Body weight reduction ≥ 20% from randomisation
!
Change from randomisation at week 0 to week 26 in:
o
Endogenous amylin
o
Soluble leptin receptor
o
Leptin 
o
Short form-36 (SF-36) v2.0 acute: 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
o
Three Factor Eating Questionnaire Revised 18-item version 2 (TFEQ-R18v2): 
Transformed scale scores for the three scales measured: Uncontrolled Eating, Cognitive 
Restraint and Emotional Eating 
!
Time to permanent discontinuation of randomised trial product (weeks)
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5
Trial design
5.1
Overall design
This is a 26-week, randomised, double blind placebo-controlled, twelve-armed, parallel group, 
multi-centre, multi-national dose finding trial comparing five doses (0.3, 0.6, 1.2, 2.4 and 4.5 mg 
OW) of NNC0174-0833 with placebo and liraglutide 3.0 mg OD when added as an adjunct to 
reduced-calorie diet and increased physical activity in subjects with overweight or obesity. 
The trial includes a screening visit to assess subject’s eligibility. At visit 2 (randomisation) eligible 
subjects will enter an up to 6-week dose escalation period, depending on which arm the subject is 
randomised to, followed by a maintenance period until end of treatment (week 26). To assess 
subject safety after the trial product has been washed out a follow-up visit (‘end of trial’) is 
scheduled 6 weeks after end of treatment. The total duration for each subject will be approximately 
33 weeks.
Each NNC0174-0833 treatment arm will administer different dose volumes, but is blinded towards 
placebo with matching injection volumes. 
Subjects will be randomised 6:1 between the active treatment arms and the placebo arms. This will 
result in approximately 100 subjects in each treatment arm and approximately 100 subjects in total 
in the placebo arms.
The five different NNC0174-0833 placebo arms and the one liraglutide placebo arm will be pooled 
into one placebo group in the main analyses.
The trial design is outlined in Figure 5-1.
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Figure 5-1
Trial design
5.2
Subject and trial completion
Approximately 933 subjects will be screened to achieve a planned 700 subjects randomly assigned 
to trial products.
Trial period completion for a subject
Trial period completion is defined as when the randomised subject has completed the final 
scheduled visit (‘end of trial’ (week 32) according to the flowchart). 
For subjects who have tested positive for antibodies against NNC0174-0833 at visit 12 (‘end of 
trial’) two additional analyses may be performed up to 12 months after visit 12 (Section 9.4.5). For 
these subjects the trial period completion is also defined as when the randomised subject has 
completed the final scheduled visit (‘end of trial’ (week 32) according to the flowchart).
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Treatment period completion for a subject 
Treatment period completion is defined as when the randomised subject has received the required 
treatment, and attended the ‘end of treatment’ visit (week 26) according to the flowchart. 
5.3
End of trial definition
The end of the trial is defined as the date of the last visit of the last subject in the trial, not including 
the potential two follow-up analyses for subjects testing positive for antibodies against NNC0174-
0833 at visit 12. 
5.4
Scientific rationale for trial design
Parallel treatment groups and a randomised double-blinded, controlled design have been chosen in 
accordance with the trial objectives. To avoid bias in the assessment of the different NNC0174-
0833 doses and the liraglutide dose, the trial will be double-blinded within treatment arms to 
placebo. The treatment arms will not be blinded towards each other because of different dose 
escalations, different pens, and different target volumes. All treatments are added to a standardised 
diet and exercise counselling.
In order to compare efficacy and safety with a widely approved medication for weight management 
(i.e. standard of care) a liraglutide 3.0 mg/liraglutide placebo arm has been included. 
A treatment duration of 26 weeks is considered adequate to assess whether various doses of 
NNC0174-0833 may induce a clinically meaningful weight loss and provide sufficient insight into 
the NNC0174-0833 safety and tolerability profile.
Dose escalation every other week (for the 1.2 mg, 2.4 mg and 4.5 mg NNC0174-0833 treatment 
arms) is chosen because it is expected to attenuate the GI side effects.
5.5
Justification for dose
Based on the phase 1 multiple-ascending dose trial it was concluded that NNC0174-0833 is safe 
and well tolerated up to 800 μg OD following proper dose escalation for 3 weeks. Dose escalation 
by weekly increments reduced the frequency and severity of GI AEs. On this basis it is expected 
that transition into OW dosing with escalations every other week will provide a good balance 
between minimising GI AEs and efficacy.
Population PK modelling demonstrated that an OW dose of 4.5 mg NNC0174-0833 provides a 
steady state maximum concentration of NNC0174-0833 (Cmax) similar to the mean plasma 
concentration observed with the highest tested dose of 800 μg OD in the multiple-ascending dose 
trial (NN9838-4021). Therefore, 4.5 mg OW was selected as the top dose to be explored in phase 2. 
Due to its higher peak-to-trough fluctuation, an OW dose of 4.5 mg NNC0174-0833 will provide 
20% lower average exposure at steady state compared to OD dose of 800 μg. The lowest dose of 
0.3 mg OW is anticipated to represent the ‘minimal effective dose’. A trial design with 5 
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maintenance doses ranging from 0.3 mg to 4.5 mg including approximately two-fold increments in 
doses is expected to give adequate exploration of the dose-response curve for NNC0174-0833 on 
weight loss.
Refer to Section 7.1 for more details on treatment doses.
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6
Trial population
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1
Inclusion criteria
Subjects are eligible to be included in the trial only if all of the following criteria apply:
1. Informed consent obtained before any trial related activities. Trial related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial.
2. ≥ 18 years at the time of signing the informed consent 
3. Female subject of non-childbearing potential1
or
Male subject who is surgically sterilised (vasectomy) or who is willing to use adequate 
contraceptive methods (as required by local regulation or practice) throughout the trial (until 
‘end of trial’)
4. BMI ≥ 30.0 kg/m2 or BMI ≥ 27.0 kg/m2 with the presence of at least one of the following 
weight-related comorbidities (treated or untreated): hypertension or dyslipidaemia (to be 
assessed at the investigator’s discretion).
For country specific requirements see Appendix 8.
6.2
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply:
Glycaemia-related
1. HbA1c ≥ 48 mmol/mol (6.5%) as measured by the central laboratory at screening 
2. History of type 1 or type 2 diabetes mellitus
3. Treatment with glucose-lowering agent(s) within 90 days prior to screening
Obesity-related
4. A self-reported change in body weight > 5 kg (11 lbs) within 90 days prior to screening 
irrespective of medical records
5. Treatment with any medication  indicated for weight management within 90 days prior to 
screening
1 See Appendix 5 for the definition of a woman of childbearing potential (WOCBP)
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6. Previous or planned (during the trial period) obesity treatment with surgery or a weight loss 
device. However, the following are allowed: (1) liposuction and/or abdominoplasty, if 
performed > 1 year prior to screening, (2) lap banding, if the band has been removed > 1 year 
prior to screening, (3) intragastric balloon, if the balloon has been removed > 1 year prior to 
screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year prior to 
screening
7. Uncontrolled thyroid disease, defined as thyroid stimulating hormone (TSH) > 4.78 mIU/L or < 
0.55 mIU/L as measured by the central laboratory at screening
Mental health
8. History of major depressive disorder within 2 years prior to screening
9. History of other severe psychiatric disorders (e.g. schizophrenia or bipolar disorder)
10. A lifetime history of a suicidal attempt
General safety
11. Male subject whose partner is pregnant or breastfeeding
12. Renal impairment measured as estimated glomerular filtration rate (eGFR) value of < 60 
ml/min/1.73m2 as defined by Kidney Disease Improving Global Outcomes (KDIGO) 201237 by 
the central laboratory at screening
13. Impaired liver function, defined as alanine aminotransferase (ALT) ≥ 2.5 times or bilirubin > 
1.5 times upper normal limit (UNL), as measured by the central laboratory at screening 
14. Inadequately treated blood pressure defined as systolic ≥180 mmHg or diastolic ≥110 mmHg at 
screening 
15. History of malignant neoplasms within the past 5 years prior to screening. Basal and squamous 
cell skin cancer and any carcinoma in-situ are allowed.
16. Presence or history of cardiovascular disease including stable and unstable angina pectoris, 
myocardial infarction, transient ischaemic attack, stroke, cardiac decompensation, clinically 
significant arrhythmias or clinically significant conduction disorders
17. Subject presently classified as being in New York Heart Association (NYHA) Class IV heart 
failure
18. Surgery scheduled during the duration of the trial, except for minor surgical procedures, in the 
opinion of the investigator 
19. Known or suspected abuse of alcohol or recreational drugs
20. Known or suspected hypersensitivity to trial product(s) or related products
21. Previous participation in this trial. Participation is defined as signed informed consent.
22. Participation in another clinical trial within 90 days prior to screening
23. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma
24. Presence of acute pancreatitis within 180 days prior to screening
25. History or presence of chronic pancreatitis
26. Other subject(s) from the same household participating in any trial testing NNC0174-0833
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27. Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, 
which in the investigator’s opinion, might jeopardise the subject’s safety or compliance with the 
protocol
The criteria will be assessed at the investigator’s discretion unless otherwise stated.
6.3
Lifestyle restrictions
To ensure alignment in regards to performance of assessments across subjects and trial sites, the 
below restrictions apply.
6.3.1
Meals and dietary restrictions
!
Subjects must attend the relevant visits fasting according to the flowchart.
!
Fasting is defined as at least 8 hours overnight before the visit, 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 samples have been obtained. 
!
If the subject is not fasting as required, the subject should be called in for a new visit within the 
visit window to have the fasting assessments done. 
!
Assessments requiring subject to fast include blood sampling of lipids, FPG, fasting serum 
insulin, leptin, soluble leptin receptor, and endogenous amylin. 
6.3.2
Caffeine and tobacco
Subject should avoid caffeine and smoking for at least 30 minutes prior to measuring the blood 
pressure at clinic visits.
6.3.3
Physical activity
Subject should avoid physical activity for at least 30 minutes prior to measuring the blood pressure.
6.4
Screen/randomisation failures
Screen/randomisation failures are defined as subjects who consent to participate in the clinical trial 
but are not eligible for participation according to in/exclusion criteria or randomisation criteria. A 
minimal set of information is required to ensure transparent reporting to meet requirements from 
regulatory authorities. Minimal information includes date of visit, date of informed consent, 
demography, violated incl/excl/rand criteria, screen/randomisation failure date and reason and any 
SAE. A screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. Re-
sampling is not allowed if the subject has failed one of the inclusion criteria or fulfilled one of the 
exclusion criteria related to laboratory parameters. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
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6.5
Randomisation criteria 
To be randomised, all randomisation criteria must be answered ‘yes’.
1. A Patient Health Questionnaire-9 (PHQ-9)38 score of < 15 at randomisation 
2. No suicidal behaviour within 30 days prior to randomisation
3. No suicidal ideation corresponding to type 4 or 5 on the Columbia-Suicide Severity Rating 
Scale (C-SSRS) within 30 days prior to randomisation
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7 Treatments
7.1
Treatments administered
!
All trial products listed in Table 7-1 are considered investigational medicinal products (IMPs) 
and are supplied by Novo Nordisk A/S.
!
Liraglutide 3.0 mg/liraglutide placebo must only be used, if it appears clear and colourless. 
!
NNC0174-0833/NNC0174-0833 placebo must only be used, if it appears clear and almost 
colourless. 
Table 7-1
Trial products provided by Novo Nordisk A/S
Trial product  name 
NNC0174-0833 A  
10 mg/ml
Placebo NNC0174-
0833 A
Liraglutide 
6.0 mg/ml
Liraglutide placebo
Dosage form
Solution for injection
Solution for injection
Solution for injection
Solution for injection
Route of 
administration 
Subcutaneous
Subcutaneous
Subcutaneous
Subcutaneous
Dosing 
instructions
Once-weekly
Once-weekly
Once-daily
Once-daily
Packaging
3 mL cartridge under-
filled with 1 mL 
extractable volume 
inserted into a 
NovoPen® 4 
3 mL cartridge under-
filled with 1 mL 
extractable volume 
inserted into a 
NovoPen® 4 
3 mL PDS290 pen-
injector
3 mL PDS290 pen-
injector
!
Subjects randomised to NNC0174-0833/NNC0174-0833 placebo will be instructed to inject 
OW on the same day of the week (to the extent possible) throughout the trial.
!
Subjects randomised to liraglutide 3.0 mg/liraglutide placebo will be instructed to inject OD 
throughout the trial.
!
Trial products can be taken at any time of day, irrespective of timing of meals. 
!
Trial product injections should be administered in the thigh, abdomen or upper arm.
!
Dose escalation of NNC0174-0833/NNC0174-0833 placebo and liraglutide 3.0 mg/liraglutide 
placebo should take place during the first 6 weeks after randomisation according to Table 7-2
and Table 7-3. 
!
Dosing information must be collected in designated paper dosing diary and entries must be 
entered in the case report form (CRF). 
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Table 7-2
Dose escalation, target dose, injection volume and pen units for NNC0174-833                   
arms and corresponding placebo arms
Target 
dose
Unit
Randomisation
Week 2
Week 4
Week 6
until end of treatment
0.3 mg
Dose (mg)
Volume (μL)
Pen unit (U)
0.3
30
3
0.3
30
3
0.3
30
3
0.3
30
3
0.6 mg
Dose (mg)
Volume (μL)
Pen unit (U)
0.6
60
6
0.6
60
6
0.6
60
6
0.6
60
6
1.2 mg
Dose (mg)
Volume (μL)
Pen unit (U)
0.6
60
6
1.2
120
12
1.2
120
12
1.2
120
12
2.4 mg
Dose (mg)
Volume (μL)
Pen unit (U)
0.6
60
6
1.2
120
12
2.4
240
24
2.4
240
24
4.5 mg
Dose (mg)
Volume (μL)
Pen unit (U)
0.6
60
6
1.2
120
12
2.4
240
24
4.5
450
45
Table 7-3
Dose escalation, target dose and injection volume for liraglutide 3.0 mg arm and 
corresponding placebo arm
Target
dose
Unit
Randomisation
Week 1
Week 2
Week 3
Week 4
until end of treatment
3.0 mg
Dose (mg)
Volume (μL)
0.6
100
1.2
200
1.8
300
2.4
400
3.0
500
!
In case of intolerable GI AEs as judged by the investigator, dose escalation can be postponed by 
one week per escalation step. As such the maximum time to reach the highest target dose of 
NNC0174-0833 (4.5 mg) and liraglutide 3.0 mg (3.0 mg) will be 9 weeks and 8 weeks, 
respectively. 
!
If a subject does not tolerate the randomised target dose, the subject may stay at a lower dose 
level. This should only be allowed if the subject would otherwise discontinue trial product 
completely and if considered safe to continue on trial product, as per investigator’s discretion. 
!
It is recommended that the investigator consults Novo Nordisk in case of persistent deviations 
from the planned escalation regimen.
!
Auxiliary supplies will be provided by Novo Nordisk in accordance with the trial materials 
manual (TMM), see Table 7-4.
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Table 7-4: Auxiliary supplies provided by Novo Nordisk A/S
Auxiliary supply
Details
Needles
Needles for NovoPen® 4 and for the 3 mL PDS290 pen-injector              
Types of needle will be specified in the TMM                                                                          
Only needles provided by Novo Nordisk must be used for administration of trial product
Maximum needle length of 6 mm should be used
Direction for use (DFU)
DFU for NovoPen® 4 
DFU for 3 mL PDS290 pen-injector
DFUs are not included in the dispensing unit and must be handed out separately
7.1.1
Medical devices
Non-investigational medical devices: 
!
NovoPen® 4
!
PDS290 pen-injector
NovoPen® 4 is a durable device which is not under investigation in this trial. The use of NovoPen®
4 for s.c. administration of NNC0174-0833/NNC0174-0833 placebo for the treatment of subjects 
with obesity is supported by a risk assessment addressing the safety of the use of NovoPen® 4 in 
this trial. Information about NovoPen® 4 can be found in the current edition of the IB34 and any 
updates hereof.
The PDS290 pen-injector is a prefilled pen-injector used as a delivery system for liraglutide 3.0 
mg/liraglutide placebo. The PDS290 pen-injector is not under investigation in this trial. The 
PDS290 pen-injector has been documented for use in patients with obesity and to be in compliance 
with relevant standards and regulations. Information about the PDS290 pen-injector can be found in 
the current edition of the IB36 and any updates hereof.
Training in NovoPen® 4 and PDS290 pen-injector
The subjects must be trained according to the DFU in how to handle the NovoPen® 4 and the 
PDS290 pen-injector, when handed out the first time. Training must be repeated during the trial at 
regular intervals in order to ensure correct use of the NovoPen® 4 and for PDS290 pen-injector. 
The investigator must document that the DFU is given to the subject orally and in writing at the first 
dispensing visit.
7.1.2
Diet and physical activity counselling
All subjects will receive counselling with regards to diet (a goal of 500 kcal deficit per day relative 
to the estimated total daily energy expenditure (TEE) calculated once at randomisation) and 
physical activity (a goal of 150 min of physical activity per week). Counselling should be done by a 
dietician or a similar qualified healthcare professional at visits outlined in the flowchart.
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Subjects will be instructed to record their food intake and physical activity daily (via paper diary, 
app or similar tool) in order to assist and evaluate their lifestyle intervention.
The subjects can use a tool of their own choice (paper/app/other tool) for recording, ensuring it can 
be reviewed for content and number of entries during diet and physical activity counselling.  
Calculation of estimated TEE
The TEE is calculated by multiplying the estimated basal metabolic rate (BMR) (Table 7-5) with a 
physical activity level value of 1.339.
TEE = BMR × 1.3
Table 7-5
Equation for estimated BMR
Sex
Age
BMR (kcal/day)
Male
18-30 years
31-60 years
> 60 years
15.057 × weight at randomisation in kg + 692.2
11.472 × weight at randomisation in kg + 873.1
11.711 × weight at randomisation in kg + 587.7
Female
18-30 years
31-60 years
> 60 years
14.818 × weight at randomisation in kg + 486.6
8.126 × weight at randomisation in kg + 845.6
9.082 × weight at randomisation in kg + 658.5
If a BMI ≤ 22.5 kg/m2 is reached the recommended energy intake should be recalculated with no 
kcal deficit (maintenance diet) for the remainder of the trial. If deemed necessary the investigator 
could consult Novo Nordisk to discuss when maintenance diet can be initiated.
7.2
Dose modification
Not applicable for this trial.
7.3
Method of treatment assignment
All subjects will be centrally randomised using an IWRS and assigned to the next available 
treatment according to randomisation schedule. Trial product will be dispensed at the trial visits 
summarised in the flowchart. 
7.4
Blinding
The active trial product and matching placebo are visually identical for the following trial products:
!
NNC0174-0833/NNC0174-0833 placebo
!
Liraglutide 3.0 mg/liraglutide placebo 
The IWRS is used for blind-breaking instructions. The blind may be broken in a medical emergency 
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if knowing the actual treatment would influence the treatment of the subject. Novo Nordisk will be 
notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the source documentation.
Whenever the blind is broken, the person breaking the blind must print the ‘code break 
confirmation’ notification generated by the IWRS and sign and date the document. 
When the blind is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. IftheIWRS is not accessible at thetime of blind break,
the IWRS helpdesk should be contacted. Contact details are listed in Attachment I. 
If the blind has been broken by investigator, the subject must discontinue treatment with trial
product and a treatment status session to register discontinuation of treatment must be completed in 
the IWRS.
7.5
Preparation/Handling/Storage/Accountability
Only subjects enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product. 
!
Trial product storage, in-use conditions and in-use time will be available on the label and in the
TMM.
!
Each trial site will be supplied with sufficient trial products for the trial on an ongoing basis
controlled by the IWRS. Trial product will be distributed to the trial sites according to screening
and randomisation.
!
The investigator must confirm that appropriate temperature conditions have been maintained
during transit for all trial products received and any discrepancies are reported and resolved
before use of the trial products.
!
All trial products must be stored in a secure, controlled, and monitored (manual or automated)
area in accordance with the labelled storage conditions with access limited to the investigator
and authorised site staff.
!
The investigator must inform Novo Nordisk immediately if any trial product has been stored
outside specified conditions. Additional details regarding handling of temperature deviations
can be found in the 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 is responsible for drug accountability and record maintenance (i.e. receipt,
accountability and final disposition records).
!
For subjects randomised to liraglutide 3.0 mg/liraglutide placebo, drug accountability should be
performed on a pen level for the PDS290 pen-injector.
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!
For subjects randomised to NNC0174-0833/NNC0174-0833 placebo, drug accountability 
should be performed on a cartridge level for the cartridges supplied for the NovoPen® 4. No 
accountability is performed for the NovoPen® 4.
!
Drug accountability must be documented in the IWRS.
!
The subject must return all used, partly used and unused trial product including empty 
packaging materials during the trial as instructed by the investigator.
!
Destruction of trial products can be performed on an ongoing basis and will be done according 
to local procedures after accountability is finalised by the site and reconciled by the monitor. 
!
Destruction of trial products must be documented in the IWRS. 
!
All returned, expired or damaged trial products (for technical complaint samples see Appendix 
6) must be stored separately from non-allocated trial products. No temperature monitoring is 
required.
!
Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the trial site. 
7.6
Treatment 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 a single dose of NNC0174-0833/NNC0174-0833 placebo is missed, it should be administered 
as soon as noticed, provided the time to the next scheduled dose is at least 2 days (48 hours). If 
the next scheduled dose is less than 48 hours away, the missed dose should be skipped and the 
subject should await the next scheduled dose. The scheduled dosing day of the week should be 
kept the same, to the extent possible. 
!
If two or more consecutive doses of NNC0174-0833/NNC0174-0833 placebo are missed, 
continuation of NNC0174-0833/NNC0174-0833 placebo should be encouraged if considered 
safe as per the investigator’s discretion and if the subject does not meet any of the 
discontinuation criteria (Section 8.1). The trial product should be administered as early as the 
situation allows unless there is less than 48 hours to the next scheduled dose. The missed doses 
should not affect the scheduled dosing day of the week. The start dose for re-initiation of 
NNC0174-0833/NNC0174-0833 placebo is at the investigator’s discretion. 
!
If one or two doses of liraglutide 3.0 mg/liraglutide placebo are missed no changes should be 
made to the following administrations.
!
If more than 3 consecutive doses of liraglutide 3.0 mg/liraglutide placebo are missed, 
continuation of liraglutide 3.0 mg/liraglutide placebo should be encouraged if considered safe as 
per the investigator’s discretion and if the subject does not meet any of the discontinuation 
criteria (Section 8.1). The start dose for re-initiation of liraglutide 3.0 mg/liraglutide placebo is 
at the investigator’s discretion.
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!
In case of questions related to re-initiation or re-escalation of trial product, the investigator 
should consult Novo Nordisk.
!
Dosing information must be collected in designated paper dosing diary and entries must be 
entered in the CRF (Section 9).
7.7
Concomitant medication
Any medication (including over-the-counter or prescription medicines), other than the trial product, 
that the subject is receiving at the time of visit 2 or receives during the trial must be recorded along 
with:
!
Trade name or generic name
!
Indication
!
Start and stop dates
During the trial subjects should not initiate any weight management treatment (e.g. medication) 
which is not part of the trial procedures. If such treatment is initiated, the subject should be 
instructed to stop the weight management treatment.
Changes in concomitant medication must be recorded at each visit. If a change is due to an
AE/SAE, then this must be reported according to Section 9.2.
7.8
Treatment after the end of the trial
When discontinuing trial products, either at the scheduled ‘end of treatment’ visit or if trial product 
is discontinued, the subject should be treated at the discretion of the investigator.
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8
Discontinuation/Withdrawal criteria 
8.1
Discontinuation of trial product
The subject may be discontinued from trial product at any time during the trial at the discretion of 
the investigator for safety, behavioural, compliance or administrative reasons.
The subject must be discontinued from trial product, if one or more of the following applies:
1. Safety concern as judged by the investigator
2. Pregnancy
3. Simultaneous participation in another clinical trial of an approved or non-approved IMP.
The subjects randomised to liraglutide 3.0 mg/liraglutide placebo must also be discontinued from 
trial product, if any of the following applies: 
4. Calcitonin ≥ 100 ng/L 
5. Suspicion of pancreatitis
If acute pancreatitis is suspected appropriate management should be initiated, including local 
measurement of amylase and lipase (see Appendix 4 for reporting).
Subjects meeting discontinuation of trial product criteria no. 1 and 2 are allowed to resume trial 
product, if the criteria are no longer met (Section 8.1.1).
Subjects meeting discontinuation of trial product criterion no. 5 are allowed to resume trial product 
if the Atlanta criteria40 are not fulfilled and thus the suspicion of acute pancreatitis is not confirmed. 
Trial product may be resumed for subjects with a gallstone-induced pancreatitis in case of 
cholecystectomy.
The primary reason for discontinuation of trial product must be specified in the medical record at 
the time of treatment discontinuation and in the ‘end of treatment’ form in the CRF, and final drug 
accountability must be performed. A treatment status session to register discontinuation of 
treatment must be made in the IWRS.
Efforts must be made to have the subjects, who discontinue trial product, attend and complete all 
scheduled visit procedures. Only subjects who withdraw consent will be considered as withdrawn 
from the trial. Subjects must be educated about the continued scientific importance of their data, 
even if they discontinue trial product.
If the subject does not wish to attend the scheduled clinic visits efforts should be made to have the 
visits converted to phone contacts. However, all efforts should be made to attend at least visit 11 
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‘end of treatment’ (26 weeks post-randomisation), containing the final data collection of the 
primary endpoint, and visit 12 ‘end of trial’ (32 weeks post-randomisation). 
The ‘end of trial’ visit is scheduled approximately 6 weeks after the ‘end of treatment’ visit (week 
26), to ensure the safety of the subject.
If the subject refuses to attend the ‘end of treatment’ visit and/or the ‘end of trial’ visit, information 
about the attempts to follow up with the subject must be documented in the subject’s medical 
record.
8.1.1
Temporary discontinuation of trial product
If a subject has discontinued trial product, the subject should follow the guide for missed doses 
(Section 7.6) if treatment should be resumed. 
If a ‘treatment status’ session previously has been made in IWRS to indicate discontinuation of trial 
product, a new ‘treatment status’ session must be made to resume trial product.
8.2
Withdrawal from the trial
A subject may withdraw consent at any time at his/her own request. Only subjects who withdraw 
consent will be considered as withdrawn from the trial.
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessments performed according to the ‘end of treatment’ visit. See the flowchart 
for data to be collected. 
Final drug accountability must be performed even if the subject is not able to come to the trial site.  
A treatment status session to register discontinuation of treatment must be made in the IWRS. 
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record.
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent.
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights. 
Where the reasons are obtained, the primary reason for withdrawal must be specified in the ‘end of 
trial’ form in the CRF.
8.2.1
Replacement of subjects
Subjects who discontinue trial product or withdraw from trial will not be replaced.
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8.3
Lost to follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site at the ‘end of treatment’ visit. 
The following actions must be taken if a subject fails to return to the trial site for a required visit:
!
The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule or at least 
attend visit 11 and ascertain whether or not the subject wishes to and/or should continue in the 
trial.
!
Before a subject is deemed lost to follow-up, the investigator must make every effort to regain 
contact with the subject (where possible, at least three telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). If 
attempts have failed, family members or other contacts consented by the subject can be 
contacted for alternative contact details. These contact attempts should be documented in the 
subject’s medical record.
!
Should the subject continue to be unreachable at the ‘end of treatment’ visit, he/she will be 
considered to have withdrawn from the trial with a primary reason of lost to follow-up. 
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9
Trial assessments and procedures
!
Trial procedures and their timing are summarised in the flowchart and in Appendix 2. 
!
Informed consent must be obtained before any trial related activity, see Appendix 3.
!
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
!
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable.
!
At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant trial site staff. 
!
Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
!
Assessments should be carried out according to the clinic’s standard of practice unless 
otherwise specified in the current section. Efforts should be made to limit bias between 
assessments. The suggested order of the assessments:
o
Blood sampling (at fasting visits)
o
Electrocardiogram (ECG) and vital signs
o
Other assessments
!
Source data of clinical assessments performed and recorded in the CRF must be available and 
will usually be the subject’s medical records. Additional recordings to be considered source data 
include, but are not limited to laboratory reports, ECGs and diaries. 
!
Subjects must be instructed how to collect dosing information in a designated paper dosing 
diary and entries must be entered in the CRF. 
!
Only the subject can make entries and corrections in the diaries, unless the section is specified 
for site staff.
!
Subjects must receive instructions in how to capture their diet and physical activity. The entries 
from the diet and physical activity diary will not be entered into the CRF.
!
Only the subject can make entries and corrections in the diaries, unless the section is specified 
for site staff.
!
The barriers and motivation interview identifies barriers to and motivation for lifestyle change 
and compliance with the protocol. The interview must be conducted at screening to assist in 
identifying subjects who are unable or unwilling to comply with protocol procedures as per the 
exclusion criteria. In addition, the interview will ensure that any minor barriers are addressed 
during lifestyle counselling.  
!
The results of the barriers and motivation interview will not be entered into the CRF. It will be 
at the investigator’s discretion to evaluate the motivation of the subject and related eligibility.
!
Weight history must be recorded in the subject’s medical record and the CRF. Weight history 
should include the following questions: what was subject’s weight a year ago?, what has been 
the subject’s maximum weight?, how old was the subject at that time when he/she gained 
maximum weight?, in the subject’s own opinion, was the subject obese when 5 years old, 11 
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years old, 18 years old?, what is the least the subject has ever weighed as an adult?, how many 
times has the subject intentionally lost ≥ 11 lb/5 kg?, did any of the subject’s first degree 
relatives ever have overweight or obesity?
!
Review of completed diaries, clinical outcome assessments (COAs), ECG, laboratory reports 
etc. must be documented either on the documents or in the subject’s medical record. If 
clarification of entries or discrepancies in the diary or COA 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.
!
Repeat laboratory samples may be taken for technical issues and unscheduled samples or 
assessments may be taken for safety reasons. Refer to Appendix 2 for further details on 
laboratory samples.
9.1
Efficacy assessments 
9.1.1
Body measurements
!
Body weight should be measured without shoes, on an empty bladder and only wearing light 
clothing. It should be measured on a digital scale and recorded in kilograms or pounds (both to 
one decimal precision) using the same scale throughout the trial. The scale must be calibrated 
according to local requirements. 
!
Height is measured without shoes in inches (one decimal precision) or to the nearest centimeter 
(cm). BMI will be calculated automatically in the CRF.
!
Waist circumference is defined as the abdominal circumference located midway between the 
lower rib margin and the iliac crest. Measures must be obtained in standing position with a non-
stretchable measuring tape and to the nearest cm or inch. The tape should touch the skin but not 
compress soft tissue. The subject should be asked to breathe normally. The same measuring tape 
should be used throughout the trial. 
9.1.2
Clinical efficacy laboratory assessments
All protocol required efficacy laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the flowchart in Section 2 and the laboratory flowchart.
9.1.3
Efficacy clinical outcome assessments
Efficacy COAs will be obtained at visit 2, 6 and 11. 
The COAs will be available on a tablet in a linguistically validated version. Subjects should be 
given the opportunity to complete the questionnaires by themselves without interruption. Each 
questionnaire takes approximately 10 minutes to complete. The questionnaires should preferably be 
completed after fasting related activities (i.e. blood sampling) have been concluded.
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The following efficacy COAs will be used:
!
SF-36 v2.0 acute41 measures the subject’s overall health related quality of life. It is a 36-item 
generic measure of health status that yields two summary scores for physical health and mental 
health, and eight domain scores.
!
TFEQ-R18v242 measures dietary restraint. There are three different factors: (1) Cognitive 
Restraint, comprised of three items, (2) Uncontrolled Eating, comprised of nine items, and (3) 
Emotional Eating, comprised of six items. TFEQ-R18v2 comprises a total of 18 items, which 
are aggregated to three separate scale scores. Higher scores indicate more uncontrolled eating, 
cognitive restraint and emotional eating.
9.2
Adverse events
The definitions of AEs and SAEs can be found in Appendix 4.
The investigator is responsible for detecting, documenting, recording and following up on events 
that meet the definition of an AE or SAE.
9.2.1
Time period and frequency for collecting AE and SAE information
All AEs will be collected from the first trial related activity after obtaining informed consent and 
until the ‘end of trial’ visit, at the time points specified in the flowchart.
All SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as indicated 
in Appendix 4. The investigator must submit any updated SAE data to Novo Nordisk within 24 
hours of it being available.
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the investigational trial product or trial participation, the investigator 
must promptly notify Novo Nordisk.
The method of recording, evaluating and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 4.
Timelines for reporting of AEs are listed in Figure 9-1.
Some AEs require additional data collection via a specific event form. This includes medication 
errors observed during the trial. The relevant specific events are listed in Table 9-1 and the 
reporting timelines in Figure 9-1.
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Table 9-1
AEs requiring additional data collection (via specific event form)
Event type
Medication error
Acute gallbladder disease
Acute coronary syndrome
Cerebrovascular events
Heart failure
Coronary artery revascularisation
Neoplasm
Hypocalcaemia
AE identified
AE form ≤  24 hours
SIF ≤5 calendar days
Sign off ≤ 7 calendar days
Is the AE serious or 
non-serious?
AE form
Is the AE listed as 
requiring a Specific Event 
Form to be completed?
Non-serious
Serious
No additional action
No
Specific event form
For SAE:
≤14 calendar days
Yes
Timelines are from the awareness of an AE.
Queries and follow-up requests to be resolved ≤14 calendar days.
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety Information Form
Figure 9-1
Decision tree for determining the event type and the respective forms to 
complete with associated timelines
9.2.2
Method of detecting AEs and SAEs
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events.
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9.2.3
Follow-up on AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilisation, or if the event is 
otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in Section 
8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4
Regulatory reporting requirements for SAEs
Prompt notification by the investigator to Novo Nordisk of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met. 
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo N ordisk 
will comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Independent Ethics Committee (IEC) and Institutional Review Board (IRB), 
and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
(SUSARs) according to local regulatory requirements and Novo Nordisk policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other specific safety 
information (e.g. summary or listing of SAEs), from Novo Nordisk will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
9.2.5
Cardiovascular and death events
Cardiovascular and death events will be handled and reported according to AE/SAEs description in 
Section 9.2.1.
9.2.6
Disease related events and/or disease related outcomes not qualifying as an AE or 
SAE
Not applicable for this trial.
9.2.7
Pregnancies and associated adverse events
Details of pregnancies in female subjects and female partners of male subjects (paternal) will be 
collected after the first trial related activity after obtaining informed consent and until the ‘end of 
trial’ visit.
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If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in
Figure 9-2 and Appendix 5.
If a pregnancy is reported in female partners of male subjects, the pregnancy should be documented 
in the medical record of the male subject and in case of abnormal outcome, the investigator should 
inform Novo Nordisk within 14 calendar days of learning of the abnormal outcome and should 
follow the procedures outlined in Figure 9-3 and Appendix 5
Pregnancy outcome should be documented in the subject’s medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE.
Maternal form 1b
≤14 calendar days after birth
Maternal form 1a
≤14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2 ≤14 calendar days
Paternal form*1 ≤14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent .
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 9.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
Figure 9-2
Decision tree for determining the forms to complete with associated timelines 
for pregnancy 
Pregnancy outcome?
After birth/
termination 
of pregnancy
No additional action
Normal outcome *1
Paternal form ≤14 calendar days
Maternal form 1a*1 ≤14 calendar days
Maternal form 1b*1 ≤14 calendar days
Maternal form 2*1 ≤14 calendar days
Abnormal outcome *1
Pregnancy verified
for female partner
*1Further information collected on Maternal form 1a, 1b and 2 form from the 
female partner of male subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn should 
follow the timelines in Figure 9.1.
For male subjects
Document in 
subjects medical 
records
Figure 9-3
Decision tree for determining the forms to complete with associated timelines 
for pregnancy
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9.2.8
Medical device incidents (including malfunctions)
Section is not applicable for this trial. Refer to technical complaints in Section 9.2.9.
9.2.9
Technical complaints
The investigator must assess whether a technical complaint is related to an AE. The definitions and
reporting process for technical complaints can be found in Appendix 6.
Timelines for reporting technical complaints are listed in Figure 9-4.
Technical complaint form : ≤ 24 hours 
AE form: ≤ 24 hours 
SIF: ≤ 5 calendar days
Is it related to an SAE?
Technical complaint 
identified
Is it related
to an AE?
Yes
No
Technical complaint form
≤ 5 calendar days
Technical complaint form : 
≤ 5 calendar days
AE form: ≤ 5 calendar days
No
Yes
AE: Adverse Event, SAE: Serious Adverse Event,  SIF: Safety Information Form
Figure 9-4
Decision tree for determining the forms to complete with associated timelines 
for technical complaints
9.3
Treatment of overdose
An overdose is defined at the investigator’s discretion and must be reported as a medication error. 
Remember that symptoms can develop over time. Refer to Section 9.2.1 for further details.
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE and laboratory abnormalities until clinically safe, taking into account the long half-life of 
NNC0174-0833. Decisions regarding dose interruptions or modifications will be made by the 
investigator based on the clinical evaluation of the subject.
Repeated doses of NNC0174-0833 up to 1300 μg/weekly without dose escalation and 800 μg/day 
with appropriate dose escalation have been found safe and well tolerated. Dosing a similar dose 
without escalation may lead to GI side effects like nausea and vomiting.
Likewise, based on clinical trials and marketed use of liraglutide 3.0 mg, overdoses up to 24 times 
the recommended dose have been reported (72 mg/day vs 3 mg/day). One case of a 6-fold overdose 
(18 mg/day) given for 7 months has been reported. Generally, the patients reported severe nausea, 
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vomiting and diarrhoea, but recovered without complications. None of the reports included severe 
hypoglycaemia.
For more information on potential clinical effects of an overdose, also consult the current edition of 
the liraglutide 3.0 mg or NNC0174-0833 IB34, 36 and any updates hereof and/or contact Novo 
Nordisk. 
9.4
Safety assessments 
A concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit) or 
found as a result of a screening procedure or other trial procedures performed before exposure to 
trial product. 
Medical history is a medical event that the subject has experienced in the past. Only relevant and 
significant medical history as judged by the investigator should be recorded. 
As part of the medical history information related to history of gallbladder disease, breast 
neoplasms, colon neoplasms, skin cancer and psychiatric disorders will be recorded. Follow-up 
questions will be asked at the ‘end of treatment’ and ‘end of trial’ visits, related to the breast 
neoplasm (for female subjects) and colon neoplasm.
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the ‘Medical History/Concomitant Illness’ form in the CRF if it is present at screening. Any new 
finding fulfilling the AE definition (Appendix 4) during the trial and any clinically significant 
worsening from screening (visit 1) must be reported as an AE (Section 9.2.1).
Tobacco use will be recorded at screening. Smoking is defined as smoking at least one cigarette or 
equivalent daily.
9.4.1
Physical examinations
!
A physical examination will include assessments of the general appearance, thyroid gland, 
abdomen, as well as the cardiovascular, respiratory, central and peripheral nervous systems.
!
Investigators should pay special attention to clinical signs related to previous serious illnesses.
9.4.2
Vital signs
!
Pulse rate, as well as diastolic and systolic blood pressure will be assessed.
!
Blood pressure and pulse measurements should be preceded by at least five minutes of rest for 
the subject in a quiet setting without distractions (e.g. television, cell phones).
!
Blood pressure at screening will consist of 3 diastolic and systolic blood pressure measurements
with intervals of at least 1 minute. All three readings must be entered in the CRF and the 
average of the 3 blood pressure readings will be calculated in the CRF. At the subsequent visits, 
the blood pressure should only be measured once.
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!
Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
9.4.3
Electrocardiograms
!
12-lead ECG will be obtained as outlined in the flowchart using a local ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals. 
9.4.4
Clinical safety laboratory assessments
All protocol required safety laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart in Section 2 and the laboratory flowchart.
!
Urine pregnancy tests, supplied by central laboratory, must be performed for postmenopausal 
female subjects who have stopped menstruating within the last 5 years and for female subjects 
with bilateral tubal ligation. Urine pregnancy test must be repeated at any time during the trial if 
pregnancy is suspected. 
!
Urinalysis: Proteinuria should be assessed using urine collection to measure urine protein-to-
creatinine ratio. The urine specimen should be collected on first morning sample on the day of 
visit 2, 4, 6, 9 and 11. 
9.4.5
Immunogenicity assessments
Assessment of antibodies against NNC0174-0833 in serum will be performed by a laboratory 
assigned by Novo Nordisk for subjects randomised to NNC0174-0833/NNC0174-0833 placebo.
Blood samples to be analysed for serum antibodies against NNC0174-0833 will be drawn as 
outlined in Appendix 2 and the laboratory flowchart. All samples must be drawn prior to trial 
product administration if trial product administration is planned on the sampling day.
The in vivo neutralising effect of anti-NNC0174-0833 antibodies will be evaluated by correlation to 
PK, weight loss and other relevant parameters, if relevant.
In addition, samples confirmed positive for NNC0174-0833 antibodies at visit 12 will be further 
characterised for in vitro neutralising effect using a neutralising antibody assay. Detailed 
description of the assay methods will be included in an analytical report. Antibody assays will be 
validated according to international guidelines and recommendations.
As native amylin is extremely prone to fibrillation it may not be feasible to analyse for cross 
reactivity to endogenous amylin or the potential neutralising effect on endogenous amylin.
Follow-up analyses
Subjects who have tested positive for antibodies against NNC0174-0833 (high titre antibodies 
and/or in vitro neutralising antibody response) at visit 12 (‘end of trial’ visit) will be requested to 
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have a follow-up analysis performed 6 months after visit 12. If the follow-up analysis is positive for 
antibodies against NNC0174-0833, the subject will be requested to have an additional follow-up 
analysis performed 12 months after visit 12. 
The result from additional follow-up analyse(s) will be reported in separate analytical report. Thus, 
the results will not be part of the clinical trial report (CTR). 
9.4.6
Hypersensitivity
In case of suspicion of a severe systemic hypersensitivity reaction to the trial product, the subject 
must be discontinued from trial product but should remain in the trial. 
The following information in Section 9.4.6 is only relevant for subjects randomised to NNC0174-
0833/NNC0174-0833 placebo.
In the event of a severe systemic hypersensitivity reaction possibly or probably related to trial 
product, a blood sample should be taken as soon as possible and no later than 1-2 weeks after the 
reaction. A second sample should be taken 3-4 weeks after the reaction.
The following assessments will be performed:
!
Anti-NNC0174-0833 IgE antibodies 
!
Anti-NNC0174-0833 binding antibodies 
!
Tryptase
If deemed relevant by Novo Nordisk other relevant exploratory tests may be performed, e.g. 
basophil activation, complement tests, prick tests and/or intra-dermal tests. 
The analyses will be performed by a laboratory assigned by Novo Nordisk.
9.4.7
Safety clinical outcome assessments
Safety COAs will be obtained at visit 2, 4, 6, 8, 9, 10 and 11. 
The following COAs will be used:
!
PHQ-938 is a 9-item depression module of the patient health questionnaire, which is a self -
administered diagnostic tool used for assessment of mental disorders. 
o
The questionnaire will be available in a linguistically validated translated version. 
!
C-SSRS43 is a detailed questionnaire assessing both suicidal behaviour and suicidal ideation.
o
The questionnaire (C-SSRS Baseline and C-SSRS Since Last Visit) will be available in a 
linguistically validated translated version.
o
The questionnaire will be administered as an interview by the investigator or a qualified 
delegate, who prior to administering the questionnaire, must complete sufficient training.
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At the randomisation visit PHQ-9 and C-SSRS should be obtained, prior to randomising the subject, 
and scores evaluated according to the randomisation criteria. If the subject does not fulfil the 
randomisation criteria, SF-36 and the TFEQ-R18v2 are not required.  
If a subject has a PHQ-9 score of 10-14 (both inclusive) the subject should be referred to a mental 
health professional (MHP) if judged relevant by the investigator. If referral is not deemed relevant 
this along with the reason why must be documented in the subject’s medical records.
A subject must be referred to a MHP if:
!
the subject has a PHQ-9 score ≥15 or
!
the subject has any suicidal behaviour or
!
the subject has any suicidal ideation of type 4 or type 5 on any C-SSRS assessment or
!
in the opinion of the investigator, it is necessary for the safety of the subject
If one or more of the referral criteria are met, the investigator should explain to the subject why the 
referral and psychiatric evaluation by a MHP is needed. If the subject refuses to be referred to a 
MHP, the subject’s decision should be documented in subject’s medical record and the investigator 
must assess if it is safe for the subject to continue in the trial or if the subject should be discontinued 
from trial product.
If a subject’s psychiatric disorder can be adequately treated with psychotherapy and/or 
pharmacotherapeutic treatment, then the subject, at the discretion of the investigator (and in 
agreement with the MHP), may continue in the trial. Otherwise, the subject must be discontinued 
from trial product due to safety concern as judged by the investigator.
9.4.8
Ambulatory blood pressure monitoring 
At, the end of visit 1 all subjects will have an ambulatory blood pressure monitoring (ABPM) 
device attached, by site personal, and blood pressure monitoring must be performed for a full 24 
hours. At visit 11, only subjects randomised to NNC0174-0833/NNC0174-0833 placebo, will have 
an ABPM device attached and blood pressure monitoring performed for 24 hours.
During the 24 hour periods the subject is allowed to leave the clinic.
The subject must be trained by the investigator or delegated site staff to remove the ABPM device 
after 24 hours of blood pressure monitoring and bring the ABPM device to the clinic at the next 
visit. The investigator or delegated site staff must assess if all blood pressure data have been 
collected. In case of invalid data the subject must have ABPM performed for another 24 hour period 
starting at the current visit. If needed the subject should be re-trained in removing the ABPM
device.
An ABPM device instruction should be handed out to the subject according to the flowchart.
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9.5
Pharmacokinetics
The plasma concentration measurements of NNC0174-0833 will be performed by a laboratory 
assigned by Novo Nordisk.
Blood samples will be used to evaluate PK of NNC0174-0833 and may also be used to evaluate 
safety or efficacy aspects that address concerns arising during the trial. 
Blood samples for measuring plasma concentration of NNC0174-0833 will be drawn and collected 
in P800 tubes, for NNC0174-0833/NNC0174-0833 placebo subjects at visits outlined in Appendix
2 and in the laboratory flowchart. Subject must be instructed to withhold their trial product dose in 
the morning of the clinic visit until blood sampling has been performed.
Long venous stasis time should be avoided when sampling, as venous stasis activates fibrinolytic 
processes, which may induce proteolytic degradation of NNC0174-0833. 
Blood sampling and handling must be performed as detailed in the laboratory flowchart.
The NNC0174-0833 plasma concentration will be measured for all samples from subjects dosed 
with NNC0174-0833 and selected NNC0174-0833 placebo samples. The remaining NNC0174-
0833 placebo samples will only be analysed if the concentration of the selected samples are not 
below the lower level of quantification.
9.6
Pharmacodynamics
Not applicable for this trial. 
9.7
Genetics 
Blood samples for genetic analyses will be collected at visit 2, 6 and 11 (Appendix 2 and the 
laboratory flowchart) from subjects who have consented to participate in the genetic analysis 
component of the trial. A blood sample for DNA sequencing will be taken at visit 2 and blood 
samples for RNA sequencing will be taken at visit 2, 6 and 11. Participation in the genetic analysis 
is optional. Subjects who do not wish to participate in the genetic analysis may still participate in 
the trial.
The RNA and DNA samples will be sequenced using RNAseq and DNA-sequencing methods. The 
sequence data will be used for analysis of correlations between weight loss efficacy and expression 
profiles (RNAseq) or SNP analysis (DNA-sequencing) to provide a better mechanistic 
understanding of the effects of NNC0174-0833, including whether weight loss can be predicted 
from baseline characteristics. 
Details on processes for collection, shipment and destruction of these samples can be found in the 
laboratory manual and the laboratory flowchart.
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These data will first be analysed after the trial has come to an end, and results will, therefore, not be 
part of the CTR.
9.8
Biomarkers 
Collection of blood samples for biomarker analysis is part of this trial and will be collected from all 
subjects in this trial as specified in Appendix 2 and in the laboratory flowchart.
9.9
Biosamples for future analysis
Collection of blood samples for future analysis is a component of this trial. Participation in this 
component is optional and subjects who do not wish to participate may still participate in the trial. 
Blood samples will be collected for future biomarker analyses at visit 2, 6 and 11 and for future 
genetic analyses at visit 2 and 11 (Appendix 2 and the laboratory flowchart). All blood samples will 
be stored for future use.
The samples are collected for the purpose of allowing future biomarker and genetic analyses when 
new knowledge or improved measurement techniques may have become available. 
Biomarker analyses may include biomarkers currently known or discovered in the future. Genetic 
analyses may include analysis of candidate genes or genetic markers throughout the genome.
Potential biomarker and genetic analyses will be performed with the purpose of understanding and 
predicting response to NNC0174-0833 as well as understanding obesity or other related diseases.
The subject will not be informed about potential results as the analyses are intended for finding 
trends in the population and not in the individual subject.
The analyses will be performed after the trial has come to an end, and results will, therefore, not be 
part of the CTR.
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10 Statistical considerations 
Taxonomy of week 26 assessments
For each subject a given assessment at week 26 may be available or missing and the subject may be 
on randomised treatment or not. Table 10-1 describes the taxonomy for this. Note, that this is done 
per assessment and per subject; subjects may be a different type for different assessments (a subject 
may have ‘available on randomised treatment (AT)’ for body weight but ‘missing on randomised 
treatment (MT)’ for waist circumference).
Table 10-1 Taxonomy for subjects based on week 26 assessments
Assessment
at week 26
Subjects on 
randomised 
treatment 
at week 26
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who complete the trial on randomised 
treatment with an assessment at week 26. This 
includes those that stop and restart trial product.
AT
No
Available but discontinued
Subjects who discontinue randomised treatment 
prematurely but return to have an assessment at 
week 26. These are also called retrieved subjects.
AD
Missing
Yes
Missing on randomised treatment:
Subjects who complete the trial on randomised 
treatment without an assessment at week 26. This 
includes those that stop and restart trial product.
MT
No
Missing and discontinued:
Subjects who discontinue randomised treatment 
prematurely and do not return to have an 
assessment at week 26. These are also called non-
retrieved subjects.
MD
Treatment non-adherence
‘Treatment non-adherence’ is defined as the occurrence of either one of the following events:
!
Missing two consecutive doses with NNC0174-0833/NNC0174-0833 placebo or seven 
consecutive doses with liraglutide 3.0 mg/liraglutide placebo
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!
Lowering the dose for:
o
two consecutive doses with NNC0174-0833/NNC0174-0833 placebo after reaching the 
target dose
o
one of the weekly collected doses with liraglutide 3.0 mg/liraglutide placebo after 
reaching the target dose
!
Initiating any other weight management drugs
!
Undergoing bariatric surgery or use of weight loss device (e.g. intragastric baloons)
!
Not reaching target dose according to the escalation regimen. For the respective treatment arms 
this will be evaluated at the following weeks:
Active 
treatment / 
placebo
NNC0174-
0833 
0.3 mg
NNC0174-
0833 
0.6 mg
NNC0174-
0833 
1.2 mg
NNC0174-
0833 
2.4 mg
NNC0174-
0833 
4.5 mg
Liraglutide 
3.0 mg
Evaluation 
week
0
0
3
6
9
8
10.1
Sample size determination 
The sample size is based on the objective of finding the optimal dose of NNC0174-0833 and is 
based on the primary endpoint. To characterise the shape of the curve for the dose-response 
relationship it is considered adequate to test 5 doses of NNC0174-0833 and the sample size for each 
dose is determined in order to achieve a good precision on this relationship. Furthermore, sample 
size estimation is based on addressing assumptions corresponding to the analyses of both the 
primary and secondary estimands.
In the imputation approach used for the sample size calculations addressing the primary estimand 
missing values (MT and MD) and assessments from retrieved subjects (AD) are assumed to be 
similar to treatment completers (AT) within the same treatment group. In the imputation approach 
used for the sample size calculations addressing the secondary estimand, missing values (MT and 
MD) are assumed to be similar to placebo subjects regardless of treatment arm.
The five different injection volumes in each of the NNC0174-0833 placebo arms and the one
liraglutide placebo arm will be pooled into one placebo group in the main analyses. This pooling 
assumes that there is no substantial effect of different placebo volumes or different dose escalation 
on the efficacy and safety endpoints. This is consistent with findings from previous obesity trials 
(NN8022-1922 and NN9536-4153). 
The assumptions for the sample size calculations are:
!
The significance level is 5%
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!
100 subjects are included in each of the NNC0174-0833 arms, 100 subjects in the liraglutide 
3.0 mg OD arm and 100 subjects in total in the pool of NNC0174-0833 placebo and liraglutide 
placebo arms
!
Assumptions corresponding to the primary estimand:
o
Standard deviation of 5.2% for relative change in weight loss at week 26 (based on data 
from trial NN9536-4153)
o
Treatment effect versus the pooled placebo group of at least 8% for the optimal dose 
among completers (based on data from trial NN9536-4153)
o
Treatment effect versus liraglutide 3.0 mg of at least 3% among completers (based on 
data from trial NN9536-4153 and NN8022-1839)
!
Assumptions corresponding to the secondary estimand:
o
Standard deviation of 5.6% for relative change in weight loss at week 26 (based on data 
from trial NN9536-4153)
o
13% of subjects discontinue randomised treatment permanently and 60% of these are 
retrieved (AD) at week 26 (Based on data from trial NN9536-4153)
o
All subjects in the pooled placebo group are assumed to have the same effect as subjects 
who complete the trial on placebo (AT)
o
Retrieved subjects (AD) in any of the active arms are assumed to have an effect 
corresponding to half the treatment difference (compared to the pooled placebo group) 
of subjects who complete the trial in that arm (AT)
o
Non-retrieved subjects (MD) in any of the active arms are assumed to have an effect 
corresponding to the pooled placebo group
o
Treatment effect versus the pooled placebo group of at least 7.3% for the optimal dose 
after adjustment for treatment discontinuation and missing data 
!
The treatment differences are analysed by two-sided t-tests which is a simplification of the 
main analyses including explanatory variables
The probabilities and power calculations beneath are based on assumptions for the secondary 
estimand (primary estimand for the treatment effect versus liraglutide 3.0 mg). However, both the 
primary and secondary estimands will be covered, since the probabilities and power for the primary 
estimand are higher compared to the secondary estimand. 
To characterise the dose-response relationship well, the precision of the mean difference between 
any NNC0174-0833 dose and the pooled placebo group is evaluated by calculating the probability 
of the half-width of the confidence interval (CI) to be equal to or below a given value. Table 10-2
gives this probability for different number of subjects and values for the CI half-width.
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Table 10-2 Probability of desired CI half-width
N per active arm /    
N for pooled 
placebo group
CI half-width (%)
Probability
100
1.7
96%
80
1.7
32%
100
1.6
69%
80
1.6
7%
A sample size of 100 subjects in each active treatment arm compared with a pooled placebo group 
of 100 subjects allows the 95% CI for the treatment difference between any active arm and placebo 
to be contained within +/-1.7% of the estimate with 96% probability. This is considered to be a 
sufficient precision to characterize the dose-response relationship. In total this requires a sample 
size of 700 subjects.
For the primary endpoint, change from randomisation at week 0 to week 26 in body weight (%), a 
sample size of 100 subjects in each active treatment arm results in a power of more than 99% for a 
significant difference between the optimal dose of NNC0174-0833 and the pooled placebo group.
For the primary endpoint a sample size of 100 subjects in each active treatment arm results in a 
power of 98% for detecting a significant difference between the optimal dose of NNC0174-0833 
and liraglutide 3.0 mg for the primary estimand.   
10.2
Definition of analysis sets
Two analysis sets are defined:
The full analysis set (FAS) includes all randomised subjects according to the intention-to-treat 
principle.
The safety analysis set (SAS) includes all randomised subjects exposed to at least one dose of 
randomised treatment. 
Any observation excluded from the analysis will be documented before database lock with the 
reason for exclusion provided.
10.2.1
Observation periods
Three observation periods are defined for each subject:
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!
In-trial: The in-trial period is defined as the uninterrupted time interval from date of 
randomisation to date of last contact with trial site. Follow-up time for positive antibodies is not 
included in the in-trial period.
!
On-treatment: A time-point is considered as ‘on-treatment’ if any dose of trial product has been 
administered within the prior 6 weeks. The on-treatment period is defined as all times which are 
considered on-treatment. The on-treatment period will therefore be from the date of first trial 
product administration to date of last trial product administration excluding potential off-
treatment time intervals triggered by at least 6 consecutive missed doses for NNC0174-0833 or 
6 consecutive weeks of missed dosing with liraglutide.
!
Treatment-adherent: A time-point is considered as ‘treatment-adherent’ if trial product has been 
administered within the prior 2 weeks with NNC0174-0833 or 1 week with liraglutide and only 
before the first event of ‘treatment non-adherence’. The derived date of the missed or lowered 
dose causing treatment non-adherence (second consecutive with NNC0174-0833 or seventh 
consecutive with liraglutide) will be used as the latest date for including assessments in this 
observation period. For subjects who initiate any other weight loss intervention before this date, 
the date of starting other weight management drugs or undergoing bariatric surgery will be used 
as latest date for using assessments in this observation period. Thus, the assessment closest in 
time and before the date of starting any weight loss intervention will be used as last assessment 
on randomised treatment. For subjects not reaching target dose according to the escalation 
regimen no post-baseline assessments will be included.
The in-trial and on-treatment periods define the patient years of observation (PYO) and patient 
years of exposure (PYE), respectively, as the total time duration in the periods.
10.3
Statistical analyses
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.
Efficacy endpoints will be analysed using the FAS; safety endpoints will be analysed using the 
SAS. 
Handling of missing baseline data
The last available and eligible observation at or before randomisation is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all subjects is used as the 
baseline value.
10.3.1
Primary endpoint
Definition of primary endpoint: % weight change
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Change from randomisation at week 0 to week 26 in body weight (%) is defined as:
% weight change =  (body weight at week 26 – body weight at baseline)
body weight at baseline
×100%
10.3.1.1
Analyses addressing the primary estimand
The primary estimand for % weight change addresses the efficacy of NNC0174-0833 and will be 
estimated based on the FAS using post-baseline measurements up to and including week 26 from 
the treatment-adherent observation period. 
The primary analysis for the primary estimand for % weight change is an analysis of covariance 
(ANCOVA) with randomised treatment as factor and baseline body weight (kg) as a covariate.
Handling of missing week 26 values for the primary estimand
Observations outside the treatment-adherent observation period such as week 26 assessments for 
retrieved drop-outs (AD) will be handled as if they were missing and will be imputed using multiple 
imputation assuming that missing data is missing at random (MAR). Missing data will be imputed 
using observed data within the same randomised treatment group. This approach makes the 
assumption that subjects with missing data and subjects with dose non-adherence or weight loss 
intervention have the same effect as subjects adhering to randomised treatment without initiating 
any other weight loss intervention.
In case the definition of treatment non-adherence is too restrictive excluding observations due to 
dose lowering will not be implemented. Next, a higher number of allowed missed dose will be 
considered.
The multiple imputation is done in three steps:
1. Imputation: 
a.
Intermittent missing values are imputed using a Markov Chain Monte Carlo (MCMC) 
method, in order to obtain a monotone missing data pattern. This imputation is done for 
each of the treatment groups separately and 1000 copies of the dataset will be generated
b. A sequential regression approach for imputing monotone missing values at planned 
visits will be implemented starting with the first visit after baseline and sequentially 
continuing to the last planned visit at week 26. A model used to impute missing values at 
each planned visit will be fitted for each of the treatment groups (each NNC0174-0833 
dose, liraglutide 3.0 mg or pooled placebo) using observed data. The model will include 
gender (male/female) and region as factors and baseline and post-baseline body weight 
(kg) values observed prior to the visit in question as covariates.
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2. Analysis: An ANCOVA with treatment as categorical effects and baseline body weight (kg) as 
a covariate will be used to analyse body weight % change at week 26 for each of the 1000 
complete data sets generated as part of the imputation of missing values. 
3. Pooling: Rubin’s rule will be used to combine the analysis results in order to draw inference.
The proportion of missing weight change data at week 26 is estimated to be 5% (based on data from 
trial NN9536-4153) and is expected to be similar in all treatment arms.
Of relevance for the estimation of the primary estimand, the combined proportion of missing data 
and subjects with treatment non-adherence is estimated to be 13%. This is based on data on 
proportion of subjects discontinuing treatment from trial NN9536-4153 and a very low expected 
proportion of subjects undergoing bariatric surgery or starting other weight management drugs. 
NNC0174-0833 treatment is expected to be effective with regard to weight loss, and this should 
reduce the number of missed doses due to ineffective therapy. A higher rate of missed doses due to 
GI AEs is expected in the high NNC0174-0833 dose treatment arms and the liraglutide 3.0 mg arm 
compared to placebo. Apart from this, the rate of missed doses due to AEs is expected to be similar 
across groups. Based on previous experience, a higher rate of treatment discontinuation due to other 
reasons is expected in the placebo group compared to active treatment. This difference may be due 
to lack of efficacy with placebo treatment. 
The estimated treatment difference between individual NNC0174-0833 doses and pooled placebo 
group will be reported together with the associated two-sided 95% CI and corresponding two-sided 
p-value. The pooled placebo group will include all subjects on NNC0174-0833 placebo as well as 
liraglutide placebo.
Confirmation of superiority for each NNC0174-0833 dose vs. placebo will be evaluated using a 
hierarchical testing procedure starting with the treatment difference between the highest NNC0174-
0833 dose and placebo and ending with the lowest dose. In the case of a non-significant treatment 
difference the testing procedure will stop. This will protect the family-wise type 1 error in the 
strong sense on a 5% level of significance.
The superiority test for NNC0174-0833 vs. placebo will be carried out as follows. Let                
μNNC0174-0833 ,x and μplacebo denote the true mean of % weight change for dose level x of NNC0174-
0833 and the pooled placebo group, respectively. The null and alternative hypotheses tested are
:  , ≥ !"#$% vs. &:  , <  !"#$%
The null hypothesis will be rejected if the upper limit of the estimated two-sided 95% CI for the 
treatment difference is below 0. 
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Dose-response modelling
In order to evaluate the effect of NNC0174-0833 dose vs. placebo on % weight change and to 
characterise the dose-response relationship the mean % weight change will be estimated using dose 
as a continuous variable.
The dose-response candidate models in Table 10-3 will be fit.
Table 10-3
Dose-response candidate models
Model
Functional form f(d,θ)
Emax
( + (*!
+
(,- + +
Sigmoidal Emax
( + (*!
+.
(,-
. + +.
Linear
( + /+
Linear log-dose
( + /log(+ + 1)
Quadratic
( + /+ + /1+1
The candidate models will be fit to the estimated % weight change means at week 26 for the 
employed NNC0174-0833 doses and placebo from the primary analysis model described above. 
Thus all subjects in the FAS will be included and the same assumptions regarding missing values 
and the impact of explanatory variables will be applied. When fitting the models estimated % 
weight change means will be weighted by their inverse estimated variances.
The model used to evaluate dose-response will be selected among the candidate models based on 
the best fit to data. The best fit will be evaluated based on convergence, model complexity, Akaike 
information criterion (AIC) value and visual evaluation. 
Dose-response curves will be estimated and plotted using the fitted dose-response model both for 
placebo-adjusted and non placebo-adjusted estimates.
Analysis addressing the effect of NNC0174-0833 vs. liraglutide 3.0 mg
This analysis will evaluate the treatment difference between NNC0174-0833 and liraglutide 3.0 mg 
using the same analysis as the primary analysis for the primary estimand described above. However, 
the treatment differences between NNC0174-0833 doses and liraglutide will be estimated and no 
confirmatory testing will be carried out.
Sensitivity analyses
Post-baseline measurements excluded for subjects with treatment non-adherence: This sensitivity 
analysis will evaluate the robustness to the assumption that post-baseline data for subjects with 
treatment non-adherence is informative for the weight change had the subjects adhered. The same 
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analysis model and multiple imputation approach as for the primary analysis will be carried out, but 
for subjects with dose treatment non-adherence all post-baseline measurements will be handled as 
missing and imputed using multiple imputation.
10.3.1.2
Analyses addressing the secondary estimand
The following statistical analyses and imputation methods are designed to address the secondary 
estimand, i.e. to assess the effectiveness of NNC0174-0833. 
The analysis model for % weight change is an ANCOVA with randomised treatment as factor and 
baseline body weight (kg) as a covariate. 
Handling of missing week 26 values for the secondary estimand
All available data at week 26 (AT and AD) are used. Missing values (MT and MD) at week 26 will 
be imputed and the endpoints will be derived from the imputed values. First, a description of the 
primary imputation approach to address the secondary estimand for the primary endpoints is given 
followed by a description of the sensitivity analyses used to assess the robustness o f the primary 
analysis results. The sensitivity analyses investigate how assumptions on body weight development 
after discontinuation of randomised treatment impact the estimated treatment contrasts between 
active doses and placebo.
Primary imputation approach for the secondary estimand (RS-MI)
The primary analysis of the secondary estimand is a retrieved subjects based multiple imputation 
approach (RS-MI) which is simplified but similar to the one described by McEvoy44. Missing body 
weight measurement at week 26 for non-retrieved subjects (MD) are imputed using assessments 
from retrieved subjects (AD). Missing body weight measurements at week 26 for subjects on 
randomised treatment (MT) are imputed using available measurements at week 26 from subjects on 
randomised treatment (AT). The multiple imputation approach is done in three steps:
1. Imputation: An imputation model is defined using retrieved subjects (AD) from the FAS. The 
model will be a linear regression of body weight (kg) at week 26 with treatment as factor and 
baseline body weight (kg), last available treatment-adherent observation of body weight (kg) 
and number of days in the treatment-adherent observation period as covariates. No interactions 
will be included. If any subjects are MT, an imputation model for missing body weight 
measurements at week 26 for MT subjects will also be defined using AT subjects in a similar 
way. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 26 body weight 
values. This will be done 1000 times, resulting in 1000 complete data sets.
2. Analysis: Analysis of each of the 1000 complete data sets using the ANCOVA with treatment 
as factor and baseline body weight as covariate, resulting in 1000 estimates for each treatment 
comparison.
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3. Pooling: The 1000 estimation results are integrated into a final result using Rubin’s formula.
Treatment comparisons for NNC0174-0833 doses vs. placebo will be carried out as described for 
the primary analysis addressing the primary estimand. However, no confirmatory testing will be 
carried out.
Dose-response modelling
The selected model shape for the primary estimand will also be estimated based on mean estimates 
and their variances for % weight change from the ANCOVA model using the primary imputation 
approach for the secondary estimand.
Analysis addressing the effect of NNC0174-0833 vs. liraglutide 3.0 mg
This analysis will evaluate the treatment difference between NNC0174-0833 and liraglutide 3.0 mg 
using the same analysis as the primary analysis for the secondary estimand described above. 
However, the treatment differences between NNC0174-0833 doses and liraglutide will be 
estimated.
Sensitivity analyses
Multiple imputation approach using retrieved subjects (J2R-MI): A jump to reference multiple 
imputation approach will be applied. Missing values of body weight at week 26 (MT and MD) for 
all treatment groups are imputed by using available assessments at week 26 in the placebo group 
(AT and AD). This approach makes the assumption that subjects with missing data (MT and MD) 
lose any effect of randomised treatment beyond what can be expected from placebo treatment as 
adjunct to diet and physical activity. The multiple imputation approach is done in three steps. The 
imputation step is described below and step two and three are similar to the primary analysis for the 
secondary estimand.
An imputation model is defined using all placebo subjects from FAS with a week 26 measurement 
(AT and AD). The model will be a linear regression of body weight (kg) at week 26 on gender 
(male/female) and region as factors and baseline body weight (kg) as covariate. No interactions will 
be included. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 26 body weight values 
for each randomised treatment arm. This will be done 1000 times and results in 1000 complete data 
sets.
Treatment comparisons for NNC0174-0833 doses vs. placebo and liraglutide will be carried out as 
described for the analyses addressing the primary estimand.
Tipping-point multiple imputation analysis (TP-MI): First, missing data are imputed according to 
the primary RS-MI analysis. Second, for the active treatment arm a penalty will be added to the 
imputed values at week 26. The approach is to gradually increase this penalty until all conclusions 
from the primary analysis are reversed. For each superiority hypothesis testing an NNC0174-0833 
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dose vs. placebo the specific value of the penalty that reverses the conclusion will be used to 
evaluate the robustness of the assumption that subjects with missing data have the same effect as 
placebo.
10.3.2
Secondary endpoints
10.3.2.1
Supportive secondary endpoints
Supportive secondary endpoints are listed in Section 4. All supportive secondary endpoints will be 
analysed to address the primary estimand.
Efficacy endpoints
Continuous efficacy endpoints
!
Change from randomisation at week 0 to week 26 in:
o
Body weight (kg)
o
Waist circumference (cm) 
o
Fasting lipids (mg/dL)

Total cholesterol

HDL cholesterol

LDL cholesterol

VLDL cholesterol

Triglycerides
These continuous supportive secondary efficacy endpoints will be analysed using the same analysis 
model as the primary analysis for the primary endpoint addressing the primary estimand described 
in Section 10.3.1.1. The outcome variable % weight change and the covariate baseline body weight 
will be replaced by the corresponding outcome and baseline assessments of the endpoint to be 
analysed. Treatment differences will be estimated comparing each NNC0174-0833 dose with 
placebo and liraglutide.
For fasting lipids a multiplicative model will be used, i.e. the ratio between post randomisation 
measurements and baseline will be analysed as the outcome variable instead of differences, and 
both the outcome variable and the baseline assessment will be log-transformed prior to analysis.
!
Change from randomisation at week 0 to week 26 in:
o
HbA1c (%-point, mmol/mol)
o
FPG (mg/dL)
o
Fasting insulin (μIU/mL)
o
HOMA-IR (%-point)
o
HOMA-β (%-point)
These endpoints will be summarised by descriptive statistics using the FAS.
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Binary efficacy endpoints
!
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 5% from randomisation
o
Body weight reduction ≥ 10% from randomisation
The analysis model for the 5% and 10% body weight reduction endpoints is a logistic regression 
using randomised treatment as a factor and baseline body weight (kg) as covariate. 
The analysis will be based on FAS using the treatment-adherent observation period and 
observations outside this observation period will be handled as missing. Missing values of body 
weight at week 26 are imputed under the same assumption of MAR as for the primary analysis for 
the primary endpoint addressing the primary estimand using multiple imputation. The imputed data 
sets for continuous weight change % as described in Section 10.3.1.1 will be used to derive the 
binary weight reduction endpoints. The logistic regression model will be used to estimate log odds 
ratios comparing each NNC0174-0833 dose with placebo and liraglutide for each complete data set 
and Rubin’s rule will be used to draw inference. The results after applying Rubin’s rule will be 
back-transformed and described by the odds ratio.
Composite strategy
The following composite variables are defined by subjects who after 26 weeks achieve (yes/no): 
!
Body weight reduction ≥ 5% from randomisation and no treatment non-adherence
!
Body weight reduction ≥ 10% from randomisation and no treatment non-adherence
The analysis approach is the same as the logistic regression model including multiple imputation 
described above addressing the primary estimand except that for subjects with treatment non-
adherence no imputation of missing data will be used. Instead they will be considered not achieving 
the composite body weight variable.
Dose-response modelling for body weight reduction endpoints
The dose-response analysis of 5% and 10% body weight reduction endpoints will be carried out on 
the mean estimates of treatment log odds for each NNC0174-0833 dose and placebo obtained via 
the logistic regression with treatment as factor addressing the primary estimand described above. 
Candidate shapes listed in Table 10-4 will be fit and evaluated based on the best fit. Normal 
distribution of the mean estimates for the specific model will be assumed. Mean estimates will be 
weighted by the inverse of the estimated variances of the mean log odds.
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Table 10-4
Binary dose-response candidate models
Model
Link function for 
probability p
Functional form f(d,θ)
Logistic
log[6/(1 −6)]
( + /+
Emax
log[p/(1-p)]
( + (*!
+
(,- + +
Sigmoidal Emax
log[p/(1-p)]
( + (*!
+.
(,-
. + +.
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
Safety endpoints
Adverse events and anti-drug antibodies
!
Number of TEAEs from randomisation at week 0 to week 32 (‘end of trial’)
!
Number of SAEs from randomisation at week 0 to week 32 (‘end of trial’)
!
Occurrence (yes/no) of anti-drug antibodies towards NNC0174-0833 from randomisation at 
week 0 to week 32 (‘end of trial’)
Adverse events will be defined as ‘treatment-emergent’ (TEAE), if the onset of the event occurs in 
the on-treatment period, see definition in Section 10.2.1. TEAEs and treatment emergent SAEs will 
be summarised by descriptive statistics, such as frequencies and rates, using the SAS. No formal 
statistical inference will be carried out based on the number of TEAEs and SAEs.
Occurrence of anti-drug antibodies towards NNC0174-0833 will be summarised by descriptive 
statistics using the SAS.
Dose-response modelling for GI AEs
Analyses of the dose-response for the probability of subjects meeting two different response 
criteria:
!
Treatment discontinuation due to a GI adverse event (yes/no)
!
Having a GI adverse event (yes/no)
Dose-response modelling will be done on the SAS with binary response status (yes/no) for each 
subject during the on-treatment observation period as the outcome variable and dose as a continuous 
covariate. Candidate shapes listed in Table 10-4 will be fit and evaluated based on the best fit.
Continuous safety endpoints
!
Change from randomisation at week 0 to week 26 in:
o
Systolic blood pressure (mmHg) 
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o
Diastolic blood pressure (mmHg)
o
Mean 24-hour systolic blood pressure (mmHg)
o
Mean 24-hour diastolic blood pressure (mmHg)
o
Pulse (bpm)
o
hsCRP (mg/L)
o
PAI-1 activity (mg/L)
o
Renin activity (ng/mL/h)
o
Aldosterone (ng/dL)
These continuous safety endpoints will be summarised by descriptive statistics using the SAS.
10.3.3
Exploratory endpoints
!
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 15% from randomisation
o
Body weight reduction ≥ 20% from randomisation 
These endpoints will be analysed using the same logistic regression approach as described for body 
weight reduction ≥ 5% and ≥ 10% in Section 10.3.2.1.
!
Change from randomisation at week 0 to week 26 in:
o
Endogenous amylin 
o
Soluble leptin receptor
o
Leptin 
o
SF-36 v2.0 acute: 

Physical component summary score 

Mental component summary scores

Scores on the individual sub-domains: 
!
Physical functioning
!
Role functioning
!
Bodily pain 
!
General health
!
Vitality
!
Social functioning
!
Role emotional 
!
Mental health
o
TFEQ-R18v2: Transformed scale scores for the three scales measured: Uncontrolled 
Eating, Cognitive Restraint and Emotional Eating.
!
Time to permanent discontinuation of randomised trial product (weeks)
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Date of permanent discontinuation of randomised trial product is evaluated by the investigator in 
the ‘end of treatment’ form and used to derive the time to permanent discontinuation.
Physical functioning score will be analysed using the same analysis model as the primary analysis 
for the primary endpoint addressing the primary estimand described in Section 10.3.1.1. The 
outcome variable % weight change and the covariate baseline body weight will be replaced by the 
corresponding outcome and baseline assessments of the physical functioning score. Treatment 
differences will be estimated comparing each NNC0174-0833 dose with placebo and liraglutide.
The remaining endpoints will be summarised by descriptive statistics. 
10.3.4
Explorative statistical analysis for pharmacogenetics and biomarkers
No statistical analyses are planned for the genetic data described in Section 9.7. Planned analyses
for biomarkers are handled in Section 10.3.1, 10.3.2 and 10.3.4.
10.3.5
Other analyses
All collected data that were not defined as endpoints will be summarised by descriptive statistics.
10.4
Pharmacokinetic and/or pharmacodynamic modelling
Population PK and exposure-response analyses will be used as supportive evidence for the 
evaluation of efficacy and safety and further to support the dose selection of NNC0174-0833 for 
future clinical development in subjects with obesity. First, plasma NNC0174-0833 concentrations 
will be analysed using a population PK model, quantifying covariate (such as baseline body weight, 
age, gender, race, ethnicity, and injection site) effects on NNC0174-0833 exposure. Second, model 
based estimates of steady-state average concentrations will be derived for each subject, in order to 
facilitate subsequent exposure-response analyses. Relevant efficacy and safety endpoints will be 
related to steady-state average concentrations and subjected to model based analysis.
A modelling analysis plan will be prepared before database lock, outlining details of the analyses. 
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk and will 
be reported separately from the CTR.
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11 Appendices
Abbreviations and Trademarks
Appendix 1
AD
available but discontinued 
AE
adverse event
AIC
akaike information criterion
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ABPM
ambulatory blood pressure monitoring 
ANCOVA
analysis of covariance 
AST
aspartate aminotransferase
AT
available on randomised treatment 
BMI 
body mass index 
BMR
basal metabolic rate
CFR
Code of Federal Regulations
CI
confidence interval
CLAE
clinical laboratory adverse event
Cmax
maximum concentration of compound
COA
clinical outcome assessment
CRF
case report form
C-SSRS
columbia-suicide severity rating scale 
CtR
calcitonin receptor 
CTFG
Clinical Trial Facilitation Group 
CTR
clinical trial report
DFU
direction for use
DNA
deoxyribonucleic acid
DUN
dispensing unit number
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate 
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
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Version:
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FPG
fasting plasma glucose
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase 
GI
gastrointestinal
GLP-1 RA
glucagon-like peptide-1 receptor agonist 
HbA1c
glycated haemoglobin
hCG
human chorionic gonadotropin
HDL
high density lipoprotein 
HOMA-IR
homeostatic model assessment of insulin resistance 
HOMA-β
homeostatic model assessment of β-cell function
HRT
hormone replacement therapy
hsCRP
high sensitivity c-reactive protein 
IB 
investigator’s brochure
ICH
International Council for Harmonisation
ICMJE
International Committee of Medical Journal Editors 
IEC
Independent Ethics Committee
IMP
investigational medicinal product
INR
international normalised ratio 
IRB
Institutional Review Board
IWRS
interactive web response system 
J2R-MI
multiple imputation approach using retrieved subjects
KDIGO
Kidney Disease Improving Global Outcomes 
LDL
low density lipoprotein
LH
luteinizing hormone
MAR
missing at random
MCMC
Markov Chain Monte Carlo 
MD
missing and discontinued
MPH
mental health professional 
MT
missing on randomised treatment 
NAFLD/NASH
non-alcoholic fatty liver disease/non-alcoholic steatohepatitis 
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Trial ID: NN9838-4433
Version:
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Status:
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NYHA
New York Heart Association 
OD
once daily 
OW
once weekly 
PAI-1
plasminogen activator inhibitor-1
PCD
primary completion date
PD
pharmacodynamics 
PHQ-9
patient health questionnaire-9
PK
pharmacokinetics 
PR
specific ECG interval describing atrioventricular conduction
PTH
parathyroid hormone 
PYE
patient years of exposure
PYO
patient years of observation 
QRS
specific ECG interval describing ventricular depolarisation
QT
specific ECG interval describing ventricular depolarisation/repolarisation
QTc
heart-rate corrected QT interval
RAAS
renin-angiotensin-aldosterone system 
RNA
ribonucleic acid
RS-MI
retrieved subjects based multiple imputation approach 
SAE
serious adverse event
SAP
statistical analysis plan
SAS
safety analysis set 
s.c.
subcutaneous 
SF-36 
short form-36
SIF
safety information form
SUSAR
suspected unexpected serious adverse reaction
T2D
type 2 diabetes 
TEAE
treatment emergent adverse event
TEE
total daily energy expenditure 
TFEQ-R18v2
three factor eating questionnaire revised 18-item version 2 
TMM
trial materials manual
TP-MI
tipping-point multiple imputation 
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Version:
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TSH
thyroid stimulating hormone 
UNL
upper normal limit 
VLDL
very low density lipoprotein 
WOCBP
woman of child bearing potential
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Clinical laboratory tests
Appendix 2
Table 11-1
Protocol required efficacy laboratory assessments
Laboratory assessments
Parameters
Glucose metabolism1
(V2, V6, V9, V11)
! HbA1c (also taken at  V1) 
! FPG 
! Fasting serum insulin 
! HOMA-IR , calculated
! HOMA-β, calculated
Lipids 
(V2, V6, V9, V11)
! Total cholesterol 
! HDL cholesterol
! LDL cholesterol
! Triglycerides 
! VLDL cholesterol 
Table 11-2
Protocol required safety laboratory assessments
Laboratory assessments
Parameters
Haematology
(V1, V2, V4, V6, V8, V9, V11)
! Erythrocytes 
! Haematocrit 
! Haemoglobin 
! Leucocytes 
! Thrombocytes 
! Mean corpuscular volume 
! Differential count (absolute and percent):
o
Eosinophils
o
Neutrophils
o
Basophils
o
Lymphocytes
o
Monocytes
Biochemistry
(V1, V2, V4, V6, V8, V9, V11)
! ALT1,2
! Albumin 
! Alkaline phosphatase (ALP)
! Aspartate aminotransferase (AST)1,2 
! Creatinine
! Potassium 
! Sodium 
! Total bilirubin 
! Magnesium 
! Chloride 
! hsCRP 
! eGFR, calculated
! Bicarbonate
! Creatine kinase
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Biochemistry
(V1, V2, V4, V6, V8, V9, V11)
! Urea 
! Gamma glutamyltransferase (GGT) 
! Amylase 
! Lipase 
! Total protein 
! Uric acid 
! Phosphate 
! Total calcium3
! Albumin adjusted calcium3, calculated
Biomarkers
! Calcitonin (V2, V6, V9, V11)
! Parathyroid hormone (PTH) (V2,  V4, V6, V8, V9, V11)
! Calcitriol (V2, V4, V6, V8, V9, V11)
! TSH (V1)
! Follicle-stimulating hormone (FSH)4 (V1)
! Cortisol (V2, V6, V9, V11) 
! PAI-1 activity (V2, V6, V9, V11) 
! Renin activity (V2, V6, V9, V11) 
! Aldosterone (V2, V6, V9, V11)
! Alpha-subunit5 (V2, V6, V11)
Antibodies
(V2, V4, V6, V8, V11, V12)
! Anti-NNC0174-0833 antibodies6
Pregnancy testing
(V1, V2, V4, V6, V7, V8, V9, 
V10, V11, V12)
! Urine human chorionic gonadotropin (hCG) pregnancy test7,8
Urinanalysis
(V2, V4, V6, V9, V11) 
! Protein-to-creatinine ratio 
Other tests
(V4, V6, V8, V11, V12)
! NNC0174-0833 plasma concentration6
Notes:
1 If ALT or AST > 3x UNL, additional blood samples should be taken from the subject to analyse international 
normalised ratio (INR) (except at screening visit). Repeated testing of the abnormal lab assessments should be 
performed for the subject until abnormalities return to normal or baseline state.   
2 A laboratory 'hepatic event’ form should be completed in the CRF once for each time that the liver parameters increase 
the below thresholds:
!
ALT > 5x UNL or
!
AST > 5x UNL
3 If the investigator has a suspicion of hypocalcaemia, additional blood sample must be taken from the subject to 
measure the ionised calcium level at local laboratory. If hypocalcaemia is confirmed then an AE must be reported and 
the ionised calcium result must be entered on an additional data collection form for hypocalcaemia in the CRF. 
4 Only applicable for postmenopausal women.
5 Alpha-subunit is a pituitary tumour marker corresponding to the common alpha-subunit peptide in luteinizing hormone 
(LH), FSH, hCG and TSH.
6 Only applicable for subjects randomised to NNC0174-0833/NNC0174-0833 placebo.
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7 Only for postmenopausal female subjects who have stopped menstruating within the last 5 years and for female 
subjects with bilateral tubal ligation.
8 Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC.
Table 11-3
Protocol required exploratory laboratory assessments
Laboratory assessments
Parameters
Biomarkers
(V2, V6, V9, V11) 
! Leptin 
! Soluble leptin receptor 
! Endogenous amylin 
Genetics analyses1
! DNA sequencing (V2)
! RNA sequencing (V2, V6, V11)
Biosamples for future 
analysis1
! Biomarkers analyses (V2, V6, V11)                                                                                      
! Genetic analyses (V2, V11) 
Notes:
1 Only to be taken from subjects who have consented.
!
The tests detailed in Table 11-1, Table 11-2 and Table 11-3 will be performed by a central 
laboratory, with the exception of the following which will be performed at a specialised 
laboratory: 
o
NNC0174-0833 plasma concentration
o
Anti-NNC0174-0833 antibodies
o
Leptin
o
Soluble leptin receptor
o
Endogenous amylin
o
Pregnancy testing (local urine test)
!
Laboratory results that could unblind the trial (i.e. antibodies and NNC0174-0833 plasma 
concentration) will not be reported to the trial sites until the trial has been unblinded. Additional 
tests may be performed at any time during the trial as determined necessary by the investigator 
or required by local regulations.
!
Only laboratory samples specified in the protocol should be sent to the central laboratory for 
analysis; if additional laboratory sampling is needed, e.g. to follow up on AEs, this must be 
done at a local laboratory.
!
The 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.
!
Laboratory samples will be destroyed no later than at finalisation of the CTR except human 
biosamples for future analysis and samples for measurements of NNC0174-0833 plasma 
concentration and antibodies, which will be stored as described in Appendix 7.
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!
For haematology samples (differential count) where the test result is not normal, then a part of 
the sample may be kept for up to two years or according to local regulations. 
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Trial governance considerations
Appendix 3
1) Regulatory and ethical considerations
!
This trial will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki45 and applicable International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guideline46
o
Applicable laws and regulations
!
The protocol, informed consent form, IB (as applicable) and other relevant documents (e.g. 
advertisements), must be submitted to an IRB/IEC and reviewed and approved by the IRB/IEC 
before the trial is initiated.
!
Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the CTR according to national requirements.
!
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects.
!
Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received.
!
The investigator will be responsible for:
o
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities
o
notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
providing oversight of the conduct of the trial at the site and adherence to requirements 
of ICH guidelines, the IRB/IEC, and all other applicable local regulations
o
ensuring submission of the CTR synopsis to the IRB/IEC.
2) Financial disclosure
Investigators and subinvestigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial.
For US trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest.
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3) Informed consent process
!
The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial.
!
The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
!
Subjects must be informed that their participation is voluntary.
!
Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines46, Declaration of Helsinki45 and the IRB/IEC 
or trial site.
!
The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form 
before any trial related activity.
!
The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in accordance 
with local requirements.
!
Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial.
!
A copy of the informed consent form(s) must be provided to the subject.
4) Information to subjects during trial
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator.
The subject may receive a ‘welcome to the trial letter’ and a ‘thank you for your participation letter’
after completion of the trial. 
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations.
Different initiatives for subject retention will be implemented throughout this trial. Site retention 
activities may include cooking classes, group meetings, fitness memberships and others. Materials 
and items will be supplied if locally acceptable. The retention items will be relevant for the 
subjects’ participation in the trial and/or their obesity and will not exceed local fair market value.
The initiatives for subject retention 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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5) Data protection
!
Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred.
!
The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements. 
!
The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also be 
explained to the subject. 
!
The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities.
6) Committee structure
Novo Nordisk safety committee
Novo Nordisk will constitute an internal NNC0174-0833 safety committee to perform ongoing 
safety surveillance. The NNC0174-0833 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.
7) Publication policy
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information.
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial.
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial.
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial.
One investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators. The signatory investigator(s) will be 
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appointed based upon the criteria defined by the International Committee of Medical Journal 
Editors for research publications47.
Communication of results
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means. 
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial.
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property.
In all cases the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication.
Authorship
Novo Nordisk will work with one or more investigator(s) and other experts who have contributed to 
the trial concept or design, acquisition, analysis or interpretation of data to report the results in one 
or more publications.
Authorship of publications should be in accordance with the Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals by the International 
Committee of Medical Journal Editors47.
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication. 
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal. 
Site-specific publication(s) by investigator(s)
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
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request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial.
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.
8) Dissemination of clinical trial data
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE)48, the Food and Drug Administration Amendment 
Act (FDAAA)49, European Commission Requirements50, 51 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.
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last subject first treatment + 26 weeks corresponding to visit 11 ‘end of treatment’ visit. If the 
last subject is withdrawn early, the PCD is considered the date when the last subject would have 
completed visit 11. The PCD determines the deadline for results disclosure at clinicaltrials.gov 
according to FDAAA.
9) Data quality assurance
Case Report Forms 
!
Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data.
!
All subject data relating to the trial will be recorded on electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
!
For some data both electronic and paper CRFs are used.
!
The following will be provided as paper CRFs:
o
Pregnancy forms
!
The following will be provided as paper CRFs to be used when access to the CRF is revoked or 
the CRF is temporarily unavailable: 
o
AE forms 
o
Safety information forms (SIFs)
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o
Technical complaint forms (also to be used to report complaints that are not subject 
related, e.g. discovered at trial site before allocation) 
!
Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator.
!
The investigator must ensure that data is recorded in the CRF as soon as possible after the visit, 
preferably within 5 working days after the visit. Once data has been entered, it will be available 
to Novo Nordisk for data verification and validation purposes. 
Monitoring
!
The investigator must permit trial related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor 
with signed and dated printouts. In addition the relevant trial site staff should be available for 
discussions at monitoring visits and between monitoring visits (e.g. by telephone). 
!
Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site staff are accurate, complete and verifiable from source documents; 
that the safety and rights of subjects are being protected, to monitor drug accountability and 
collect completed paper CRF pages, if applicable, and that the trial is being conducted in 
accordance with the currently approved protocol and any other trial agreements, ICH GCP, and 
all applicable regulatory requirements.
!
Monitoring will be conducted using a risk based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to trial sites. 
!
Monitors will review the subject’s medical records and other source data, e.g. the diaries, to 
ensure consistency and/or identify omissions compared to the CRF. 
Protocol compliance
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed.
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database. 
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10) Source documents
!
All data entered in the CRF must be verifiable in source documentation other than the CRF.
!
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site.
!
Data reported on the paper CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available. 
!
It must be possible to verify subject’s medical history in source documents such as subject’s 
medical record. 
!
Subjects completing electronic patient reported outcomes instruments are the data originators. 
Data will be transmitted to a technology service provider database, thus the service provider 
database is the source.
!
The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested and who was contacted.
!
Definition of what constitutes source data can be found in a source document agreement at each 
trial site. There will only be one source document defined at any time for any data element.
11) Retention of clinical trial documentation
!
Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk. 
!
The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems and/or 
electronic devices supplied by Novo Nordisk. Site-specific CRFs and other subject data (in an 
electronic readable format or as paper copies or prints) must be retained by the trial site. If the 
provided electronic 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.
!
Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice.
12) Trial and site closure
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the 
investigator must inform the subjects promptly and ensure appropriate therapy and follow-up. The 
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investigator and/or Novo Nordisk must also promptly inform the regulatory authorities and 
IRBs/IECs and provide a detailed written explanation.
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed.
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, Novo Nordisk procedures or GCP guidelines
!
Inadequate recruitment of subjects by the investigator
!
Discontinuation of further trial product development
13) 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 subinvestigator for the trial, must be responsible 
for all trial related medical decisions. 
The investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the data 
produced) in the investigator trial master file. The documents, including the subject identification 
code list must be kept in a secure locked facility so that no unauthorized persons can get access to 
the data. 
The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. 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 o f 
subjects to a specific qualified physician who will be readily available to subjects during that time.
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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 staff must have sufficient English skills according to their assigned 
task(s).
14) 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 may pay additional costs incurred in relation to assessments relevant for following 
the safety of the subject. Investigator must contact Novo Nordisk on a case by case basis for 
whether the costs will be covered.
Novo Nordisk accepts liability in accordance with: Belgian law concerning experiments on the 
human person of 07 May 2004 - Article 29: §1.
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Adverse events: definitions and procedures for 
Appendix 4
recording, evaluation, follow-up, and reporting
AE definition
! An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
! An AE can be any unfavourable and unintended sign, including an abnormal laboratory finding, symptom or disease 
(new or exacerbated) temporally associated with the use of a medicinal product.
Events meeting the AE definition
! Any abnormal laboratory test results or safety assessments, including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator.
! A clinical laboratory adverse event (CLAE): a clinical abnormal laboratory finding 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.
! Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or 
intensity of the condition.
! Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction.
! Signs, symptoms or the clinical sequelae of a suspected overdose of trial product regardless of intent.
Events NOT meeting the AE definition 
! Pre-existing conditions, anticipated day-to-day fluctuations of pre-existing conditions, including those identified 
during screening or other trial procedures performed before exposure to trial product. 
Note: pre-existing conditions should be recorded as medical history/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.
Definition of an SAE
An SAE is an AE that fulfils at least one of the following criteria:
! Results in death
! Is life-threatening
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the subject was at risk of death at 
the time of the event. It does not refer to an event which hypothetically might have caused death, if it were more 
severe.
! Requires inpatient hospitalisation or prolongation of existing hospitalisation
o
Hospitalisation signifies that the subject has been detained at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalisation are AEs. If a complication prolongs hospitalisation or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether ‘hospitalisation’ occurred or was 
necessary, the AE should be considered serious.
o
Hospitalisation for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE.
Note:

Hospitalisations for administrative, trial related and social purposes do not constitute AEs and should 
therefore not be reported as AEs or SAEs.

Hospital admissions for surgical procedures, planned before trial inclusion, are not considered AEs or SAEs.
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! Results in persistent disability/incapacity
o    The term disability means a substantial disruption of a person’s ability to conduct normal life functions
o    This definition is not intended to include experience of relatively minor medical significance such as
uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma (e.g. sprained ankle), 
which may interfere with or prevent everyday life functions but do not constitute a substantial disruption.
! Is a congenital anomaly/birth defect
! Important medical event:
o
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other 
situations. This includes important medical events that may not be immediately life-threatening or result in death 
or hospitalisation, but may jeopardise the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition. These events should usually be considered serious and 
reported as SAEs using the important medical event criterion.
o
The following adverse events must always be reported as SAEs using the important medical event criterion, if no 
other seriousness criteria are applicable:

suspicion of transmission of infectious agents via the trial product. 

risk of liver injury defined as ALT or AST >3x UNL and total bilirubin >2x UNL, where no alternative 
aetiology exists (Hy's law).
Description of AEs requiring additional data collection (via specific event form) 
AEs requiring additional data collection
AEs requiring additional data collection are AEs where the additional data will benefit the evaluation of the safety of 
the trial product, see Table 9-1.
Event type
Description
Medication error 
A medication error concerning trial products is defined as:
!
Administration of wrong drug.
o
Note: Use of wrong dispensing unit number (DUN) is not considered a 
medication error unless it results in a confirmed administration of 
wrong drug.
!
Wrong route of administration, such as intramuscular instead of 
subcutaneous.
!
Administration of an overdose with the intention to cause harm, misuse or 
abuse of trial product.
!
Accidental administration of more than the planned dose of liraglutide 
and/or NNC0174-0833 or a higher dose(s) than intended during dose 
escalation. The administered dose(s) must deviate from the intended dose(s) 
to an extent where clinical consequences for the subject were likely to 
happen as judged by the investigator, although they did not necessarily 
occur.
Acute gallbladder disease
Events of symptomatic acute gallbladder disease (including gallstones and 
cholecystitis)
Acute coronary syndrome
Acute Coronary Syndrome conditions include all types of acute myocardial
infarction and hospitalisation for unstable angina pectoris
Cerebrovascular events
Episode of focal or global neurological dysfunction that could be caused by
brain, spinal cord, or retinal vascular injury as a result of haemorrhage or
infarction
Heart failure
Presentation of the patient for an urgent, unscheduled clinic/office/emergency 
department visit or hospital admission, with a primary diagnosis of heart failure 
(new episode or worsening of existing heart failure)
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Coronary artery 
revascularisation
A coronary revascularisation procedure is a catheter-based (percutaneous 
coronary intervention) or 
a surgical procedure (coronary artery bypass grafting) designed to improve 
myocardial blood flow
Neoplasm
Neoplasm by histopathology or other substantial clinical evidence
Hypocalcaemia
A suspicion of hypocalcaemia or assessment of  concentration of ionised 
calcium lower than 0.9 mmol/L (3.6 mg/dL) (must be confirmed by a single 
repeat test at local lab)
The selection of these events is based on the non-clinical and clinical data with NNC0174-0833 and liraglutide, 
knowledge from the glucagon-like peptide-1 receptor agonist (GLP-1 RA) drug class as well as regulatory 
requirements.
AE and SAE recording
! The investigator will record all relevant AE/SAE information in the CRF.
! The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. In such cases, the diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.
! When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (e.g. hospital 
progress notes, laboratory and diagnostics reports) related to the event.
! There may be instances when copies of source documents (e.g. medical records) for certain cases are requested by 
Novo Nordisk. In such cases, all subject identifiers, with the exception of the subject number, will be redacted on the 
copies of the source documents before submission to Novo Nordisk.
! For all non-serious AEs the applicable forms should be signed when the event is resolved or at the end of the trial at 
the latest. For sign-off of SAE related forms refer to ‘SAE reporting via paper CRF’ later in this section.
! Novo Nordisk products used as concomitant medication: if an AE is considered to have a causal relationship with a 
Novo Nordisk marketed product used as concomitant medication in the trial, it is important that the suspected 
relationship is reported to Novo Nordisk, e.g. in the alternative aetiology section on the SIF. Novo Nordisk may need 
to report this adverse event to relevant regulatory authorities.
Assessment of severity
The investigator will assess intensity for each event reported during the trial and assign it to one of the following 
categories: 
! Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering with everyday 
activities.
! Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities.
! Severe: An event that prevents normal everyday activities. 
Note: Severe is a category used for rating the intensity of an event; and both an AE and SAE can be assessed as 
severe. An event is defined as ‘serious’ when it meets at least one of the outcomes described in the definition of an 
SAE and not when it is rated as severe.
Assessment of causality
The investigator is obligated to assess the relationship between trial product and the occurrence of each AE/SAE.
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as: 
! Probable - Good reason and sufficient documentation to assume a causal relationship.
! Possible - A causal relationship is conceivable and cannot be dismissed.
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! Unlikely - The event is most likely related to aetiology other than the trial product.
Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk factors, as well as the 
temporal relationship of the event to trial product administration will be considered and investigated.
The investigator should use the IB for the assessment. For each AE/SAE, the investigator must document in the medical 
records that he/she has reviewed the AE/SAE and has provided an assessment of causality
There may be situations in which an SAE has occurred and the investigator has minimal information to include in the 
initial report. However, it is important that the investigator always makes an assessment of causality for every 
event before the initial transmission of the SAE data.
The investigator may change his/her opinion of causality in light of follow-up information and send a follow-up report 
with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting requirements.
Final outcome
The investigator will select the most appropriate outcome:
! Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the condition has returned 
to the level observed 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 sequelae 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 a fatal outcome must be reported as 
an SAE.
! Unknown: This term is only applicable if the subject is lost to follow-up.
Follow-up of AE and SAE
The investigator is obligated to perform or arrange for the conduct of supplemental measurements and/or evaluations as 
medically indicated or as requested by Novo Nordisk to elucidate the nature and/or causality of the AE or SAE as fully 
as possible (e.g. severe hypersensitivity reactions). This may include additional laboratory tests (e.g. skin prick test) or 
investigations, histopathological examinations, or consultation with other health care professionals.
If a subject dies during participation in the trial or during a recognised follow-up period, the investigator should provide 
Novo Nordisk with a copy of autopsy report including histopathology.
New or updated information will be recorded in the CRF.
SAE reporting via electronic CRF
! Relevant forms (AE and SIF) must be completed in the CRF. 
! For reporting and sign-off timelines, see box below. 
! If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form and if the CRF is 
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unavailable for more than 5 calendar days then the site will use the paper SIF (see box below).
! The site will enter the SAE data into the CRF as soon as it becomes available, see Section 9.2.1.
! After the trial is completed at a given site, the CRF will be decommissioned to prevent the entry of new data or 
changes to existing data. If a site receives a report of a new SAE from a subject or receives updated data on a 
previously reported SAE after CRF decommission, then the site can report this information on a paper AE and SIF 
(see box below) or to Novo Nordisk by telephone.
SAE reporting via paper CRF
! Relevant CRF forms (AE and SIF) must be forwarded to Novo Nordisk either by fax, e-mail or courier.
! Initial notification via telephone is acceptable, although it does not replace the need for the investigator to complete 
the AE and SIF within the designated reporting time frames (as illustrated in Figure 9-1):
o   AE form within 24 hours
o   SIF within 5 calendar days
o   Both forms must be signed within 7 calendar days
Contact details for SAE reporting can be found in the investigator trial master file.
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Contraceptive guidance and collection of pregnancy 
Appendix 5
information
Definitions
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. 
Women in the following categories are not considered WOCBP
1. Premenopausal female with one of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
!
Documented bilateral tubal ligation1
Note: Documentation can come from the site staff’s review of subject’s medical records, 
medical examination or medical history interview.
2. Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone replacement 
therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
!
Females on HRT and whose menopausal status is in doubt must discontinue HRT to allow 
confirmation of postmenopausal status before trial enrolment.
Pregnancy testing
Only women not considered WOCBP are eligible for inclusion in this trial. 
!
Urine pregnancy tests must be performed for postmenopausal female subjects who have stopped 
menstruating within the last 5 years and for female subjects with bilateral tubal ligation.
!
Urine pregnancy test must be repeated at any time during the trial if pregnancy is suspected.
1 Female subjects with bilateral tubal ligation must ensure the use of an occlusive cap (e.g. diaphragm) with/without the 
use of spermicide or that their male partner uses a condom throughout the trial (until ‘end of trial’).
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Collection of pregnancy information 
Male subjects with partners who become pregnant
!
Investigator will attempt to collect pregnancy information on any female partner who becomes 
pregnant while male subject is participating in this trial. This applies only in case of abnormal 
outcome of the pregnancy and in case male subject receives trial product.
!
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and submit 
it to Novo Nordisk within 14 calendar days of learning of the abnormal outcome of the 
partner’s pregnancy. Information on the status of the mother and child will be included.
!
Generally, follow-up will be 1 month following the delivery date. Any termination of the 
pregnancy will be reported regardless of foetal status (presence or absence of anomalies) or 
indication for procedure.
Female subjects who become pregnant 
!
Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this trial.
!
Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject’s pregnancy.
!
Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the delivery 
date.
!
Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure.
!
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. 
!
A spontaneous abortion is always considered to be an SAE and will be reported as such.
!
Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial product by the investigator will be reported to Novo Nordisk as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting. 
Any female subject who becomes pregnant while participating in the trial must discontinue trial 
product. 
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Technical complaints: Definition and procedures for 
Appendix 6
recording, evaluation, follow-up and reporting
Technical complaint definition
! A technical complaint is any written, electronic or oral communication that alleges product (medicine or device)
defects. The technical complaint may be associated with an AE, but does not concern the AE itself.
Examples of technical complaints:
!
Problems with the physical or chemical appearance of trial products (e.g. discoloration,
particles or contamination).
!
Problems with packaging material including labelling.
!
Problems related to medical devices (e.g. to the injection mechanism, dose setting mechanism,
push button or interface between the pen-injector and the needle).
Time period for detecting technical complaints 
All technical complaints, which occur from the time of receipt of the product at trial site until the time of the last usage 
of the product, must be collected for products predefined on the technical complaint form. 
Reporting of technical complaints to Novo Nordisk
Contact details (fax, e-mail and address) for Customer Complaint Center –refer to Attachment I
Technical complaints must be reported on a separate technical complaint form:
1.
One technical complaint form must be completed for each affected DUN
2.
If DUN is not available, a technical complaint form for each batch, code or lot number must be completed
Timelines for reporting of technical complaints to Novo Nordisk
The investigator must complete the technical complaint form in the CRF within the timelines specified in Figure 9-4 .
If the CRF is unavailable or when reporting a technical complaint that is not subject related, the information must be 
provided on a paper form by fax, e-mail or courier to Customer Complaint Center, Novo Nordisk, within the same 
timelines as stated above. When the CRF becomes available again, the investigator must enter the information on the 
technical complaint form in the CRF.
Follow-up of technical complaints 
The investigator is responsible for ensuring that new or updated information will be recorded on the originally 
completed form. 
Collection, storage and shipment of technical complaint samples
The investigator must collect the technical complaint sample and all associated parts that were packed in the same DUN 
and notify the monitor within 5 calendar days of obtaining the sample at trial site. The sample and all associated parts 
must be sent as soon as possible to Customer Complaint Center, Novo Nordisk, together with a copy of the completed 
technical complaint form. The technical complaint sample should contain the batch, code or lot number and, if 
available, the DUN. If the technical complaint sample is unobtainable, the reason must be stated on the technical 
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complaint form. If several samples are shipped in one shipment, the sample and the corresponding technical complaint 
form should be kept together.
Storage of the technical complaint sample must be done in accordance with the conditions prescribed for the product.
Reporting of technical complaints for Novo Nordisk products not included in technical complaint form
Technical complaints on Novo Nordisk products not included in the technical complaint form should be reported to 
local Novo Nordisk affiliate with a reference to trial ID.
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Retention of human biosamples
Appendix 7
Antibody samples and samples for measurement of NNC0174-0833 plasma concentration
!
Residual 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. Residual 
antibody samples may also be used for exploratory investigation of antibodies.
!
The antibody analyses will be performed by Immunogenicity Assessment at Novo Nordisk or a 
laboratory assigned by Novo Nordisk.
!
Residual samples for measurement of NNC0174-0833 plasma concentration may be retained to 
allow residual PK/pharmacodynamics (PD) analyses or exploratory investigation of metabolites, 
method validation purposes or further characterisation of antibody response. 
!
The residual PK/PD analyses/exploratory investigations will be performed by Development 
Bioanalysis at Novo Nordisk, or a laboratory assigned by Novo Nordisk.
!
All samples will be stored at Novo Nordisk or at a Novo Nordisk designated biorepository/ 
laboratory 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.
!
Residual samples for measurement of NNC0174-0833 plasma concentration may be stored for a 
shorter period of time pending the stability of the compound or metabolites to be assessed.
!
Only Novo Nordisk personnel and biorepository/laboratory personnel will have access to the 
stored samples.
!
The samples may be transferred to other countries for analysis, if not prohibited by local 
regulations.
!
The subject’s identity will remain confidential and the 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. The analyses will not have any medical consequences for 
the subjects or their relatives.
!
Subjects can contact the investigator if they wish to be informed about results derived from 
stored samples obtained from their own body.
!
Results will be documented independently and reported separately from the CTR.
Biosamples for future analysis
!
The trial will involve collection of human biosamples (blood samples) to be stored for future 
analysis. Subjects must sign and date a separate informed consent form before blood samples 
are collected for storage for future analysis.
!
The biosamples are collected at visit 2, 6 and 11 (Section 9.9).
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!
The biosamples will be stored at Novo Nordisk or at a Novo Nordisk designated biorepository 
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.
!
Only Novo Nordisk personnel and biorepository personnel will have access to the stored 
samples.
!
The biosamples may be transferred to other countries for analysis, if not prohibited by local 
regulations.
!
The subject may request the stored biosamples to be destroyed by withdrawing the designated 
informed consent. The results obtained from any already performed analyses of the samples will 
still be used. 
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Country-specific requirements 
Appendix 8
Section 3.3.4 Identified risks for liraglutide 3.0 mg
For Japan: Detailed information about reasonably expected AEs can be found in the local package 
insert for Victoza®.
Section 6.1 Inclusion criterion no. 2
For Japan: age ≥ 20 years at the time of signing the informed consent
Section 6.1 Inclusion criterion no. 3
For Belgium, Denmark, Finland, Ireland, Poland, Serbia and United Kingdom: Adequate 
contraceptive methods as defined by the Clinical Trial Facilitation Group (CTFG)52: Use of 
condoms (with or without spermicide) or sexual abstinence (i.e. refraining from heterosexual 
intercourse) throughout the trial (until ‘end of trial’).
Section 7.5 Preparation/Handling/Storage/Accountability
For Japan: The head of the study site or the trial product storage manager assigned by the head of 
the study site (a pharmacist in principle) is responsible for control and accountability of the trial 
products. 
Section 9.9 Biosamples for future analysis
For South Africa: Biosamples for future analysis will not be collected in South Africa.
Appendix 3, 1) Regulatory and ethical considerations
For Japan: A name and seal is accepted as a signature.
Appendix 3, 14) Indemnity statement
For Belgium: 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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02 October 2018
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Trial ID: NN9838-4433
Version:
2.0
     
Status:
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Page:
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12 References
1.
Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, 
and national prevalence of overweight and obesity in children and adults during 1980-2013: 
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Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, Lee A, et al. Health Effects of 
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Han TS, Tajar A, O'Neill TW, Jiang M, Bartfai G, Boonen S, et al. Impaired quality of life 
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Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with 
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Prospective Studies C, Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J, et al. 
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Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, et al. 
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Yumuk V, Tsigos C, Fried M, Schindler K, Busetto L, Micic D, et al. European Guidelines 
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Hofso D, Jenssen T, Hager H, Roislien J, Hjelmesaeth J. Fasting plasma glucose in the 
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Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, et al. Diabetes 
trends in the U.S.: 1990-1998. Diabetes Care. 2000;23(9):1278-83.
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Date:
02 October 2018
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
     
Status:
Final
     
Page:
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Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, et al. Obesity and 
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Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co-
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Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: 
pathophysiology and clinical implications. Gastroenterology. 2012;142(4):711-25 e6.
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after loss of massive excess weight following bariatric surgery. J Am Coll Nutr. 
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Eheman C, Henley SJ, Ballard-Barbash R, Jacobs EJ, Schymura MJ, Noone AM, et al. 
Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated 
with excess weight and lack of sufficient physical activity. Cancer. 2012;118(9):2338-66.
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Round-table discussion on obesity and weight loss. There is no miraculous cure but 
persistent physicians can help most people to reduce. Nord Med. 1975;90(5):145-53.
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European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). 
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Milan Declaration: A Call to Action on Obesity - an EASO Position Statement on the 
Occasion of the 2015 EXPO. Obes Facts. 2016;9(4):296-8.
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Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. 
Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N 
Engl J Med. 2002;346(6):393-403.
27.
Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: the effects of modest 
weight reduction. Obes Res. 2000;8(3):270-8.
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Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: 
a meta-analysis. Am J Clin Nutr. 1992;56(2):320-8.
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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 
e5; quiz e14-5.
30.
Warkentin LM, Das D, Majumdar SR, Johnson JA, Padwal RS. The effect of weight loss on 
health-related quality of life: systematic review and meta-analysis of randomized trials. 
Obes Rev. 2014;15(3):169-82.
31.
Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. 2005;82(1
Suppl):222S-5S.
32.
Young A, Denaro M. Roles of amylin in diabetes and in regulation of nutrient load. 
Nutrition. 1998;14(6):524-7.
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02 October 2018
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Trial ID: NN9838-4433
Version:
2.0
     
Status:
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Boyle CN, Lutz TA, Le Foll C. Amylin - Its role in the homeostatic and hedonic control of 
eating and recent developments of amylin analogs to treat obesity. Molecular metabolism. 
2018;8:203-10.
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Novo Nordisk A/S. Investigator's Brochure, NNC0174-0833, project NN9838, (edition 4). 
Sep 2018.
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Wells G, Chernoff J, Gilligan JP, Krause DS. Does salmon calcitonin cause cancer? A 
review and meta-analysis. Osteoporos Int. 2016;27(1):13-9.
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Novo Nordisk A/S. Investigator's Brochure, Liraglutide 3.0 mg (Saxenda®), project 
NN8022 (edition 11). 31 Mar 2018.
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Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney Int Suppl. 2013;3(1):1-150.
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Kroenke K, Spitzer RL, Williams JB. The PHQ-9 - Validity of a brief depression severity 
measure. J Gen Intern Med. 2001;16(9):606-13.
39.
FAO/WHO/UNU. Human energy requirements. Report of a joint FAO/WHO/UNU expert 
consultation. FAO: food and nutrition technical report series 1. 2004.
40.
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification 
of acute pancreatitis-2012: revision of the Atlanta classification and definitions by 
international consensus. Gut. 2013;62(1):102-11.
41.
Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. 
Conceptual framework and item selection. Med Care. 1992;30(6):473-83.
42.
Cappelleri JC, Bushmakin AG, Gerber RA, Leidy NK, Sexton CC, Lowe MR, et al. 
Psychometric analysis of the Three-Factor Eating Questionnaire-R21: results from a large 
diverse sample of obese and non-obese participants. Int J Obes (Lond). 2009;33(6):611-20.
43.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's 
pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007;164(7):1035-43.
44.
McEvoy BW. Missing data in clinical trials for weight management. J Biopharm Stat. 
2016;26(1):30-6.
45.
World Medical Association. Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013.
46.
International Conference on Harmonisation. ICH Harmonised Tripatite Guideline. Guideline 
for Good Clinical Practise E6(R2), Step 4. 09 Nov 2016.
47.
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.
48.
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1.
49.
U.S. Food and Drug Administration. Food and Drug Administration Amendments Act of 
2007 as amended by the Final Rule "Clinical Trials Registration and Results Information 
Submission". 21 September 2016.
50.
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
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Trial ID: NN9838-4433
Version:
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Status:
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Page:
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laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, article 11. Official Journal of the European Communities. 01 May 
2001.
51.
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004.
52.
Clinical Trial Facilitation Group (CTFG), Heads of Medicines Agencies. Recommendations 
related to contraception and pregnancy testing in clinical trials. 15 Sep 2014.
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CONFIDENTIAL
Date:
Novo Nordisk
Version:
1.0
Status:
Final
Page:
1 of 1
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CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
1.0
Final
6HSWHPEHU 2020
Cagrilintide
Trial ID: NN9838-4433
Clinical Trial Report
Appendix 16.1.1
CONFIDENTIAL


Protocol Amendment no 1
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN9838-4433
Version:
1.0
     
Status:
Final
     
Page:
1 of 3
Protocol Amendment
no 1
to Protocol, version 2.0
dated 02 October 2018
Trial ID:NN9838-4433
Investigation of safety and efficacy of NNC0174-0833 for weight management –
a dose finding trial
Trial phase: II
Applicable to United Kingdom
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.
*%3URWRFRO$PHQGPHQWXN_
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 1
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN9838-4433
Version:
1.0
     
Status:
Final
     
Page:
2 of 3
Table of Contents   
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Appendix 8 Country-specific requirements................................................................................3
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Protocol Amendment no 1
CONFIDENTIAL
Date:
29 November 2018
Novo Nordisk
Trial ID: NN9838-4433
Version:
1.0
     
Status:
Final
     
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
The protocol is amended for the following reasons:
!
To include the end of trial definition for the United Kingdom
!
To clarify that United Kingdom subjects meeting treatment discontinuation criterion 2 will not 
be allowed to resume trial product.
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
Appendix 8 Country-specific requirements
Section 5.3 End of trial definition
For United Kingdom: The end of the trial is defined as the date of the last visit of the last subject in 
the trial, including the potential two follow-up analyses for subjects testing positive for antibodies 
against NNC0174-0833 at visit 12.
Section 8.1 Discontinuation of trial product
For United Kingdom: Subjects meeting treatment discontinuation criterion 2 (pregnancy) will not 
be allowed to resume trial product if the criterion is no longer met.
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Protocol Amendment no 2
CONFIDENTIAL
Date:
19 April 2019
Novo Nordisk
Trial ID: NN9838-4433
Version:
1.0
Status:
Final
Page:
1 of 3
Protocol Amendment
no 2
to Protocol, version 2.0
dated 02 October 2018
Trial ID: NN9838-4433
Investigation of safety and efficacy of NNC0174-0833 for weight management –
a dose finding trial
Trial phase: 2
Applicable to Japan
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.
-33URWRFRO$PHQGPHQWMS_
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Protocol Amendment no 2
CONFIDENTIAL
Date:
19 April 2019
Novo Nordisk
Trial ID: NN9838-4433
Version:
1.0
Status:
Final
Page:
2 of 3
Table of Contents
1
Introduction including rationale for the protocol amendment...........................................................3
2
Changes ................................................................................................................................................3
2.1
Appendix 8 Country-specific requirements................................................................................3
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CONFIDENTIAL


Protocol Amendment no 2
CONFIDENTIAL
Date:
19 April 2019
Novo Nordisk
Trial ID: NN9838-4433
Version:
1.0
Status:
Final
Page:
3 of 3
1
Introduction including rationale for the protocol amendment
The protocol is amended for the following reason:
!
To specify the contraceptive methods for Japan.
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
Appendix 8
Country-specific requirements
Section 6.1
Inclusion criterion no.3
For Japan: Adequate contraceptive methods for male subjects are use of condoms (with or without 
spermicide) or sexual abstinence (i.e. refraining from heterosexual intercourse) throughout the trial 
(until ‘end of trial’)
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CONFIDENTIAL


 
 
 
Novo Nordisk A/S 
 
Telephone: 
  
Direct dial: 
Internet: 
www.novonordisk.com 
 
Completed 
Memo 
To: 
Health Authorities and Ethics Committees in Countries Affected by the 
COVID-19 Pandemic 
 
 
From: 
 
Novo Nordisk A/S 
 
Trial ID: 
 
NN9838-4433 
Pages: 
X 
 
25-JUN-2020
 
 
Notification of the impact, mitigation measures, and high-level 
risk assessment of the outbreak of the coronavirus (COVID-19) 
This memo is submitted for notification and serves as a short overview of the 
impact of the COVID-19 pandemic, with the mitigation measures taken and a 
high-level conclusion to the risk assessment for NN9838-4433 conducted in 
Country. 
In case any changes required/requiring a substantial amendment, this 
was/will be submitted separately for approval. 
It is important to emphasize, that the measures described below, only have 
been implemented where deemed needed. The trial sites should always follow 
the trial protocol to the extent possible. 
Novo Nordisk will make an update to this memo, whenever any significant 
changes to the risk-benefit balance occur, until the COVID-19 pandemic has 
stabilised, and normal practice has been restored in all countries.  
A more comprehensive impact assessment will be included in the Clinical Trial 
Report for all COVID-19 impacted trials. 
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CONFIDENTIAL


 
 
 
Page 2 of 5 
Impact, mitigation measures taken and a high-level risk assessment, trial 
level 
Trial ID: 
NN9838-4433 
Protocol title: 
Investigation of safety and efficacy of NNC0174-
0833 for weight management – a dose finding trial 
Status: 
Completed (except long-term follow-up on antibod-
ies for a few number of subjects) 
First subject first 
treatment: 
07-MAR-2019    
Last subject last treat-
ment:  
13-MAR-2020 
Database lock:  
06-MAY-2020 
The clinical trial report is expected completed Q4 
2020. 
Visit schedule: 
Only ‘End of trial’ visits (V12) were outstanding 
when the Covid-19 pandemic started.  
 
For subjects who were not allowed to attend the 
clinical trial sites or refused to attend the clinical 
trial sites, the site staff was recommended to con-
vert the V12 to phone visit and collect data as appli-
cable verbally to secure subjects' safety.  
 
In cases where site staff was concerned the clinical 
trial site would close, or subject would refuse to at-
tend the last visit, V12 could be performed at the 
clinical trial site prior to visit window, however, at 
the earliest 5 weeks after V11 (End of treatment). 
V12 then had to be followed up by a phone visit 
within V12 visit window specified in the protocol, 
where AEs, concomitant medication and urine preg-
nancy test result were collected.  
 
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Page 3 of 5 
To the extent possible, site staff continued to collect 
all trial-related information/data in the subject's 
medical records and continue to update the relevant 
data capture systems in a timely manner (e.g., 
EDC, IWRS). 
Primary endpoint: 
As primary endpoint is body weight change from 
baseline to V11, there is no impact on the primary 
endpoint. 
For a small group of subjects, body weight could not 
be performed on-site at V12 and the visit was con-
verted to phone visit. When V12 was converted to a 
phone visit, the subject was instructed to measure 
body weight on own scale. 
Trial product treat-
ment: 
No impact 
Subject safety: 
For very few subjects, where V12 clinic visit was 
converted to a phone visit, pulse and blood pressure 
and blood sampling for protocol-required assess-
ments (antibody and PK) were not collected, these 
are considered missing. Pregnancy testing was ad-
vised to be performed at home for the subjects re-
quiring a pregnancy test at V12 according to proto-
col.  
Informed Consent: 
No changes to the IC form have been required. 
Substantial amend-
ment: 
No substantial amendment has been submitted.  
Conclusion on risk 
assessment: 
The Trial Team has evaluated that the measures 
recommended do not impact the overall integrity 
and quality of the trial and did not impose an in-
creased risk for the participating subjects.  
 
Below section to be completed by Local affiliate: 
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CONFIDENTIAL


 
 
 
Page 4 of 5 
Adjust on local level and complete according to expectation from local authorities. 
The section can be deleted, if not a local requirement 
Keep the text short. Only describe relevant local changes which are different than the 
above or not implemented locally.  
Impact, mitigation measures taken and a high-level risk assessment, country 
level 
Visit schedule: 
Implemented as described above at all/some sites, 
'not applicable’ or describe if different than above  
Primary endpoint: 
‘Implemented as described above’ ‘not applicable, or 
describe if different than above 
Trial Product treatment: 
‘Implemented as described above’ ‘not applicable, or 
describe if different than above 
Subject safety: 
‘Implemented as described above’ ‘not applicable, or 
describe if different than above 
Informed Consent: 
‘Implemented as described above’ ‘not applicable, or 
describe if different than above 
Monitoring: 
When necessary, on-site monitoring has been re-
placed by additional off-site monitoring activities 
and centralised monitoring.  
 
Please add any relevant country specific infor-
mation. 
Alternative dispensing of trial 
product, from site to sub-
ject: 
‘Not applicable’ or describe if any of the alternative 
dispensing methods have been implemented: 
The following alternative dispensing method(s) 
has/have been implemented where the subject can-
not visit the site and the investigator has judged it 
safe to continue treatment:  
1.
Trial Products are collected at site by ap-
pointed substitute 
2.
Trial Products are delivered by a site staff 
member to the subject/substitute off site 
3.
Trial Products are delivered to the subject by 
an approved courier. 
4.
Shipment of trial product from sponsor (cen-
tral or local depot) directly to subjects  
 
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Page 5 of 5 
If information on alternative dispensing method has 
already been submitted to your Health Authority; 
then consider deleting the text and only refer to that 
application. 
 
Please note that option 4 requires Health Authority 
approval. Include information if you have option 4 
approved in your country, e.g., with a reference to 
the application and approval. 
Substantial amendment: 
Comment on whether any of the above or other mit-
igations have been submitted as a substantial 
amendment 
Conclusion on risk assess-
ment: 
Include a short conclusive description of the local 
risk assessments  
 
 
Novo Nordisk will continue to keep Health Authorities and Ethics Committees 
notified of changes to trial conduct, in accordance with local regulations and 
guidance on reporting of impacted trial conduct due to the COVID-19 pan-
demic. 
 
 
With regards 
 
Local affiliate contact 
 
 
 
 
 
 
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CONFIDENTIAL

SAP_001.pdf: 
Cover Page for Statistical Analysis Plan  
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03856047  
Sponsor trial ID: 
NN9838-4433  
Official title of study: 
Investigation of safety and efficacy of cagrilintide for weight 
management – a dose finding trial  
Document date: 
18 September 2020 
 


Link
List of contents
Statistical analysis plan......................................................................................................................
CONFIDENTIAL
Date:
Novo Nordisk
Version:
Status:
Cagrilintide
Trial ID: NN9838-4433
Clinical Trial Report
Appendix 16.1.9
18 September 2020
1.0
Final
16.1.9 Documentation of statistical methods
CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
1 of 23
Statistical Analysis Plan
Trial ID: NN9838-4433
Investigation of safety and efficacy of cagrilintide for weight 
management – a dose finding trial
Trial phase: 2
Author
 Principal Statistician
Biostatistics Obesity and Metabolism
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Includes redaction of personal identifiable information only. 
. 


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
2 of 23
Table of contents   
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Table of contents...............................................................................................................................................2 
List of abbreviations.........................................................................................................................................3 
1 
Introduction...............................................................................................................................................4 
1.1 
Trial information............................................................................................................................4 
1.2 
Scope of the statistical analysis plan..............................................................................................4 
2 
Statistical considerations ..........................................................................................................................4 
2.1 
Sample size determination.............................................................................................................6 
2.2 
Definition of analysis sets..............................................................................................................9 
2.2.1 
Observation periods.....................................................................................................9 
2.3 
Statistical analyses.......................................................................................................................10 
2.3.1 
Primary endpoint........................................................................................................10 
2.3.1.1 
Analyses addressing the primary estimand .........................................11 
2.3.1.2 
Analyses addressing the secondary estimand......................................14 
2.3.2 
Secondary endpoints..................................................................................................16 
2.3.2.1 
Supportive secondary endpoints..........................................................16 
2.3.3 
Exploratory endpoints................................................................................................19 
2.3.4 
Explorative statistical analysis for pharmacogenetics and biomarkers......................20 
2.3.5 
Other analyses............................................................................................................20 
2.4 
Pharmacokinetic and/or pharmacodynamic modelling................................................................21 
3 
Changes to the statistical analyses planned in the protocol.................................................................22 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
3 of 23
List of abbreviations
Include the list of the abbreviations used in the document in alphabetical order. Do not include 
abbreviations that are not used in the SAP and do not include well known abbreviations such as 
mmHg.
ABPM:
ambulatory blood pressure monitoring 
ANOVA
analysis of variance
AUC:
area under the curve
BMI
body mass index
CI
confidence interval
CRF
case report form
CTR
clinical trial report
DBP:
Diatolic blood pressure
EoT
end-of-text
FAS
Full analysis set
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MMRM         Mixed model for repeated measurements
OD
Once daily
OW
Once weekly
PD
pharmacodynamics
PK
pharmacokinetics
PP
per protocol
SAS
Safety analysis set
SBP
Systolic blood pressure
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
4 of 23
1
Introduction
1.1
Trial information
The primary objective is to compare the dose-response of increasing doses of cagrilintide once 
weekly (OW) versus placebo and versus liraglutide 3.0 mg once daily (OD) on body weight, in 
subjects with overweight or obesity, when added as an adjunct to a reduced-calorie diet and 
increased physical activity. 
The primary estimand will quantify the average treatment effect of cagrilintide relative to placebo 
and liraglutide 3.0 mg after 26 weeks, as an adjunct to a reduced-calorie diet and increased physical 
activity, in all randomised subjects had they remained on their randomised treatment for the entire 
planned duration of the trial and not started any other weight loss intervention (‘Trial product 
estimand’/’hypothetical estimand’). The secondary estimand will quantify the average treatment 
effect of cagrilintide relative to placebo and liraglutide 3.0 mg after 26 weeks, as an adjunct to a 
reduced-calorie diet and increased physical activity, in all randomised subjects regardless of 
adherence to treatment and regardless of starting any other weight loss intervention (‘treatment 
policy estimand’).
For more details on the trial, see the trial protocol.
1.2
Scope of the statistical analysis plan
This SAP is based on the protocol “Investigation of safety and efficacy of cagrilintide for weight 
management – a dose finding trial”, version 2.0.
2
Statistical considerations
Treatment non-adherence
To address the primary estimand the concept of ‘Treatment non-adherence’ is defined as the 
occurrence of either one of the following events:
A subject is treatment adherent until first time of non-adherence, defined as:
x
The subject has not been dosed with trial product within the prior 14 days.
x
The subject has received other weight management drug or bariatric surgery
x
The subject has not reached target dose at the following pre-specified evaluation week (relative 
to first dose administration):
Active 
treatment / 
placebo
Cagrilintide
0.3 mg
Cagrilintide
0.6 mg
Cagrilintide
1.2 mg
Cagrilintide
2.4 mg
Cagrilintide
4.5 mg
Liraglutide 
3.0 mg
Evaluation 
week
2
2
3
6
9
8
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
5 of 23
x
After the pre-specified evaluation week for the target dose, the subject has not received the 
target dose ±10% within the prior 14 days.
Taxonomy of week 26 assessments
To address the secondary estimand the following taxonomy is introduced: For each subject a given 
assessment at week 26 may be available or missing and the subject may be on randomised treatment 
or not (Table 2-1). Note, that this is done per assessment and per subject; subjects may be a 
different type for different assessments (a subject may have ‘available on randomised treatment 
(AT)’ for body weight but ‘missing on randomised treatment (MT)’ for waist circumference).
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
6 of 23
Table 2-1 Taxonomy for subjects based on week 26 assessments
Assessment
at week 26
Subjects on 
randomised 
treatment 
at week 26
Type description
Type
Abbreviation
Available
Yes
Available on randomised treatment:
Subjects who complete the trial on randomised 
treatment with an assessment at week 26. This 
includes those that stop and restart trial product.
AT
No
Available but discontinued
Subjects who discontinue randomised treatment 
prematurely but return to have an assessment at 
week 26. These are also called retrieved subjects.
AD
Missing
Yes
Missing on randomised treatment:
Subjects who complete the trial on randomised 
treatment without an assessment at week 26. This 
includes those that stop and restart trial product.
MT
No
Missing and discontinued:
Subjects who discontinue randomised treatment 
prematurely and do not return to have an 
assessment at week 26. These are also called non-
retrieved subjects.
MD
2.1
Sample size determination 
The sample size is based on the objective of finding the optimal dose of cagrilintide and is based on 
the primary endpoint. To characterise the shape of the curve for the dose-response relationship it is 
considered adequate to test 5 doses of cagrilintide and the sample size for each dose is determined 
in order to achieve a good precision on this relationship. Furthermore, sample size estimation is 
based on addressing assumptions corresponding to the analyses of both the primary and secondary 
estimands.
In the imputation approach used for the sample size calculations addressing the primary estimand 
missing values (MT and MD) and assessments from retrieved subjects (AD) are assumed to be 
similar to treatment completers (AT) within the same treatment group. In the imputation approach 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
7 of 23
used for the sample size calculations addressing the secondary estimand, missing values (MT and 
MD) are assumed to be similar to placebo subjects regardless of treatment arm.
The five different injection volumes in each of the cagrilintide placebo arms and the one liraglutide 
placebo arm will be pooled into one placebo group in the main analyses. This pooling assumes that 
there is no substantial effect of different placebo volumes or different dose escalation on the 
efficacy and safety endpoints. This is consistent with findings from previous obesity trials 
(NN8022-1922 and NN9536-4153). 
The assumptions for the sample size calculations are:
x
The significance level is 5%
x
100 subjects are included in each of the cagrilintide arms, 100 subjects in the liraglutide 3.0 mg 
OD arm and 100 subjects in total in the pool of cagrilintide placebo and liraglutide placebo arms
x
Assumptions corresponding to the primary estimand:
o
Standard deviation of 5.2% for relative change in weight loss at week 26 (based on data 
from trial NN9536-4153)
o
Treatment effect versus the pooled placebo group of at least 8% for the optimal dose 
among completers (based on data from trial NN9536-4153)
o
Treatment effect versus liraglutide 3.0 mg of at least 3% among completers (based on 
data from trial NN9536-4153 and NN8022-1839)
x
Assumptions corresponding to the secondary estimand:
o
Standard deviation of 5.6% for relative change in weight loss at week 26 (based on data 
from trial NN9536-4153)
o
13% of subjects discontinue randomised treatment permanently and 60% of these are 
retrieved (AD) at week 26 (Based on data from trial NN9536-4153)
o
All subjects in the pooled placebo group are assumed to have the same effect as subjects 
who complete the trial on placebo (AT)
o
Retrieved subjects (AD) in any of the active arms are assumed to have an effect 
corresponding to half the treatment difference (compared to the pooled placebo group) 
of subjects who complete the trial in that arm (AT)
o
Non-retrieved subjects (MD) in any of the active arms are assumed to have an effect 
corresponding to the pooled placebo group
o
Treatment effect versus the pooled placebo group of at least 7.3% for the optimal dose 
after adjustment for treatment discontinuation and missing data 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
8 of 23
x
The treatment differences are analysed by two-sided t-tests which is a simplification of the 
main analyses including explanatory variables
The probabilities and power calculations beneath are based on assumptions for the secondary 
estimand (primary estimand for the treatment effect versus liraglutide 3.0 mg). However, both the 
primary and secondary estimands will be covered, since the probabilities and power for the primary 
estimand are higher compared to the secondary estimand. 
To characterise the dose-response relationship well, the precision of the mean difference between 
any cagrilintide dose and the pooled placebo group is evaluated by calculating the probability of the 
half-width of the confidence interval (CI) to be equal to or below a given value. Table 2-2 gives this 
probability for different number of subjects and values for the CI half-width.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
9 of 23
Table 2-2 Probability of desired CI half-width
N per active arm/N 
for pooled placebo 
group
CI half-width (%)
Probability
100
1.7
96%
80
1.7
32%
100
1.6
69%
80
1.6
7%
A sample size of 100 subjects in each active treatment arm compared with a pooled placebo group 
of 100 subjects allows the 95% CI for the treatment difference between any active arm and placebo 
to be contained within +/-1.7% of the estimate with 96% probability. This is considered to be a 
sufficient precision to characterize the dose-response relationship. In total this requires a sample 
size of 700 subjects.
For the primary endpoint, change from randomisation at week 0 to week 26 in body weight (%), a 
sample size of 100 subjects in each active treatment arm results in a power of more than 99% for a 
significant difference between the optimal dose of cagrilintide and the pooled placebo group.
For the primary endpoint a sample size of 100 subjects in each active treatment arm results in a 
power of 98% for detecting a significant difference between the optimal dose of cagrilintide and 
liraglutide 3.0 mg for the primary estimand.   
2.2
Definition of analysis sets
Two analysis sets are defined:
The full analysis set (FAS) includes all randomised subjects according to the intention-to-treat 
principle.
The safety analysis set (SAS) includes all randomised subjects exposed to at least one dose of 
randomised treatment. 
Any observation excluded from the analysis will be documented before database lock with the 
reason for exclusion provided.
2.2.1
Observation periods
Three observation periods are defined for each subject:
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
10 of 23
Period
Characteristics
Definition
Purpose
In-trial
Observation period: 
Patient Years of 
Observation (PYO)
The in-trial period is defined as the uninterrupted 
time interval from date of randomisation to date 
of last contact with trial site. Follow-up time for 
positive antibodies is not included in the in-trial 
period.
Used for 
reporting of 
adverse 
events 
(AEs)
On-
treatment
Exposure period using 
6-weeks ascertainment 
window irrespective of 
rescue interventions: 
Patient Years of 
Exposure (PYE)
A time-point is considered as ‘on-treatment’ if 
any dose of trial product has been administered 
within the prior 6 weeks. The on-treatment 
period is defined as all times which are 
considered on-treatment. The on-treatment period 
will therefore be from the date of first trial 
product administration to date of last trial 
product administration excluding potential off-
treatment time intervals triggered by at least 6 
consecutive missed doses for cagrilintide or 6 
consecutive weeks of missed dosing with 
liraglutide.
Used for 
reporting of 
treatment 
emergent 
adverse 
events 
(TEAEs)
Treatment-
adherent
Treatment period using 
2-weeks ascertainment 
window with no rescue 
interventions
A subject is treatment adherent until the first time 
of non-adherence defined as
x
The subject has not been dosed with trial 
product within the prior 14 days.
x
The subject has received other weight
management drug or bariatric surgery
x
The subject has not reached target dose at a 
pre-specified week (section 2)
x
After the pre-specified evaluation week for the 
target dose, the subject has not received the 
target dose ±10% within the prior 14 days.
Use for 
determining 
the primary 
estimand
2.3
Statistical analyses
Efficacy endpoints will be analysed using the FAS; safety endpoints will be analysed using the 
SAS. 
Handling of missing baseline data
The last available and eligible observation at or before randomisation is used as the baseline value. 
If no assessments are available, the mean value at randomisation across all subjects is used as the 
baseline value.
2.3.1
Primary endpoint
Definition of primary endpoint: % weight change
Change from randomisation at week 0 to week 26 in body weight (%) is defined as:
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
11 of 23
% weight change =  (body weight at week ʹ͸ – body weight at baseline)
body weight at baseline
 ×100%
2.3.1.1
Analyses addressing the primary estimand
The primary estimand for % weight change addresses the efficacy of cagrilintide and will be 
estimated based on the FAS using post-baseline measurements up to and including week 26 from
the treatment-adherent observation period. 
The primary analysis for the primary estimand for % weight change is an analysis of covariance 
(ANCOVA) with randomised treatment as factor and baseline body weight (kg) as a covariate.
Handling of missing week 26 values for the primary estimand
Observations outside the treatment-adherent observation period such as week 26 assessments for 
retrieved drop-outs (AD) will be handled as if they were missing and will be imputed using multiple 
imputation assuming that missing data is missing at random (MAR). Missing data will be imputed 
using observed data within the same randomised treatment group. This approach makes the 
assumption that subjects with missing data and subjects with dose non-adherence or weight loss 
intervention have the same effect as subjects adhering to randomised treatment without initiating 
any other weight loss intervention.
If the definition of treatment non-adherence is too restrictive then excluding observations due to 
dose lowering will not be implemented. If this is also too restrictive then a higher number of 
allowed missed dose will be considered.
The multiple imputation is done in three steps:
1. Imputation: 
a.
Intermittent missing values are imputed using a Markov Chain Monte Carlo (MCMC) 
method, in order to obtain a monotone missing data pattern. This imputation is done for 
each of the treatment groups separately and 1000 copies of the dataset will be generated
b. A sequential regression approach for imputing monotone missing values at planned
visits will be implemented starting with the first visit after baseline and sequentially 
continuing to the last planned visit at week 26. A model used to impute missing values at 
each planned visit will be fitted for each of the treatment groups (each cagrilintide dose, 
liraglutide 3.0 mg or pooled placebo) using observed data. The model will include 
gender (male/female) and region (Europe, North America, and rest of the world) as 
factors and baseline and post-baseline body weight (kg) values observed prior to the visit 
in question as covariates.
2. Analysis: An ANCOVA with treatment as categorical effects and baseline body weight (kg) as 
a covariate will be used to analyse body weight % change at week 26 for each of the 1000 
complete data sets generated as part of the imputation of missing values. 
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
12 of 23
3. Pooling: Rubin’s rule will be used to combine the analysis results in order to draw inference.
The proportion of missing weight change data at week 26 is estimated to be 5% (based on data from 
trial NN9536-4153) and is expected to be similar in all treatment arms.
Of relevance for the estimation of the primary estimand, the combined proportion of missing data 
and subjects with treatment non-adherence is estimated to be 13%. This is based on data on 
proportion of subjects discontinuing treatment from trial NN9536-4153 and a very low expected 
proportion of subjects undergoing bariatric surgery or starting other weight management 
interventions. cagrilintide treatment is expected to be effective with regard to weight loss, and this 
should reduce the number of missed doses due to ineffective therapy. A higher rate of missed doses 
due to GI AEs is expected in the high cagrilintide dose treatment arms and the liraglutide 3.0 mg 
arm compared to placebo. Apart from this, the rate of missed doses due to AEs is expected to be 
similar across groups. Based on previous experience, a higher rate of treatment discontinuation due 
to other reasons is expected in the placebo group compared to active treatment. This difference may 
be due to lack of efficacy with placebo treatment. 
The estimated treatment difference between individual cagrilintide doses and pooled placebo group 
will be reported together with the associated two-sided 95% CI and corresponding two-sided p-
value. The pooled placebo group will include all subjects on cagrilintide placebo as well as 
liraglutide placebo.
Confirmation of superiority for each cagrilintide dose vs. placebo will be evaluated using a 
hierarchical testing procedure starting with the treatment difference between the highest cagrilintide
dose and placebo and ending with the lowest dose. In the case of a non-significant treatment 
difference the testing procedure will stop. This will protect the family-wise type 1 error in the 
strong sense on a 5% level of significance.
The superiority test for cagrilintide vs. placebo will be carried out as follows. Let                μcagrilintide
,x and μplacebo denote the true mean of % weight change for dose level x of cagrilintide and the 
pooled placebo group, respectively. The null and alternative hypotheses tested are
ܪ଴ǣߤ୒୒େ଴ଵ଻ସି଴଼ଷଷǡ௫൒ߤ௣௟௔௖௘௕௢vs.ܪ஺ǣ ߤ୒୒େ଴ଵ଻ସି଴଼ଷଷǡ௫൏ߤ௣௟௔௖௘௕௢
The null hypothesis will be rejected if the upper limit of the estimated two-sided 95% CI for the 
treatment difference is below 0. 
Dose-response modelling
In order to evaluate the effect of cagrilintide dose vs. placebo on % weight change and to 
characterise the dose-response relationship the mean % weight change will be estimated using dose 
as a continuous variable.
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Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
13 of 23
The dose-response candidate models in Table 2-3 will be fit if feasible.
Table 2-3
Dose-response candidate models
Model
Functional form f(dose,θ)
Emax
ܧ଴൅ܧ௠௔௫
݀݋ݏ݁
ܧܦହ଴൅݀݋ݏ݁
Sigmoidal Emax
ܧ଴൅ܧ௠௔௫
݀݋ݏ݁ఒ
ܧܦହ଴
ఒ൅݀݋ݏ݁ఒ
Linear
ܽ൅ܾή ݀݋ݏ݁
Linear log-dose
ܽ൅ܾή log(݀݋ݏ݁൅ͳሻ
Quadratic
ܽ൅ܾή ݀݋ݏ݁൅ܿή ݀݋ݏ݁ଶ
The candidate models will be fit to the estimated % weight change means at week 26 for the 
employed cagrilintide doses and placebo from the primary analysis model described above. Thus all 
subjects in the FAS will be included and the same assumptions regarding missing values and the 
impact of explanatory variables will be applied. When fitting the models estimated % weight 
change means will be weighted by their inverse estimated variances.
The model used to evaluate dose-response will be selected among the candidate models based on 
the best fit to data. The best fit will be evaluated based on convergence, model complexity, Akaike 
information criterion (AIC) value and visual evaluation. 
Dose-response curves will be estimated and plotted using the fitted dose-response model.
Analysis addressing the effect of cagrilintide vs. liraglutide 3.0 mg
This analysis will evaluate the treatment difference between cagrilintide and liraglutide 3.0 mg 
using the same analysis as the primary analysis for the primary estimand described above. However, 
the treatment differences between cagrilintide doses and liraglutide will be estimated and no 
confirmatory testing will be carried out.
Sensitivity analyses
The below sensitivity analyses will be conducted:
x
A mixed model for repeated measurements (MMRM) comparing the change from baseline 
in body weight (%) at 26 weeks between treatments. All post randomisation measurements 
at planned visits up to week 26 and obtained during treatment adherence will be included in
the model as dependent variables. Treatment will be included as fixed factors and the 
baseline body weight will be included as a covariate both nested within the factor visit. The 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
14 of 23
within subject covarance structure will be unstructured. Subjects without post randomisation
measurements of weight will be excluded from the analysis.
x
Post-baseline measurements excluded for subjects with treatment non-adherence: This 
sensitivity analysis will evaluate the robustness to the assumption that post-baseline data for 
subjects with treatment non-adherence is informative for the weight change had the subjects 
adhered. The same analysis model and multiple imputation approach as for the primary 
analysis will be carried out, but for subjects with dose treatment non-adherence all post-
baseline measurements will be handled as missing and imputed using multiple imputation.
2.3.1.2
Analyses addressing the secondary estimand
The following statistical analyses and imputation methods are designed to address the secondary 
estimand, i.e. to assess the effectiveness of cagrilintide.
The analysis model for % weight change is an ANCOVA with randomised treatment as factor and 
baseline body weight (kg) as a covariate. 
Handling of missing week 26 values for the secondary estimand
All available data at week 26 (AT and AD) are used. Missing values (MT and MD) at week 26 will 
be imputed and the endpoints will be derived from the imputed values. First, a description of the 
primary imputation approach to address the secondary estimand for the primary endpoints is given 
followed by a description of the sensitivity analyses used to assess the robustness of the primary 
analysis results. The sensitivity analyses investigate how assumptions on body weight development 
after discontinuation of randomised treatment impact the estimated treatment contrasts between 
active doses and placebo.
Primary imputation approach for the secondary estimand (RS-MI)
The primary analysis of the secondary estimand is a retrieved subjects based multiple imputation 
approach (RS-MI) which is simplified but similar to the one described by McEvoy (reference 44 in 
the protocol). Missing body weight measurement at week 26 for non-retrieved subjects (MD) are 
imputed using assessments from retrieved subjects (AD). Missing body weight measurements at 
week 26 for subjects on randomised treatment (MT) are imputed using available measurements at 
week 26 from subjects on randomised treatment (AT). The multiple imputation approach is done in 
three steps:
1. Imputation: An imputation model is defined using retrieved subjects (AD) from the FAS. The 
model will be a linear regression of body weight (kg) at week 26 with treatment as factor and 
baseline body weight (kg), last available treatment-adherent observation of body weight (kg) 
and time spent in the treatment-adherent observation period as covariates. No interactions will 
be included. If any subjects are MT, an imputation model for missing body weight 
measurements at week 26 for MT subjects will also be defined using AT subjects in a similar 
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
15 of 23
way. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 26 body weight 
values. This will be done 1000 times, resulting in 1000 complete data sets.
Analysis: Analysis of each of the 1000 complete data sets using the ANCOVA with treatment as 
factor and baseline body weight as covariate, resulting in 1000 estimates for each treatment 
comparison.
Pooling: The 1000 estimation results are integrated into a final result using Rubin’s formula.
Treatment comparisons for cagrilintide doses vs. placebo will be carried out as described for the 
primary analysis addressing the primary estimand. However, no confirmatory testing will be carried
out.
Dose-response modelling
The selected model shape for the primary estimand will also be estimated based on mean estimates 
and their variances for % weight change from the ANCOVA model using the primary imputation 
approach for the secondary estimand.
Analysis addressing the effect of cagrilintide vs. liraglutide 3.0 mg
This analysis will evaluate the treatment difference between cagrilintide and liraglutide 3.0 mg 
using the same analysis as the primary analysis for the secondary estimand described above. 
However, the treatment differences between cagrilintide doses and liraglutide will be estimated.
Sensitivity analyses
Multiple imputation approach using retrieved subjects (J2R-MI): A jump to reference multiple 
imputation approach will be applied. Missing values of body weight at week 26 (MT and MD) for 
all treatment groups are imputed by using available assessments at week 26 in the placebo group 
(AT and AD). This approach makes the assumption that subjects with missing data (MT and MD) 
lose any effect of randomised treatment beyond what can be expected from placebo treatment as 
adjunct to diet and physical activity. The multiple imputation approach is done in three steps. The 
imputation step is described below and step two and three are similar to the primary analysis for the 
secondary estimand.
An imputation model is defined using all placebo subjects from FAS with a week 26 measurement 
(AT and AD). The model will be a linear regression of body weight (kg) at week 26 on gender 
(male/female) and region as factors and baseline body weight (kg) as covariate. No interactions will 
be included. The estimated posterior distribution for the parameters (regression coefficients and 
variances) in the imputation models are then used to impute missing week 26 body weight values 
for each randomised treatment arm. This will be done 1000 times and results in 1000 complete data 
sets.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
16 of 23
Treatment comparisons for cagrilintide doses vs. placebo and liraglutide will be carried out as 
described for the analyses addressing the primary estimand.
2.3.2
Secondary endpoints
2.3.2.1
Supportive secondary endpoints
Supportive secondary endpoints are listed in the protocol. All supportive secondary endpoints will 
be analysed to address the primary estimand.
Efficacy endpoints
Continuous efficacy endpoints
Change from randomisation at week 0 to week 26 in:
o
Body weight (kg)
o
Waist circumference (cm) 
o
Fasting lipids (mg/dL)

Total cholesterol

HDL cholesterol

LDL cholesterol

VLDL cholesterol

Triglycerides
These continuous supportive secondary efficacy endpoints will be analysed using the same analysis 
model as the primary analysis for the primary endpoint addressing the primary estimand described
in Section 2.3.1.1. The outcome variable % weight change and the covariate baseline body weight 
will be replaced by the corresponding outcome and baseline assessments of the endpoint to be 
analysed. Treatment differences will be estimated comparing each cagrilintide dose with placebo 
and liraglutide.
For fasting lipids a multiplicative model will be used, i.e. the ratio between post randomisation 
measurements and baseline will be analysed as the outcome variable instead of differences, and 
both the outcome variable and the baseline assessment will be log-transformed prior to analysis.
Change from randomisation at week 0 to week 26 in:
o
HbA1c (%-point, mmol/mol)
o
FPG (mg/dL)
o
Fasting insulin (μIU/mL)
o
HOMA-IR (%-point)
o
HOMA-β (%-point)
These endpoints will be summarised by descriptive statistics using the FAS.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
17 of 23
Binary efficacy endpoints
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 5% from randomisation
o
Body weight reduction ≥ 10% from randomisation
The analysis model for the 5% and 10% body weight reduction endpoints is a logistic regression 
using randomised treatment as a factor and baseline body weight (kg) as covariate.  
The analysis will be based on FAS using the treatment-adherent observation period and 
observations outside this observation period will be handled as missing. Missing values of body
weight at week 26 are imputed under the same assumption of MAR as for the primary analysis for
the primary endpoint addressing the primary estimand using multiple imputation. The imputed data 
sets for continuous weight change % as described in Section 2.3.1.1 will be used to derive the 
binary weight reduction endpoints. The logistic regression model will be used to estimate log odds
ratios comparing each cagrilintide dose with placebo and liraglutide for each complete data set and 
Rubin’s rule will be used to draw inference. The results after applying Rubin’s rule will be back-
transformed and described by the odds ratio. 
Composite strategy
The following composite variables are defined by subjects who after 26 weeks achieve (yes/no): 
Body weight reduction ≥ 5% from randomisation and no treatment non-adherence 
Body weight reduction ≥ 10% from randomisation and no treatment non-adherence 
The analysis approach is the same as the logistic regression model including multiple imputation 
described above addressing the primary estimand except that for subjects with treatment non-
adherence no imputation of missing data will be used. Instead they will be considered not achieving 
the composite body weight variable. 
Dose-response modelling for body weight reduction endpoints 
The dose-response analysis of 5% and 10% body weight reduction endpoints will be carried out on 
the mean estimates of treatment log odds for each cagrilintide dose and placebo obtained via the 
logistic regression with treatment as factor addressing the primary estimand described above.
Candidate shapes listed in Table 2-4 will be fit and evaluated based on the best fit. Normal 
distribution of the mean estimates for the specific model will be assumed. Mean estimates will be
weighted by the inverse of the estimated variances of the mean log odds.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
18 of 23
Table 2-4
Binary dose-response candidate models
Model
Link function for 
probability p
Functional form f(d,θ)
Logistic
ሾ݌Ȁሺͳ െ݌ሻሿ
ܧ଴൅ܾή ݀݋ݏ݁
Emax
log[p/(1-p)]
ܧ଴൅ܧ௠௔௫
݀݋ݏ݁
ܧܦହ଴൅݀݋ݏ݁
Sigmoidal Emax
log[p/(1-p)]
ܧ଴൅ܧ௠௔௫
݀݋ݏ݁ఒ
ܧܦହ଴
ఒ൅݀݋ݏ݁ఒ
Sensitivity analyses for supportive secondary endpoints
For supportive secondary endpoints no sensitivity analysis will be carried out.
Safety endpoints
Adverse events and anti-drug antibodies
Number of TEAEs from randomisation at week 0 to week 32 (‘end of trial’)
Number of SAEs from randomisation at week 0 to week 32 (‘end of trial’)
Occurrence (yes/no) of anti-drug antibodies towards cagrilintide from randomisation at week 0 to
week 32 (‘end of trial’).
Adverse events will be defined as ‘treatment-emergent’ (TEAE), if the onset of the event occurs in 
the on-treatment period, see definition in Section 2.2.1. TEAEs and treatment emergent SAEs will 
be summarised by descriptive statistics, such as frequencies and rates, using the SAS. No formal 
statistical inference will be carried out based on the number of TEAEs and SAEs.
Occurrence of anti-drug antibodies towards cagrilintide will be summarised by descriptive statistics 
using the SAS.
Dose-response modelling for GI AEs
Analyses of the dose-response for the probability of subjects meeting two different response 
criteria:
x
Having a treatment emergent GI adverse event (yes/no)
x
Having a moderate or severe treatment emergent GI adverse event (yes/no)
Dose-response modelling will be done on the SAS with binary response status (yes/no) for each 
subject during the on-treatment observation period as the outcome variable and dose as a continuous 
covariate. Candidate shapes listed in Table 2-4 will be fit and evaluated based on the best fit.
Continuous safety endpoints
Change from randomisation to week 26 in:
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
19 of 23
o
Systolic blood pressure (mmHg) 
o
Diastolic blood pressure (mmHg)
o
Pulse (bpm)
o
hsCRP (mg/L)
o
PAI-1 activity (mg/L)
o
Renin activity (ng/mL/h)
o
Aldosterone (ng/dL)
These continuous safety endpoints will be summarised by descriptive statistics based on observed 
data from subjects in the SAS that are on drug at week 26.
2.3.3
Exploratory endpoints
Subjects who after 26 weeks achieve (yes/no): 
o
Body weight reduction ≥ 15% from randomisation
o
Body weight reduction ≥ 20% from randomisation 
These endpoints will be analysed using a logistic regression model with randomised treatment as a 
factor and baseline body weight (kg) as covariate as described for body weight reduction ≥ 5% and 
≥ 10% in Section 2.3.2.1.
Change from randomisation at week 0 to week 26 in:
o
Endogenous amylin 
o
Soluble leptin receptor
o
Leptin 
o
SF-36 v2.0 acute: 

Physical component summary score 

Mental component summary scores

Scores on the individual sub-domains: 
x
Physical functioning
x
Role functioning
x
Bodily pain 
x
General health
x
Vitality
x
Social functioning
x
Role emotional 
x
Mental health
o
TFEQ-R18v2: Transformed scale scores for the three scales measured: Uncontrolled 
Eating, Cognitive Restraint and Emotional Eating.
Time to permanent discontinuation of randomised trial product (weeks)
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
20 of 23
Date of permanent discontinuation of randomised trial product is evaluated by the investigator in 
the ‘end of treatment’ form and used to derive the time to permanent discontinuation.
Physical functioning score will be analysed using the same analysis model as the primary analysis 
for the primary endpoint addressing the primary estimand described in Section 2.3.1.1. The 
outcome variable % weight change and the covariate baseline body weight will be replaced by the 
corresponding outcome and baseline assessments of the physical functioning score. Treatment 
differences will be estimated comparing each cagrilintide dose with placebo and liraglutide. The 
remaining endpoints will be summarised by descriptive statistics. 
2.3.4
Explorative statistical analysis for pharmacogenetics and biomarkers
No statistical analyses are planned for genetic data. Planned analyses for biomarkers are handled in 
Section 2.3.1, 2.3.2 and 0.
2.3.5
Other analyses
Ambulatory blood pressure measurements (ABPM) are carried out during 24 hours at screening 
visit 1 (baseline) and visit 11 (end of treatment) for the cagrilintide and placebo groups for subjects 
on treatment at visit 11. If a subject is not on treatment at visit 11, the ABPM endpoints for the 
subject will be set to missing. Hourly ABPM averages with standard deviation bars for SBP, DBP, 
and heart rate at baseline and at visit 11 will be graphically displayed by treatment (cagrilintide dose 
or placebo). Invalid ABPM profiles (as judged by the investigator) will not be included in any 
statistical or descriptive analysis.
The following endpoints will be calculated based on ABPM:
x
∆SBPav, change from baseline in average 24 hour systolic blood pressure
x
∆DBPav, change from baseline in average 24 hour diastolic blood pressure
x
∆HRav, change from baseline in average 24 hour heart rate
x
∆SBPav,day, change from baseline in average day time (6:00 am – 00:00 pm) systolic blood 
pressure
x
∆DBPav,day, change from baseline in average day time (6:00 am – 00:00 pm) diastolic blood
pressure
x
∆HRav,day, change from baseline in average day time (6:00 am – 00:00 pm) heart rate
x
∆SBPav,night, change from baseline in average day time (00:01 am – 05:59 pm) systolic blood 
pressure 
x
∆DBPav,night, change from baseline in average night time (00:01 am – 05:59 pm) diastolic 
blood pressure
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
21 of 23
x
∆HRav,night, change from baseline in average night time (00:01 am – 05:59 pm) heart rate
The above endpoints are calculated as AUC (using the linear trapezoidal method) during the 
respective time period divided by the duration of the observed time period.
The endpoint ∆SBPav will be analysed using ANCOVA model with treatment as factor and baseline 
SBPav as covariate (without interaction) and the treatment difference vs. placebo will be estimated 
with 95% CI for each dose level of cagrilintide. Two approaches to handling missing data will be 
used:
1) Single imputation of missing baseline SBPav will be done using linear regression 
on baseline office SBP. A multiple imputation approach will be performed where 
missing SBP at visit 11 are imputed from a regression model with baseline SBPav
as covariate (separately for each treatment group). The targeted population is 
subjects adhering to treatment from the SAS. 1000 datasets will be imputed and 
Rubins rule will be used to combine the analysis results in order to draw 
inference.
2) A completers analysis where subjects with missing baseline or visit 11 BP and 
subjects who are not adhering to treatment are excluded
The remaining ABPM endpoints will be analysed using the same approach as for ∆SBPav.. A
subgroup analysis for subjects with hypertension will be done if possible including subjects 
according to one of the below criteria:
x
Pre-existing hypertension 
x
Age >60 years 
x
Black-American race
All collected data that were not defined as endpoints will be summarised by descriptive statistics.
2.4
Pharmacokinetic and/or pharmacodynamic modelling
Population PK and exposure-response analyses will be used as supportive evidence for the 
evaluation of efficacy and safety and further to support the dose selection of cagrilintide for future 
clinical development in subjects with obesity. First, plasma cagrilintide concentrations will be 
analysed using a population PK model, quantifying covariate (such as baseline body weight, age, 
gender, race, ethnicity, and injection site) effects on cagrilintide exposure. Second, model based 
estimates of steady-state average concentrations will be derived for each subject, in order to 
facilitate subsequent exposure-response analyses. Relevant efficacy and safety endpoints will be 
related to steady-state average concentrations and subjected to model-based analysis.
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
22 of 23
A modelling analysis plan will be prepared before database lock, outlining details of the analyses. 
The modelling will be performed by Quantitative Clinical Pharmacology at Novo Nordisk and will 
be reported separately from the clinical trial report.
3
Changes to the statistical analyses planned in the protocol
The following supportive safety endpoints based on ABPM have been added after protocol
finalisation on request from regulatory authorities:
Endpoint title
Timeframe
Description/metric used
Change from baseline in average 24 hour 
systolic blood pressure
From visit 1 (week -1 ) to visit 11 
(week 26)
mmHG
Change from baseline in average 24 hour 
diastolic blood pressure
From visit 1 (week -1 ) to visit 11 
(week 26)
mmHG
Change from baseline in average 24 hour 
heart rate
From visit 1 (week -1 ) to visit 11 
(week 26)
beats/min
Change from baseline in average day time 
(6:00 am – 00:00 pm) systolic blood 
pressure
From visit 1 (week -1 ) to visit 11 
(week 26)
mmHG
Change from baseline in average day time 
(6:00 am – 00:00 pm) diastolic blood 
pressure
From visit 1 (week -1 ) to visit 11 
(week 26)
mmHG
Change from baseline in average day time 
(6:00 am – 00:00 pm) heart rate
From visit 1 (week -1 ) to visit 11 
(week 26)
beats/min
Change from baseline in average night 
time (00:01 am – 05:59 pm) systolic blood 
pressure
From visit 1 (week -1 ) to visit 11 
(week 26)
mmHG
Change from baseline in average night 
time (00:01 am – 05:59 pm) diastolic blood 
pressure
From visit 1 (week -1 ) to visit 11 
(week 26)
mmHG
Change from baseline in average night 
time (00:01 am – 05:59 pm) heart rate
From visit 1 (week -1 ) to visit 11 
(week 26)
beats/min
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CONFIDENTIAL


Statistical Analysis Plan
CONFIDENTIAL
Date:
29 March 2020
Novo Nordisk
Trial ID: NN9838-4433
Version:
2.0
UTN: U1111-1214-0429 
Status:
Final
EudraCT No.: 2018-001945-14
Page:
23 of 23
The statistical analysis of these endpoints is described in section 2.3.5.
In addition the following changes to the protocol were made:
x
The definition of treatment adherence has been updated since the original definition was not
feasible to implement.
x
A mixed model for repeated measurements (MMRM) comparing the change from baseline
in body weight (%) at 26 weeks between treatments has been added as a sensitivity analysis
to the primary analysis using the primary estimand.
x
A tipping point analysis for body weight will not be done due to computational infeasibility.
x
Dose-response curves will be plotted without placebo-adjustments but with dose=0
corresponding to placebo.
x
Dose response modelling of Treatment discontinuation due to a treatment emergent GI
adverse event (yes/no) is not done due to too few cases of discontinuation
x
Dose response modelling of having a moderate or severe treatment emergent GI adverse
event (yes/no) has been added
x
Assessments pertaining to endogenous amylin, PAI-1 and DNA sequencing were not
performed in this trial and thus no descriptive statistics of these parameters could be done
x
Wording has been updated various places to increase readability.
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CONFIDENTIAL