Efficacy and Safety of Subcutaneous Semaglutide 2.4 mg Once-weekly in Subjects With Obesity and Prediabetes
Phase: PHASE3
Conditions: Obesity
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT05040971 
Sponsor trial ID: 
NN9536-4734 
Official title of study: 
Efficacy and safety of subcutaneous semaglutide 2.4 mg once-
weekly in subjects with obesity and prediabetes  
Document date: 
02 November 2023

Link
Link
List of contents
Protocol ...............................................................................................................................................
Protocol Attachment ..........................................................................................................................
Date:
Novo Nordisk
Version:
Status:
Semaglutide 2.4 mg once-weekly
Study ID: NN9536-4734 (pre-diabetes)
Clinical Study Report
Appendix 9.1.1
02 November 2023
1.0
Final
9.1.1 Protocol and protocol amendments
CONFIDENTIAL

Protocol 
 
Date: 
24 February 2023 Novo Nordisk 
Trial ID: NN9536-4734 
Version: 
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Status: 
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Protocol 
 
Protocol title: Efficacy and safety of subcutaneous semaglutide 2.4 mg once-weekly in 
subjects with obesity and prediabetes 
 
Substance name: semaglutide 
Universal Trial Number: U1111-1253-1956  
EudraCT Number: 2020-002939-29  
Trial phase: 3b 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.

Protocol 
 
Date: 
24 February 2023 Novo Nordisk 
Trial ID: NN9536-4734 
Version: 
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Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
Protocol version 4.0 
24 February 2023 
Global 
Protocol version 3.0 
08 February 2022 
Global 
Protocol version 2.0 
13 July 2021 
Global 
Original protocol version 1.0 
02 March 2021 
Final protocol 
 
Protocol version 4.0 (24 February 2023) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the council of the European Union, because 
it neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study.1 
Overall rationale for preparing protocol version 4.0 
 This version of the protocol was prepared to remove data base lock (DBL) and interim clinical trial 
report (CTR) after ‘safety visit’ (week 57) and plan only one DBL after completion of the ‘end of 
trial visit’ (week 80) and one CTR will be prepared including the main and the extension phase of 
the trial. 
Section # and name 
Description of change 
Brief rationale 
Section 9.7 (Reporting of the main 
part of the trial) 
Deletion of the DBL and CTR after 
‘Safety visit, P13’ (week 57) of the 
main phase of the trial. 
On re-evaluation it was 
concluded to simplify 
operational set-up of the trial, 
as DBL and CTR is not needed 
until the end of the extension 
phase. 
 
 
 
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Table of Contents 
 
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 3 
1 
Protocol summary ..................................................................................................................................... 6 
1.1 
Synopsis ........................................................................................................................................... 6 
1.2 
Flowchart ......................................................................................................................................... 9 
2 
Introduction ............................................................................................................................................. 11 
2.1 
Trial rationale ................................................................................................................................. 11 
2.2 
Background .................................................................................................................................... 12 
2.2.1 
Semaglutide ..................................................................................................................... 12 
2.2.2 
Trial population ............................................................................................................... 12 
2.3 
Benefit-risk assessment .................................................................................................................. 12 
2.3.1 
Risk assessment ............................................................................................................... 13 
2.3.2 
Benefit assessment ........................................................................................................... 15 
2.3.3 
Overall benefit-risk conclusion ....................................................................................... 15 
3 
Objectives and endpoints ........................................................................................................................ 15 
3.1 
Primary, secondary and exploratory objectives and estimands ..................................................... 15 
3.2 
Primary, secondary and exploratory endpoints .............................................................................. 17 
3.2.1 
Primary endpoints ............................................................................................................ 17 
3.2.2 
Secondary endpoints ........................................................................................................ 17 
3.2.2.1 
Confirmatory secondary endpoints ................................................................. 17 
3.2.2.2 
Supportive secondary endpoints ..................................................................... 18 
3.2.3 
Exploratory endpoints ..................................................................................................... 18 
4 
Trial design .............................................................................................................................................. 19 
4.1 
Overall design ................................................................................................................................ 19 
4.2 
Scientific rationale for trial design ................................................................................................. 20 
4.3 
Justification for dose ...................................................................................................................... 20 
4.4 
End of trial definition ..................................................................................................................... 21 
5 
Trial population ....................................................................................................................................... 21 
5.1 
Inclusion criteria ............................................................................................................................ 21 
5.2 
Exclusion criteria ........................................................................................................................... 21 
5.3 
Lifestyle considerations ................................................................................................................. 23 
5.3.1 
Meals and dietary restrictions .......................................................................................... 23 
5.3.2 
Caffeine and tobacco ....................................................................................................... 23 
5.4 
Screen failures ................................................................................................................................ 23 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria...................................................... 23 
6 
Treatments ............................................................................................................................................... 23 
6.1 
Treatments administered ................................................................................................................ 23 
6.1.1 
Medical devices ............................................................................................................... 25 
6.1.2 
Diet and physical activity counselling ............................................................................. 26 
6.2 
Preparation/handling/storage/accountability .................................................................................. 26 
6.2.1 
Shipment of trial product to subject’s home .................................................................... 27 
6.3 
Measures to minimise bias: Randomisation and blinding ............................................................. 27 
6.4 
Treatment compliance .................................................................................................................... 28 
6.5 
Concomitant medication ................................................................................................................ 28 
6.6 
Dose modification .......................................................................................................................... 29 
6.7 
Treatment after end of trial ............................................................................................................ 29 
7 
Discontinuation of trial treatment and subject discontinuation/withdrawal ..................................... 29 
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7.1 
Discontinuation of trial treatment .................................................................................................. 29 
7.1.1 
Temporary discontinuation of trial treatment .................................................................. 30 
7.2 
Subject discontinuation/withdrawal from the trial ......................................................................... 30 
7.2.1 
Replacement of subjects .................................................................................................. 31 
7.3 
Lost to follow-up ........................................................................................................................... 31 
8 
Trial assessments and procedures ......................................................................................................... 31 
8.1 
Efficacy assessments ...................................................................................................................... 32 
8.1.1 
Body measurements ......................................................................................................... 32 
8.1.2 
Clinical outcome assessments ......................................................................................... 33 
8.1.3 
Clinical laboratory assessments ....................................................................................... 33 
8.2 
Safety assessments ......................................................................................................................... 33 
8.2.1 
Physical examinations ..................................................................................................... 34 
8.2.2 
Vital signs ........................................................................................................................ 34 
8.3 
Adverse events and serious adverse events .................................................................................... 35 
8.3.1 
Time period and frequency for collecting AE and SAE information .............................. 35 
8.3.2 
Method of detecting AEs and SAEs ................................................................................ 36 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................... 36 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................. 36 
8.3.5 
Pregnancy ........................................................................................................................ 37 
8.3.6 
Cardiovascular and death events ..................................................................................... 37 
8.3.7 
Technical complaints ....................................................................................................... 37 
8.4 
Treatment of overdose ................................................................................................................... 37 
8.5 
Pharmacokinetics ........................................................................................................................... 37 
8.6 
Pharmacodynamics ........................................................................................................................ 37 
8.7 
Genetics ......................................................................................................................................... 38 
8.8 
Biomarkers ..................................................................................................................................... 38 
8.9 
Immunogenicity assessments ......................................................................................................... 38 
8.10 
Human biosamples for future research .......................................................................................... 38 
8.11 
Health economics ........................................................................................................................... 38 
9 
Statistical considerations ........................................................................................................................ 38 
9.1 
Statistical hypotheses ..................................................................................................................... 38 
9.2 
Sample size determination ............................................................................................................. 39 
9.3 
Populations for analyses ................................................................................................................ 42 
9.4 
Statistical analyses ......................................................................................................................... 42 
9.4.1 
General considerations .................................................................................................... 42 
9.4.2 
Primary endpoints ............................................................................................................ 43 
9.4.3 
Secondary endpoints ........................................................................................................ 44 
9.4.3.1 
Confirmatory secondary endpoint ................................................................... 44 
9.4.3.2 
Supportive secondary endpoints ..................................................................... 44 
9.4.4 
Exploratory endpoints ..................................................................................................... 44 
9.4.5 
Other safety analyses ....................................................................................................... 44 
9.5 
Interim analyses ............................................................................................................................. 44 
9.6 
Data monitoring committee ........................................................................................................... 44 
9.7 
Reporting of the main part of the trial............................................................................................ 45 
10 Supporting documentation and operational considerations ............................................................... 46 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations ............................................. 46 
10.1.1 
Regulatory and ethical considerations ............................................................................. 46 
10.1.2 
Financial disclosure ......................................................................................................... 46 
10.1.3 
Informed consent process ................................................................................................ 46 
10.1.4 
Information to subjects during trial ................................................................................. 47 
10.1.5 
Data protection ................................................................................................................ 47 
10.1.6 
Committees structure ....................................................................................................... 48 
10.1.6.1 Novo Nordisk safety committee...................................................................... 48 
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1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
it is continuing to increase at an alarming rate. The medical and societal impacts are extensive, and 
obesity is one of the most significant public health challenges worldwide.3-9  
Obesity is associated with a higher risk of a variety of comorbidities, including prediabetes, and the 
risk of obesity-related comorbidities increases with increasing body mass index (BMI).10 
Individuals with both obesity and prediabetes are at increased risk of type 2 diabetes (T2D) as well 
as other weight-related comorbidities associated with an increased risk of mortality, and are likely 
to benefit from weight reduction.11  
The present 52-week trial will compare the effect of semaglutide subcutaneous (s.c.) 2.4 mg once-
weekly versus placebo as an adjunct to a reduced-calorie diet and increased physical activity on 
body weight and on reversal to normoglycaemia in subjects with BMI ≥ 30.0 kg/m2  and 
prediabetes, defined as HbA1c between 6.0 and 6.4% (both inclusive) and/or fasting plasma glucose 
(FPG) between 5.5 and 6.9 mmol/L (both inclusive) at baseline.12  
Objectives and endpoints: 
Primary objective (week 0 to week 52) 
To confirm the superiority of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo, 
both as adjuncts to a reduced-calorie diet and increased physical activity in subjects with obesity 
and prediabetes, on body weight and reversal to normoglycaemia. 
Secondary objectives (week 0 to week 52) 
To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo on:  
 glucose metabolism  
 cardiovascular risk factors  
 other factors related to body weight 
Primary estimand 
The primary clinical question of interest is: what is the average treatment effect of semaglutide s.c. 
2.4 mg once-weekly as an adjunct to a reduced-calorie diet and increased physical activity, in 
subjects with obesity and prediabetes, measured by change from baseline to week 52 in body weight 
and reversal to normoglycaemia, regardless of discontinuation or dose reduction of randomised 
treatment and regardless of initiating other glucose-lowering medication or anti-obesity therapies 
(weight management drugs or bariatric surgery) (“treatment policy” strategy). 
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Primary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From randomisation (week 0) to 
end of treatment (week 52)  
% 
Change to normoglycemia* 
From randomisation (week 0) to 
end of treatment (week 52)  
Count of subjects 
*Normoglycemia is defined as having both HbA1c < 6.0% (< 42 mmol/mol) and FPG < 5.5 mmol/L (< 99 mg/dL) 
Overall design: 
Main phase 
This is a 52-week, randomised, two-arm, double-blinded, parallel-group, multi-centre, multinational 
clinical trial comparing semaglutide s.c. 2.4 mg once-weekly with semaglutide placebo once-
weekly as an adjunct to a reduced-calorie diet and increased physical activity in subjects with 
obesity (BMI ≥30.0 kg/m2) and prediabetes, defined as HbA1c between 6.0 and 6.4% (both 
inclusive) and/or FPG between 5.5 and 6.9 mmol/L (both inclusive) at baseline.12 A safety visit 
(phone visit) will take place 5 weeks after end of treatment (week 57).  
Extension phase 
The extension phase is a 28-week off-treatment period after the last visit in the main phase 
(visit 12), including standard diet and physical activity counselling according to local guidelines. 
Two visits are planned at week 66 and week 80 for assessment of body weight, and glycaemic and 
cardiovascular parameters. Total trial duration (main phase and extension phase) for each subject is 
approximately 82 weeks. 
Eligible subjects will be randomised in a 2:1 manner to receive either semaglutide s.c. 2.4 mg once-
weekly or placebo. Randomisation will take place 1-2 weeks after screening. 
Key inclusion criteria 
 Male or female aged ≥18 years at the time of signing informed consent. 
 BMI ≥30.0 kg/m2  
 Prediabetes defined as at least one of the following:12 
 
HbA1c between 6.0 and 6.4 % (42 and 47 mmol/mol) (both inclusive) as measured by 
central laboratory at screening. 
 
FPG between 5.5 and 6.9 mmol/L (99 and 125 mg/dL) (both inclusive) as measured by 
central laboratory at screening. 
Key exclusion criteria 
 History of type 1 or type 2 diabetes. 
 Treatment with glucose-lowering agent(s) within 90 days before screening. 
 HbA1c ≥6.5 % (≥48 mmol/mol) as measured by central laboratory at screening. 
 FPG ≥ 7.0mmol/L (126 mg/dL) as measured by central laboratory at screening. 
 A self-reported change in body weight >5 kg (11 lbs) within 90 days before screening 
irrespective of medical records. 
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 Treatment with any medication for the indication of obesity within the past 90 days before 
screening.  
Number of subjects: 
Approximately 201 subjects will be randomly assigned to trial product. 
Treatment groups and duration: 
The total trial duration (main phase and extension phase) for the individual subject will be 
approximately 82 weeks. The trial includes 2 screening visits (weeks -2 and -1) followed by 
randomisation (week 0) and visits every 4th week during dose escalation. From week 20, visits will 
take place every 8th week for the remaining maintenance period until end of treatment (week 52). In 
the off-treatment extension phase, there will be a phone visit at week 57, and 2 visits with 14 weeks 
apart (week 66 and week 80). 
The following trial products will be supplied by Novo Nordisk A/S for the duration of the trial: 
 Semaglutide D 0.5 mg/mL, solution for injection, DV3396 0.5 mL pen-injector 
 Semaglutide D 1.0 mg/mL, solution for injection, DV3396 0.5 mL pen-injector 
 Semaglutide D 2.0 mg/mL, solution for injection, DV3396 0.5 mL pen-injector 
 Semaglutide D 2.27 mg/mL, solution for injection, DV3396 0.75 mL pen-injector 
 Semaglutide D 3.2 mg/mL, solution for injection, DV3396 0.75 mL pen-injector  
 Semaglutide placebo Ia, solution for injection, 0.5mL pen-injector 
 Semaglutide placebo Ib, solution for injection, 0.75 mL pen-injector 
 
Data monitoring committee: No 
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2 
Introduction 
2.1 
Trial rationale 
The prevalence of obesity has reached epidemic proportions in most countries around the world and 
the prevalence is still increasing at an alarming rate. The medical and societal impacts are extensive, 
and obesity is one of the most significant public health challenges worldwide.3-9 Obesity is 
associated with an increased risk of a variety of comorbidities including hyperglycaemia, T2D, 
hypertension, dyslipidaemia, obstructive sleep apnoea, atherosclerosis,  osteoarthritis, urinary 
incontinence, non-alcoholic steatohepatitis, cardiovascular disease, certain types of cancers, and risk 
of early death.13-27 Moreover, obesity adversely affects physical and mental health and reduces 
health-related quality of life.28, 29 
Even a body weight loss of > 5% has been shown to have significant health benefits on many 
obesity-related comorbidities as well as physical symptoms and health-related quality of life30 and 
studies suggest a beneficial impact of weight loss on cardiovascular risk and mortality in individuals 
with obesity.31-33 
Lifestyle intervention in the form of diet and exercise is first line treatment for obesity, but most 
individuals with obesity struggle to achieve and maintain their weight loss.34-42 Surgical 
interventions for weight loss offer an effective alternative for some individuals with severe obesity, 
but surgery carries a risk in connection with the procedure and may not be without complications. 
43, 44 Furthermore, surgery is limited in terms of the number of individuals it can be offered to 
compared with the number of individuals requiring intervention to treat obesity.34,  37,  38,  43- 47 
Therefore, pharmacotherapy may serve as a valuable adjunct to lifestyle intervention for individuals 
with obesity in order to achieve and maintain a clinically relevant weight loss, to improve comorbid 
conditions and to facilitate a healthier lifestyle.  
The risk of obesity-related comorbidities increases with increasing BMI10, and individuals with both 
obesity and prediabetes are at significant risk of T2D, other weight-related comorbidities and 
mortality and are likely to benefit from weight reduction and improvement in glycaemic status. 
The present trial will compare the effect on reversal to normoglycaemia of 52 weeks of treatment 
with semaglutide s.c. 2.4 mg once-weekly versus placebo as an adjunct to a reduced-calorie diet and 
increased physical activity in subjects with obesity (BMI ≥ 30.0) and prediabetes, defined as HbA1c 
between 6.0 and 6.4% (both inclusive) and/or FPG between 5.5 and 6.9 mmol/L (both inclusive).12 
Furthermore, the trial will compare the effect on body weight of semaglutide s.c. 2.4 mg once-
weekly versus placebo. An off-treatment extension phase from week 52 to week 80 is included to 
obtain a better understanding of how glucose metabolism, body weight, and cardiovascular risk 
factors develop after completed pharmacotherapy intervention in people living with obesity and 
prediabetes. The extension phase of this trial mimics a real-world setting and can thereby provide 
better guidance to health care professionals, as well as to patients, in the future management of 
obesity and prediabetes. 
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2.2 
Background 
2.2.1 
Semaglutide 
Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA), approved for 
the treatment of T2D in adults (Ozempic®), which is currently under development by Novo Nordisk 
for the treatment of weight management at higher doses. Semaglutide has a half-life of 
approximately 160 hours, making it suitable for once-weekly dosing.48  
GLP-1 is a physiological regulator of appetite and postprandial GLP-1 response is present in several 
areas of the brain involved in appetite regulation.49 In line with this, clinical50-55 and non-clinical 
data56 indicate that the body weight-reducing effect of semaglutide is mainly mediated by a reduced 
energy intake.  
A global phase 3a clinical development programme with semaglutide s.c. 2.4 mg once-weekly has 
been completed (STEP programme), having enrolled approximately 4,500 adults with overweight 
or obesity. The programme consists of four trials (NN9536-4373, NN9536-4374, NN9536-4375 and 
NN9536-4376). The 68-week phase 3a weight management trial STEP 1 (NN9536-4373) 
demonstrated clinically significant weight loss with semaglutide s.c. 2.4 mg once-weekly: a total of 
1,961 subjects with overweight or obesity were included, and at week 68, subjects in the 
semaglutide s.c. 2.4 mg group achieved an average weight loss of 14.85% compared to 2.41% in the 
placebo group.  
A comprehensive review of results from the non-clinical and clinical studies of semaglutide can be 
found in the current edition of the investigator’s brochure (IB)57 and any updates hereof.  
2.2.2 
Trial population 
The trial population will consist of subjects with BMI ≥30.0 kg/m2 and prediabetes, defined as 
HbA1c between 6.0 and 6.4% (both inclusive) and/or FPG between 5.5 and 6.9 mmol/L (both 
inclusive) at baseline.12 These subjects are at significant risk for weight-related comorbidities and 
mortality and are likely to benefit from weight reduction and improvement in glycaemic status 
(reversal to normoglycaemia).  
 
2.3 
Benefit-risk assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events (AEs) of 
semaglutide can be found in the IB57 and any updates hereof. 
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Secondary objectives (week 0 to week 52) 
To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo on:  
 glucose metabolism  
 cardiovascular risk factors  
 other factors related to body weight 
Secondary safety objective (week 0 to week 57) 
To compare the safety and tolerability of semaglutide s.c. 2.4 mg once-weekly versus semaglutide 
placebo. 
Exploratory objectives 
Main phase (week 0 to week 52) 
To compare the efficacy of semaglutide s.c. 2.4 mg once-weekly versus semaglutide placebo on 
physical functioning, vitality, work productivity, and progression to T2D. 
 
Main and extension phase (week 0 to week 80) 
To explore the change in body weight, reversal to normoglycemia, glucose metabolism, 
cardiovascular risk factors, other factors related to body weight, and progression to T2D in subjects 
after treatment with semaglutide s.c. 2.4 mg once-weekly or semaglutide placebo followed by an 
off-treatment period. 
Primary estimand 
The primary clinical question of interest is: what is the average treatment effect of semaglutide s.c. 
2.4 once-weekly as an adjunct to a reduced-calorie diet and increased physical activity, in subjects 
with obesity and prediabetes, measured by relative change from baseline to week 52 in body weight 
and reversal to normoglycaemia, regardless of discontinuation or dose reduction of randomised 
treatment and regardless of initiating other glucose-lowering medication or anti-obesity therapies 
(weight management drugs or bariatric surgery) (“treatment policy” strategy). 
The estimand is described by the following attributes (according to International Council for 
Harmonisation (ICH) E9(R1)58): 
 Treatment condition: The randomised treatment regardless of discontinuation or dose reduction 
of randomised treatment or initiation of other glucose-lowering medication or anti-obesity 
therapies (as defined above) 
 Other intercurrent events: none 
 Population: Subjects with obesity and prediabetes 
 Endpoints: The two primary endpoints relative change in body weight and reversal to 
normoglycaemia, both from baseline to week 52 
 Population-level summary: For change in body weight, the treatment effect will be quantified by 
the difference in mean changes between treatment conditions. For reversal to normoglycaemia, 
the treatment effect will be quantified by the odds ratio between treatment conditions. 
A similar estimand applies to all supportive secondary endpoints, which is called the secondary 
estimand. 
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Rationale for estimand: The primary (and secondary) estimand aims at reflecting how patients with 
obesity are treated in clinical practice. 
Additional estimand 
An additional clinical question of interest is: what is the average treatment effect of semaglutide s.c. 
2.4 mg once-weekly as an adjunct to a reduced-calorie diet and increased physical activity, in 
subjects with obesity and prediabetes, measured by relative change from baseline to week 52 in 
body weight and reversal to normoglycaemia, had they remained on their randomised treatment for 
the entire planned duration of the trial and not initiated other glucose-lowering medication or anti-
obesity therapies (weight management drugs or bariatric surgery) (“hypothetical” strategy). 
The estimand is described by the following attributes (according to ICH E9(R1)58): 
 Treatment condition: The randomised treatment if subjects had adhered for the entire duration 
of the trial and not initiated other glucose-lowering medication or anti-obesity therapies (as 
defined above) 
 Other intercurrent events: none 
 Population: Subjects with obesity and prediabetes 
 Endpoints: The primary endpoints relative change in body weight and reversal to 
normoglycaemia, both from baseline to week 52 
 Population-level summary: For relative change in body weight, the treatment effect will be 
quantified by the difference in mean changes between treatment conditions. For reversal to 
normoglycaemia, the treatment effect will be quantified by the odds ratio between treatment 
conditions. 
Rationale for estimand: The additional estimand aims at reflecting the treatment effect in the 
absence of intercurrent events. 
3.2 
Primary, secondary and exploratory endpoints 
3.2.1 
Primary endpoints 
Endpoint title 
Time frame 
Unit 
Change in body weight 
From randomisation (week 0) to end 
of treatment (week 52)  
% 
Change to normoglycemia* 
From randomisation (week 0) to end 
of treatment (week 52)  
Count of subjects 
* Normoglycemia is defined as having both HbA1c < 6.0% (< 42 mmol/mol) and FPG < 5.5 mmol/L (< 99 mg/dL) 
3.2.2 
Secondary endpoints 
3.2.2.1 
Confirmatory secondary endpoints 
Not applicable for this trial 
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3.2.2.2 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in HbA1c 
From randomisation (week 0) to end 
of treatment (week 52) 
%-points 
Change in FPG 
From randomisation (week 0) to end 
of treatment (week 52) 
mmol/L 
Change in waist circumference 
From randomisation (week 0) to end 
of treatment (week 52) 
cm 
Change in systolic blood pressure 
From randomisation (week 0) to end 
of treatment (week 52) 
mmHg 
Change in lipids 
 Triglycerides 
 Total cholesterol 
 High density lipoprotein (HDL) 
cholesterol 
 Low density lipoprotein (LDL) 
cholesterol 
 Very low density lipoprotein 
(VLDL) cholesterol 
From randomisation (week 0) to end 
of treatment (week 52) 
% 
 
 
3.2.3 
Exploratory endpoints 
Endpoint title 
Time frame 
Unit 
Change in EuroQol five dimensions 
three level (EQ-5D-3L) index score 
From randomisation (week 0) to end 
of treatment (week 52) 
Score points 
Change in EQ-5D-3L visual 
analogue scale (VAS) score 
From randomisation (week 0) to end 
of treatment (week 52) 
Score points  
Change in Work Limitations 
Questionnaire 25-item version 
(WLQ-25) Six-item Physical 
Demands scale 
From randomisation (week 0) to end 
of treatment (week 52) 
Score points 
Change in WLQ-25 total score 
From randomisation (week 0) to end 
of treatment (week 52) 
Score points 
Change to normoglycemia* 
From randomisation (week 0) to end 
of extension phase (week 80)  
Count of subjects 
Change in body weight 
From randomisation (week 0) to end 
of extension phase (week 80)  
% 
Change in HbA1c 
From randomisation (week 0) to end 
of extension phase (week 80) 
%-points 
Change in FPG 
From randomisation (week 0) to end 
of extension phase (week 80) 
mmol/L 
Change in waist circumference 
From randomisation (week 0) to end 
of extension phase (week 80) 
cm 
Change in systolic blood pressure 
From randomisation (week 0) to end 
of extension phase (week 80) 
mmHg 
Change in lipids 
 Triglycerides 
 Total cholesterol 
 High-density lipoprotein (HDL) 
cholesterol 
 Low-density lipoprotein (LDL) 
cholesterol 
From randomisation (week 0) to end 
of extension phase (week 80) 
% 
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 Very low-density lipoprotein 
(VLDL) cholesterol 
Progression to T2D** 
From randomisation (week 0) to end 
of treatment (week 52) 
Count of subjects 
Progression to T2D** 
From randomisation (week 0) to end 
of extension phase (week 80) 
Count of subjects 
* Normoglycemia is defined as having both HbA1c < 6.0% (< 42 mmol/mol) and FPG < 5.5 mmol/L (< 99 mg/dL) 
**Diagnosis of T2D is defined as HbA1c ≥6.5% (≥ 48 mmol/mol) and/or FPG ≥ 7.0 mmol/L (≥ 126 mg/dL) verified 
with a repeated blood sample within 4 weeks. 
4 
Trial design 
4.1 
Overall design 
Main phase 
This is a 52-week, randomised, two-arm, double-blinded, parallel-group, multi-centre, multinational 
clinical trial comparing semaglutide s.c. 2.4 mg once-weekly with semaglutide placebo once-
weekly on body weight and reversal to normoglycaemia in subjects with obesity (BMI ≥ 
30.0 kg/m2) and prediabetes (HbA1c between 6.0 and 6.4%, both inclusive and/or FPG between 5.5 
and 6.9 mmol/L, both inclusive12) at baseline. 
The trial includes 2 screening visits (week -2 and week -1) to assess the subject’s eligibility 
followed by randomisation (week 0) and visits every 4th week during dose escalation. From 
week 20, visits will take place every 8th week for the remaining maintenance period until end of 
treatment at week 52. A safety visit (phone visit) will take place 5 weeks after end of treatment 
(week 57). 
Extension phase 
All subjects will continue in the 28-week off-treatment extension phase after the last visit in the 
main phase (visit 12). Two visits with 14 weeks apart will take place (week 66 and week 80) for 
assessment of body weight, and glycaemic and cardiovascular parameters.  
The total trial duration (main phase and extension phase) for each subject is approximately 
82 weeks (up to 2 weeks screening, 52 weeks treatment and 28 weeks off treatment). 
Approximately 201 eligible subjects will be randomised in a 2:1 manner to receive either 
semaglutide s.c. 2.4 mg once-weekly or semaglutide placebo once-weekly as an adjunct to a 
reduced-calorie diet and increased physical activity.  
The trial design is outlined in Figure 4-1. 
Figure 4-1  
Schematic diagram of the trial design 
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4.2 
Scientific rationale for trial design 
The trial population will consist of subjects with obesity (BMI ≥ 30.0 kg/m2) and prediabetes, 
defined as HbA1c between 6.0 and 6.4% (both inclusive) and/or FPG between 5.5 and 6.9 mmol/L 
(both inclusive) at baseline.12 These subjects are likely to benefit from weight reduction and 
improvement in glycaemic status (reversal to normoglycaemia).  
The treatment duration is 52 weeks which is the same as the length of the phase 2 trial (NN9536-
4153) where the mean weight loss was 13.8% with the highest dose of semaglutide (0.4 mg once-
daily) compared to 2.3% with placebo59. Also, mean weight loss at 52 weeks was very near the 
maximum reached in the phase 3a programme. Thus, a 52-week treatment period (including 
36 weeks on target dose) is considered sufficient to realise the weight loss potential of the 
intervention. A safety visit (phone visit) will take place 5 weeks after end of treatment (week 57) to 
account for the exposure and the long half-life of semaglutide. A 28-week off-treatment period is 
included to explore how body weight, cardiovascular risk factors and glucose metabolism develop 
after completed pharmacotherapy in subjects with obesity and prediabetes. 
A randomised, double-blinded, placebo-controlled, multi-centre trial design is chosen to minimise 
bias in the assessment of the effect and safety of semaglutide s.c. 2.4 mg once-weekly versus 
semaglutide placebo, as an adjunct to a reduced-calorie diet and increased physical activity.  
4.3 
Justification for dose 
A maintenance dose of semaglutide s.c. 2.4 mg once-weekly has been chosen for the phase 3 weight 
management development programme. The 68-week phase 3a weight management trial STEP 1 
(NN9536-4373) demonstrated clinically significant weight loss with semaglutide s.c. 2.4 mg once-
weekly. In STEP 1, 1,961 subjects with overweight or obesity were included. At week 68, subjects 
in the semaglutide s.c. 2.4 mg once-weekly group achieved an average weight loss of 14.85% 
compared to 2.41% in the placebo group. In the STEP 1 trial, semaglutide s.c. 2.4 mg once-weekly 
had a safe and well-tolerated profile, consistent with previous findings. 
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It is well known that to mitigate gastrointestinal side effects with GLP-1 RA treatment, dose 
escalation to the target dose is required. Based on experience from the STEP 1–4 trials, a fixed-dose 
escalation regimen is selected, with dose escalation every 4 weeks until the target dose is reached. 
Treatment will be initiated at a once-weekly dose of 0.25 mg and follow a fixed-dose escalation 
regimen, with dose increases every 4 weeks (to doses of 0.5, 1.0, 1.7 and 2.4 mg/week), until the 
target dose is reached after 16 weeks. 
4.4 
End of trial definition 
A subject is considered to have completed the trial if he/she has completed all phases of the trial 
including the last visit ('end of trial' according to the flowchart). 
The end of the trial is defined as the date of the 'end of trial' visit of the last subject in the trial 
globally. 
5 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability for 
the trial. 
2. Male or female aged ≥ 18 years at the time of signing informed consent. 
3. BMI ≥ 30.0 kg/m2  
4. Prediabetes defined as at least one of the following:12 
a. HbA1c between 6.0 and 6.4 % (42 and 47 mmol/mol) (both inclusive) as measured 
by central laboratory at screening. 
b. FPG between 5.5 and 6.9 mmol/L (99 and 125 mg/dL) (both inclusive) as measured 
by central laboratory at screening. 
The criteria will be assessed at the investigator’s discretion unless otherwise stated. 
5.2 
Exclusion criteria  
Subjects are excluded from the trial if any of the following criteria apply: 
1. History of type 1 or type 2 diabetes. 
2. Treatment with glucose-lowering agent(s) within 90 days before screening. 
3. HbA1c ≥ 6.5 % (≥ 48 mmol/mol) as measured by central laboratory at screening. 
4. FPG ≥ 7.0 mmol/L (126 mg/dL) as measured by central laboratory at screening. 
5. A self-reported change in body weight > 5 kg (11 lbs) within 90 days before screening 
irrespective of medical records. 
6. Treatment with any medication for the indication of obesity within the past 90 days before 
screening. 
7. 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 
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performed > 1 year before screening, (2) lap banding, if the band has been removed > 1 year 
before screening, (3) intragastric balloon, if the balloon has been removed > 1 year before 
screening or (4) duodenal-jejunal bypass sleeve, if the sleeve has been removed > 1 year before 
screening. 
8. Uncontrolled thyroid disease. 
9. Known or suspected hypersensitivity to trial product or related products. 
10. Previous participation in this trial. Participation is defined as signed informed consent. 
11. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method (highly effective contraceptive 
measures as required by local regulation or practice). 
12. Participation in any clinical trial of an approved or non-approved investigational medicinal 
product within 90 days before screening* 
13. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 or medullary 
thyroid carcinoma. 
14. History of chronic pancreatitis or acute pancreatitis within 180 days prior to screening 
15. End-stage renal disease or chronic or intermittent haemodialysis or peritoneal dialysis. 
16. Presence or history of malignant neoplasms (other than basal and squamous cell skin cancer, 
in situ carcinomas of the cervix, or in situ prostate cancer) within 5 years before screening. 
17. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 60 days prior to the day of screening. 
18. Chronic heart failure classified as being in New York Heart Association (NYHA) Class IV at 
screening. 
19. Other subject(s) from the same household participating in any semaglutide trial. 
20. Presence or history of severe psychiatric disorders (e.g., schizophrenia, bipolar disorder, major 
depressive disorder or anxiety), as judged by the investigator. 
21. Known or suspected abuse of alcohol or recreational drugs. 
22. Surgery scheduled for the duration of the trial, except for minor surgical procedures, in the 
opinion of the investigator. 
23. Any disorder, unwillingness or inability, not covered by any of the other exclusion criteria, 
which in the investigator’s opinion might jeopardise subject’s safety or compliance with the 
protocol. 
The criteria will be assessed at the investigator’s discretion unless otherwise stated. 
*Simultaneous participation in a trial with the primary objective of evaluating an approved or non-
approved investigational medicinal product for prevention or treatment of COVID-19 disease or 
postinfectious conditions is allowed if the last dose of the investigational medicinal product has 
been received more than 30 days before screening. 
Denmark, Finland, Spain and United Kingdom: see local requirements in Appendix 7 
(Section 10.7). 
5.3 
Lifestyle considerations 
To ensure alignment regarding performance of assessments across subjects and trial sites, the below 
restrictions apply. 
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5.3.1 
Meals and dietary restrictions 
Subjects must attend the visits fasting according to the flowchart. 
Fasting is defined as at least 8 hours 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 procedures done. Procedures requiring subject to fast include blood 
sampling of FPG. 
5.3.2 
Caffeine and tobacco 
Subject should avoid caffeine and smoking at least 30 minutes prior to measuring the blood 
pressure.  
Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
5.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial but are not 
eligible for participation according to inclusion/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes informed consent date, 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE). A 
screen failure session must be made in the interactive web response system (IWRS). 
Individuals who do not meet the criteria for participation in this trial may not be rescreened. If the 
subject has failed one of the inclusion criteria or fulfilled one of the exclusion criteria related to 
laboratory parameters, re-sampling is not allowed. However, in case of technical issues (e.g. 
haemolysed or lost), re-sampling is allowed for the affected parameters. 
5.5 
Run-in criteria, randomisation criteria and dosing day criteria 
Not applicable for this trial. 
6 
Treatments 
6.1 
Treatments administered 
Investigational medicinal products (IMP) 
All trial products listed in Table 6-1 are considered investigational medicinal products (IMP). 
Table 6-1 
Investigational medicinal products provided by Novo Nordisk A/S 
Trial product name 
Dose 
Dosage 
form 
Route of 
administration 
Dosing 
instructions 
Delivery device 
Semaglutide D 0.5 
mg/mL DV3396 
0.25 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL single-dose pen-
injector 
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Semaglutide D 1.0 
mg/mL DV3396 
0.5 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL single-dose pen-
injector 
Semaglutide D 2.0 
mg/mL DV3396 
1.0 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL single-dose pen-
injector 
Semaglutide placebo Ia 
N/A 
Solution for 
injection 
s.c. 
Once-weekly 
0.5 mL single-dose pen-
injector 
Semaglutide D 2.27 
mg/mL DV3396 
1.7 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.75 mL single-dose pen-
injector 
Semaglutide D 3.2 
mg/mL DV3396 
2.4 mg 
Solution for 
injection 
s.c. 
Once-weekly 
0.75 mL single-dose pen-
injector 
Semaglutide placebo Ib 
N/A 
Solution for 
injection 
s.c. 
Once-weekly 
0.75 mL DV3396 single-
dose pen-injector 
 Dose escalation of semaglutide/semaglutide placebo should take place during the first 16 weeks 
after randomisation as described in Table 6-2. All subjects should aim at reaching the 
recommended target dose of semaglutide 2.4 mg once weekly or semaglutide placebo. 
 If a subject does not tolerate the recommended target dose of 2.4 mg once weekly, the subject 
may stay at a lower dose level of 1.7 mg once weekly. This should only be allowed if the 
subject would otherwise discontinue trial product completely and if considered safe to continue 
trial product, as per the investigator’s discretion. It is recommended that the subject makes at 
least one attempt to re-escalate to the recommended target dose of 2.4 mg once-weekly, as per 
the investigator’s discretion.  
 It is recommended that the investigator consults Novo Nordisk in case of persistent deviations 
from the planned escalation regimen.  
 A dose reminder card will be handed out to the subjects at each site visit during the escalation 
period. Once the target dose has been reached, the dose reminder card is only handed out as 
needed. 
Table 6-2 
Dose escalation and maintenance of semaglutide /semaglutide placebo  
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The following should be emphasised during training of subjects: 
 use of the pen-injector (according to instruction guidelines given in the DFU) 
 long-term and in-use storage conditions of the pen-injector (as specified on the label and in the 
TMM). 
The investigator must document that directions for use are given to the subject verbally and in 
writing as a DFU document at the first dispensing visit (as specified in the flowchart (Section 1.2)) 
and that subjects are trained. Training must be repeated as specified in the flowchart and, if needed, 
during the trial at regular intervals in order to ensure correct use of the pen-injector and correct 
injection technique. Training is the responsibility of the investigator or a delegate. 
The first dose of trial product must be taken on the day of randomisation (V3) at the clinical site by 
self-administration under supervision by trained site staff.  
6.1.2 
Diet and physical activity counselling 
At every visit in the first 52-week period the subject should be offered individual counselling with 
regards to diet and physical activity by a dietician or a similar qualified healthcare professional. 
During the 28-week off-treatment extension period, subjects should be offered healthy lifestyle 
counselling as per normal clinical practise and according to local guidelines. 
6.2 
Preparation/handling/storage/accountability 
Only subjects randomised to treatment may use trial product and only delegated site staff may 
supply or administer trial product. 
 Acceptable temperature ranges and conditions for storage and handling of each trial product 
when not in use and when in use are described in the TMM. 
 Each site will be supplied with enough trial products for the trial on an ongoing basis controlled 
by the IWRS. Trial product will be distributed to the sites according to screening and 
randomisation. 
 The investigator or designee must confirm that appropriate temperature conditions have been 
maintained during transit for all trial products received, and that any discrepancies are reported 
and resolved before use of the trial products. 
 All trial products must be stored in a secure, controlled, and monitored (manual or automated) 
area in accordance with the labelled storage conditions with access limited to the investigator 
and delegated site staff. 
 The investigator must inform Novo Nordisk immediately if any trial product has been stored 
outside specified conditions. The trial product must not be dispensed to any subject before it has 
been evaluated and approved for further use by Novo Nordisk. Additional details regarding 
handling of temperature deviations can be found in the TMM. 
 The investigator or designee is responsible for drug accountability and record maintenance (i.e. 
receipt, accountability and final disposition records). 
 The investigator or designee must instruct the subject in what to return at next visit. 
 Drug accountability must be performed in the IWRS by registering pen-injectors as used, 
unused or lost.  
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 The subject must return all 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, un-used, expired or damaged trial products (for technical complaint samples, see 
Section 10.5) must be stored separately from non-allocated trial products. No temperature 
monitoring is required. 
 Non-allocated trial products including expired or damaged products must be accounted as 
unused, at the latest at closure of the site. 
6.2.1 
Shipment of trial product to subject’s home 
For selected countries and if permitted by local regulations, the investigator may offer to send trial 
product and auxiliaries from the trial site or pharmacy to the subject’s home by courier service.  
The process for sending trial product from the trial site or pharmacy to a subject’s home is 
described in the “Trial site/pharmacy instruction for shipment of trial product to subjects’ homes” 
document. This document contains detailed instructions for preparing packaging and setting up the 
pick-up of trial product, handover of trial product from the trial site or pharmacy staff to the courier, 
required temperature monitoring of trial product, delivery to and receipt of trial product by the 
subject. The process for returning trial product to the trial site or pharmacy by courier is also 
described in this document.  
Investigators, trial site/pharmacy staff and subjects who will be involved in shipment of trial 
product to the subject’s home will be adequately trained in this process. 
6.3 
Measures to minimise bias: Randomisation and blinding 
All subjects will be screened and 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. 
Semaglutide once-weekly and semaglutide placebo will be double blinded. The active drug and 
placebo are visually identical for the following trial products: 
 Semaglutide D 0.5 mg/mL, Semaglutide D 1.0 mg/mL, Semaglutide D 2.0 mg/mL DV3396 and 
Semaglutide placebo Ia 
 Semaglutide D 2.27 mg/mL, Semaglutide D 3.2 mg/mL and Semaglutide placebo Ib 
The specific treatment for a subject will be assigned using an IWRS. The site will access the IWRS 
before the start of trial product administration for each subject. 
The IWRS is used for blind-breaking. In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a subjects’ treatment is warranted. Subject safety 
must always be the first consideration in making such a determination. If the investigator decides 
that unblinding is warranted, the investigator should make every effort to contact Novo Nordisk 
prior to unblinding a subjects’ treatment unless this could delay emergency treatment of the subject. 
If a subject’s treatment is unblinded, Novo Nordisk (Global Safety department) must be notified 
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6.6 
Dose modification 
Not applicable for this trial. Please refer to Section 6.1 for description of missed dose(s). 
6.7 
Treatment after end of trial 
There is no treatment following the end of trial. When discontinuing trial products, the subject 
should be treated at the discretion of the investigator. 
7 
Discontinuation of trial treatment and subject 
discontinuation/withdrawal 
Treatment of a subject may be discontinued at any time during the trial at the discretion of the 
investigator for safety, behavioural, compliance or administrative reasons. 
Efforts must be made to have subjects, who discontinue trial product, to continue in the trial. 
Subjects must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. Only subjects who withdraw consent will be considered as withdrawn 
from the trial.  
Temporary or permanent discontinuation of treatment with trial product will not lead to withdrawal 
from the trial. 
7.1 
Discontinuation of trial treatment 
 Discontinuation of treatment can be decided by both the investigator and the subject. 
 Subjects who discontinue trial product should continue with the scheduled visits and 
assessments to ensure continued counselling and data collection.  
 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 effort should be made to have the subject 
attend at least the ‘end of treatment’ clinic visit (V12) containing the final data collection of 
primary endpoints. 
 The ‘safety visit’ (P13) is scheduled approximately 5 weeks after end of treatment to ensure the 
safety of the subject. If the subject has discontinued trial product >5 weeks prior to the ‘end of 
treatment’ visit, and the requirements for the follow-up period prior to the ‘safety visit’ is 
fulfilled, then the ‘safety visit ’can be omitted. 
 If the subject refuses to attend the ‘end of treatment’ visit and/or ‘end of trial’ visit, information 
about the attempts to follow up with the subject must be documented in the subject’s medical 
record.  
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern as judged by the investigator 
2. Suspicion of acute pancreatitis 
3. Pregnancy 
4. Intention of becoming pregnant 
5. Simultaneous use of an approved or non-approved investigational medicinal product in another 
clinical trial* 
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*Simultaneous participation in a trial with the primary objective of evaluating an approved or non-
approved investigational medicinal product for prevention or treatment of COVID-19 disease or 
postinfectious conditions is allowed at the investigator discretion without discontinuing trial 
product. 
If acute pancreatitis is suspected, appropriate actions should be initiated, including local 
measurements of amylase and lipase (see Appendix 3 (Section 10.3) for reporting). 
Subjects meeting discontinuation of trial product criterion no. 2 are allowed to resume trial product 
if the Atlanta criteria60 are not fulfilled at the investigators discretion 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.  
Subjects meeting discontinuation of trial product criteria no. 1, 3 and 4 are allowed to resume trial 
product, if the criteria are no longer met (Section 7.1.1).  
The primary reason for discontinuation of trial product must be specified in the end-of-treatment-
form in the eCRF, and final drug accountability must be performed. A ‘treatment status session’ 
must be made in the IWRS to discontinue trial product. 
7.1.1 
Temporary discontinuation of trial treatment 
If a subject has discontinued trial product due to temporary safety concern not related to trial 
product and is allowed to resume, the subject should follow the guide for missed doses 
(Section 6.1). Similarly, a subject who discontinues trial product on their own initiative should be 
encouraged to resume trial product (Section 6.1).  
A treatment status session must be made in the IWRS when a subject pauses treatment or resumes 
treatment. 
In case of suspicion of acute pancreatitis, the trial product must promptly be discontinued; however, 
‘treatment status session’ should not be made in IWRS before diagnosis of acute pancreatitis is 
confirmed. If acute pancreatitis is confirmed, treatment with trial product must not be restarted, and 
a ‘treatment status session’ should be made in IWRS. 
7.2 
Subject discontinuation/withdrawal from the trial 
A subject may withdraw consent at any time at his/her own request. 
If a subject withdraws consent, the investigator must ask the subject if he/she is willing, as soon as 
possible, to have assessment performed according to the ‘end of treatment’ visit or the ‘end of trial’ 
visit, depending on the timing of the withdrawal the consent. See the flowchart (Section 1.2) for 
data to be collected. 
Final drug accountability must be performed even if the subject is not able to come to the site. The 
investigator must make a ‘treatment status session’ in IWRS to discontinue trial product. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
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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. 
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 eCRF. 
7.2.1 
Replacement of subjects 
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
7.3 
Lost to follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the site. 
The following actions must be taken if a subject fails to return to the site for a required visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial. 
 Before a subject is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the subject (where possible, at least three telephone calls and, if 
necessary, a certified letter to the subject's last known mailing address or local equivalent 
methods). These contact attempts should be documented in the subject's source document. 
 Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the trial with a primary reason of `lost to follow-up'. 
8 
Trial assessments and procedures 
 The following sections describe the assessments and procedures, while their timing is 
summarised in the flowchart. 
 Informed consent must be obtained before any trial-related activity, see Section 10.1.3. 
 All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all inclusion criteria and none of the exclusion criteria. 
 Screening visits 1 and 2 must not be combined. 
 The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
 At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant site staff that can be contacted in case of emergency.  
 Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct.  
 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 the bias between 
assessments. The suggested order of the assessments:  
1. Vital signs (see Section 8.2.2) and body measurements (see Section 8.1.1) 
2. Blood samples 
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3. Patient-reported outcomes (PROs) (see Section 8.1.2) 
4. Other assessments 
 The Barriers and Motivation Interview identify barriers to and motivation for lifestyle change 
and compliance with the protocol. The interview can 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 can ensure that any minor barriers are addressed 
during lifestyle counselling.  
 
The results of the interview will not be entered into the eCRF. It will be at the investigator’s 
discretion to evaluate the motivation of the subject and related eligibility.  
 Review of laboratory reports must be documented either on the documents or in the subject's 
source documents.  
 Repeat laboratory samples may be taken for technical issues and must be taken in the event of 
HbA1c ≥ 6.5% (≥ 48 mmol/mol) or FPG ≥ 126 mg/dL (7.0 mmol/L) any time during the trial. 
Please refer to Appendix 2 (Section 10.2) for further details on laboratory samples. 
 Results of pregnancy testing must be documented in the subject’s medical records. 
 For subjects receiving antihypertensive or lipid-lowering treatment, the investigator should 
evaluate changes in the subjects’ treatment intensity within each therapeutic area. The 
evaluation should be based on whether an overall change from randomisation to end of 
treatment (V12) and from end of treatment (V12) to end of trial (V15ext) has occurred (i.e., 
either increase, decrease or no change) after reviewing all available relevant information e.g., 
changes in drug dose, drug class, number of drugs or a combination of these. 
 The investigator will evaluate the subject’s glycaemic status during the trial as detailed in the 
flowchart based on all available relevant information e.g. medical records, concomitant 
medication, blood glucose parameters (HbA1c, FPG) and AEs. The subject’s glycaemic status 
will be categorised as normoglycaemia, prediabetes or diagnosed with T2D according to local 
guidelines. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2). 
8.1.1 
Body measurements 
Body weight should be measured at all site visits without shoes, with an empty bladder and only 
wearing light clothing. Body weight should be measured on a digital scale and recorded in 
kilograms or pounds (one decimal) using the same scale throughout the trial. The scale must be 
calibrated according to manufacturer’s recommendation or local requirements – the strictest 
requirement must be followed. 
Height is measured without shoes in centimetres or inches (one decimal). BMI will be calculated in 
the eCRF from screening data.  
Waist circumference is defined as 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 recorded to the nearest cm or inch. The tape should touch the skin but not 
compress soft tissue and twists in the tape should be avoided. The subject should be asked to 
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breathe normally. The same measuring tape should be used throughout the trial. The measuring tape 
will be provided by Novo Nordisk to ensure standardisation. 
8.1.2 
 Clinical outcome assessments 
Subjects should be given the opportunity to complete the questionnaires by themselves without 
interruption. The subject must transcribe directly into a site-pad/web-solution. Each questionnaire 
takes approximately 10 minutes to complete.  
The following PRO questionnaires will be used:  
The WLQ-25 version 2.0 
The WLQ-25 evaluates at-work disability and productivity loss. It contains 25 items arranged under 
four subscales addressing four dimensions of job demands: time demands, physical demands, 
mental/interpersonal demands, and output demands. 
The EQ-5D-3L questionnaire – Digital Self-Complete Tablet 
The EQ-5D-3L questionnaire evaluates general health status. It consists of the EQ-5D-3L 
descriptive system and the EQ VAS. The EQ-5D-3L descriptive system comprises the following 
five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each 
dimension has 3 levels: no problems, some problems, and extreme problems. The EQ VAS records 
the subject’s self-rated health on a vertical VAS where the endpoints are labelled ‘Best imaginable 
health state’ and ‘Worst imaginable health state’.  
8.1.3 
Clinical laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (section 10.2), must be 
conducted in accordance with the flowchart and the laboratory manual. 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart.  
A concomitant illness is any illness that is already present at the time point from which AEs are 
collected or found as a result of a screening procedure or other trial procedures performed before 
exposure to trial product.  
Medical history is a medical event that the subject experienced prior to the time point from which 
AEs are collected. Only relevant and significant medical history as judged by the investigator 
should be recorded. Special attention should be made on recording comorbidities related to obesity 
such as hypertension, dyslipidaemia, obstructive sleep apnoea, knee and hip osteoarthritis, non-
alcoholic fatty liver disease and steatohepatitis, cardiovascular disease, asthma, chronic obstructive 
pulmonary disease, polycystic ovary syndrome, and kidney disease.  
In case of an abnormal and clinically significant finding fulfilling the definition of a concomitant 
illness or medical history, the investigator must record the finding on the Medical History/ 
Concomitant Illness form.  
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As part of the medical history, information on the following will be collected: 
 Weight history (incl. previous weight, debut time of overweight, previous weight loss attempts, 
previous use of prescription medication for obesity, considerations regarding bariatric surgery, 
and family history of overweight/obesity) 
 History of weight disorder 
 History of breast neoplasm 
 History of cardiovascular disorder and procedure 
 History of dyslipidaemia 
 History of gallbladder disease and procedure 
 History of gastrointestinal disorder and neoplasm 
 History of genitourinary tract disorder 
 History of kidney disease 
 History of liver disease 
 History of musculoskeletal system disorder 
 History of pancreatic disease 
 History of psychiatric disorder 
 History of respiratory disorder 
 History of skin cancer and skin disorder 
 Other relevant concomitant illness/medical history (also including COVID-19 and malignant 
neoplasms not covered by the above categories) 
8.2.1 
Physical examinations 
A physical examination will include assessments of: 
 general appearance  
 skin 
 head, ears, eyes, nose, throat and neck  
 thyroid gland  
 cardiovascular and respiratory systems  
 abdomen  
 musculoskeletal system  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital signs 
Pulse rate, as well as systolic and diastolic blood pressure will be assessed. 
The method for measuring pulse rate, systolic and diastolic blood pressure needs to follow the 
standard clinical practice at site. 
However, as a minimum: 
 Blood pressure (diastolic and systolic) and pulse rate measurements should be preceded by at 
least 5 minutes of rest for the subject in a quiet setting without distractions (e.g. television, cell 
phones). 
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 Blood pressure and pulse rate measurements will be assessed in a sitting position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available. 
8.3 
Adverse events and serious adverse events 
Main phase 
The trial will employ selective safety data collection. The investigator is responsible for detecting, 
documenting, recording and following up on all the events listed below:  
 Serious AEs (SAEs)  
 Following AEs irrespective of seriousness: 
 
AEs leading to premature discontinuation of trial product 
 
Selected types of AEs (SAEs and non-SAEs) requiring additional data collection 
(Table 8-1) 
 
Pregnancies and pregnancy related AEs  
 
AEs of COVID-19, irrespective of seriousness*  
*Note: Suspected COVID-19 should be reported if the clinical presentation is suggestive of 
COVID-19, even in the absence of a COVID-19 test or without a positive COVID-19 test 
result. In the absence of clinical symptoms, a positive COVID-19 test (antigen or antibody) 
should be reported, if available 
Note, that also events not allowed in accordance with the protocol e.g. bariatric surgery should, if 
they take place, be reported on an AE form with both the procedure and medical condition 
specified. 
The definition of AEs and SAEs can be found in Appendix 3 (Section 10.3), along with a 
description of AEs requiring additional data collection. 
Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs) 
Event type  
AE requiring additional data collection 
Medication error 
X 
Misuse and abuse 
X 
Acute pancreatitis 
X 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(Section 10.3). 
8.3.1 
Time period and frequency for collecting AE and SAE information 
In the main phase of the trial, all events specified in Section 8.3 (for events related to pregnancy, 
see Appendix 4 (Section 10.4)) must be collected and reported. The events must be collected from 
the first trial-related activity after obtaining informed consent until, and including, P13 at time 
points specified in the flowchart (Section 1.2). In the extension phase (including V14ext and 
V15ext, see flowchart in Section 1.2), only SAEs will be collected. 
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Medical occurrences that take place or have onset prior to the time point from which AEs are 
collected will be recorded as concomitant illness/medical history. AE and SAE reporting timelines 
can be found in Appendix 3 (Section 10.3). All SAEs must be recorded and reported to Novo 
Nordisk or designee within 24 hours, and the investigator must submit any updated SAE data to 
Novo Nordisk 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 trial product or related to trial participation, the investigator must 
promptly notify Novo Nordisk. 
8.3.2 
Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs should be followed until final outcome of the event or the 
subject is lost to follow-up as described in Section 7.3. Further information on follow-up and final 
outcome of events is given in Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk or designee of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of subjects and the safety of a trial 
product under clinical investigation are met.  
Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk 
will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review board (IRB)/independent ethics committee (IEC), and 
investigators. This also includes suspected unexpected serious adverse reactions (SUSARs). 
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (e.g. summary or listing of SAEs) from Novo Nordisk will review and then file it 
along with the investigator's brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.5 
Pregnancy  
Details of pregnancies in female subjects will be collected after first exposure to trial product and 
until the ‘end of trial’ visit. 
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If a female subject becomes pregnant, the investigator should inform Novo Nordisk within 14 
calendar days of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
8.3.6 
Cardiovascular and death events 
Cardiovascular and death events will be handled and reported according to Section 8.3. 
8.3.7 
Technical complaints  
Technical complaints will be collected for all products listed on the technical complaint form. 
Instructions for reporting technical complaints can be found in Appendix 5 (Section 10.5). 
In order for Novo Nordisk to perform a complete investigation of reported SAEs, Novo Nordisk 
might ask the investigator to complete a technical complaint form. 
8.4 
Treatment of overdose 
 Overdoses of up to 4 mg in a single dose, and up to 4 mg in multiple doses in a week have been 
reported in clinical trials. The most commonly reported AE was nausea. All subjects recovered 
without complications.  
 There is no specific antidote for overdose with semaglutide. In the event of an overdose, 
appropriate supportive treatment should be initiated according to subject’s clinical signs and 
symptoms.  
Accidental overdose must be reported as a medication error. Intentional overdose must be reported 
as misuse and abuse, please refer to Section 8.3 and Appendix 3 (Section 10.3) for further details. 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE. A prolonged period of observation and treatment may be necessary, considering the long 
half-life of semaglutide of approximately one week. 
Decisions regarding dose interruptions or modifications will be made by the investigator based on 
the clinical evaluation of the subject. 
For more information on overdose, also consult the current version of the investigator's brochure57 
and any updates hereof. 
8.5 
Pharmacokinetics 
Not applicable for this trial. 
8.6 
Pharmacodynamics 
Not applicable for this trial. 
8.7 
Genetics  
Genetic samples are collected for future research. Refer to Section 8.10 (Human biosamples for 
future research) and to Appendix 6 (Section 10.6) for retention. For Finland, see country-specific 
requirements in Appendix 7 (Section 10.7). 
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8.8 
Biomarkers 
Biosamples are collected for future biomarker research. Refer to Section 8.10 (Human biosamples 
for future research) and to Appendix 6 (Section 10.6) for retention. For Finland, see country-
specific requirements in Appendix 7 (Section 10.7). 
8.9 
Immunogenicity assessments 
Not applicable for this trial. 
8.10 
Human biosamples for future research 
Collection of biosamples for future analysis is a component of this trial. The samples will be stored 
in a biobank and allow for future analyses when new knowledge or improved testing technologies 
may have become available during or after the trial. Participation is optional and participants must 
sign a separate informed consent to indicate their participation in the biobank component of the 
trial. Participants who do not wish to participate in the biobank component may still participate in 
the trial. Blood samples will be collected according to Appendix 6 (Section 10.6) and stored for use. 
For Finland, see country-specific requirements in Appendix 7 (Section 10.7). 
Genetic analyses may include analysis of selected genes or genetic markers throughout the genome 
with the purpose of understanding and predicting response to semaglutide as well as to understand 
obesity, prediabetes or other related conditions.  
Analyses of circulating biomarkers will measure hormones, metabolites or other serum entity with 
the purpose of understanding and predicting response to semaglutide as well as understanding 
obesity, prediabetes or other related conditions.  
The human biosamples for future research will be stored for up to 15 years and after end of trial in a 
central laboratory or appropriate storage facility (see Appendix 6 (Section 10.5.2)). 
8.11 
Health economics  
Health economics data, associated with occupation, current employment status and time missed 
from work due to feeling unwell, will be collected in the eCRF by the investigator and site staff for 
all subjects throughout the trial. The data collected may be used to conduct exploratory economic 
analyses. 
9 
Statistical considerations  
9.1 
Statistical hypotheses 
The tests of superiority of semaglutide 2.4 mg to semaglutide placebo for the primary endpoints are 
performed using the fixed-sequence statistical strategy and will be based only on analyses 
addressing the primary estimand. This strategy tests the endpoints using a predefined hierarchical 
order, all at the significance level of 5%, moving to test the next endpoint only after a statistically 
significant superiority result (p-value < 5%) on the previous endpoint. The test hierarchy is given in 
Table 9-1 with underlying assumptions, marginal power and effective power. The effective power is 
calculated under the assumption of independence of endpoints by multiplying the respective 
marginal powers successively. 
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9.2 
Sample size determination  
The sample size and thereby the power for this trial is primarily defined to ensure both that 
sufficient efficacy data are available from each of the participating countries, and that a sufficient 
number of subjects complete the end of trial visit at week 80. However, no formal statistical testing 
is planned either by country, or based on endpoints collected at week 80. Given the trial sample 
size, the power of statistical tests for the primary endpoints is described below. 
The trial is designed with an effective power of > 99% to detect differences on the primary 
endpoints. The effective power was calculated under the assumption of independence of endpoints 
by multiplying the respective marginal powers successively which is a conservative approach. The 
power calculations for continuous endpoints are based on a t-test on the mean difference assuming 
equal variances, whereas those for the categorical endpoints are based on the Pearson chi-square 
test for two independent proportions. 
Assumptions for these power calculations are presented in Table 9-1 and are based on findings from 
NN9536-4373. 
Due to less frequent in-person visits than in the NN9536 global Phase 3a trials, it is conservatively 
assumed that 30% of subjects will discontinue permanently and 50% of these are retrieved at week 
52. All subjects in the semaglutide placebo arm are assumed to have same effect as subjects who 
complete the trial on semaglutide placebo. Retrieved subjects in the semaglutide s.c. 2.4 mg once-
weekly arm are assumed to have an effect corresponding to half the treatment difference (compared 
to semaglutide placebo) of subjects who complete the trial on semaglutide s.c. 2.4 mg once-weekly. 
Non-retrieved subjects in the semaglutide s.c. 2.4 mg once-weekly arm are assumed to have an 
effect corresponding to semaglutide placebo. Based on data from the NN9536 global Phase 3a 
trials, it is expected that <1% of subjects will initiate other glucose-lowering medication or anti-
obesity therapies, so the impact of this intercurrent event is expected to be negligible. 
Under these assumptions and a 2:1 randomisation ratio, a sample size of 201 subjects randomised to 
either receive semaglutide s.c. 2.4 mg once-weekly (134 subjects) or semaglutide placebo 
(67 subjects) yields an effective power of >99% for both primary endpoints. 
Table 9-1 
Assumptions, marginal power and effective power for each endpoint in the 
hierarchical testing procedure given an anticipated number of 201 randomised 
subjects 
Order 
Endpoint 
Assumed mean (±SD) or 
proportion for completers 
Expected 
mean (±SD) 
or 
proportion 
Expected 
difference or 
proportion ratio 
Marginal 
power 
(%) 
Effective 
power 
(%) 
Semaglutide s.c. 
2.4 mg once-
weekly 
Semaglutide 
placebo 
Semaglutide 
s.c. 2.4 mg 
once-
weekly 
1 
% body weight 
change 
15.8 (±10) 
3.0 (±10) 
12.9 (±11) 
9.9%-points 
>99 
>99 
2 
Reversal to 
normoglycaemia 91.2% 
39.9% 
79.7% 
2.0 
>99 
>99 
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Table 9-2 shows how sensitive the power is to deviations from the design assumptions in terms of 
responder proportions. 
Table 9-2 
Power by proportions reversing to normoglycaemia with a sample size of 201 
subjects 
Proportion reversing to normoglycaemia 
Semaglutide s.c. 2.4 mg 
Semaglutide placebo 
Power 
79.7% 
39.9% 
>99% 
79.7% 
50.0% 
99.0% 
75.0% 
39.9% 
>99% 
75.0% 
50.0% 
94.1% 
70.0% 
39.9% 
98.6% 
70.0% 
45.0% 
93.1% 
70.0% 
50.0% 
79.0% 
 
The effective power versus total number of subjects randomised is shown in Figure 9-1, indicating 
that the power remains above 90% even for large reductions of the sample size. 
 
Figure 9-1 
Effective power including all confirmatory tests versus total number of subjects 
randomised 
 
All above outlined sample size and power considerations are for the primary estimand (treatment 
policy strategy). It is assumed that up to 30% of subjects discontinue permanently and 50% of these 
are retrieved at week 52, which amounts to 15% expected missing data at week 52. This is higher 
than observed on NN9536-4373, in which 10.8% missing in-trial FPG data were observed after 
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68 weeks for the primary estimand. Any superiority conclusions will be based on the primary 
estimand. 
For the additional estimand (hypothetical strategy) however, data from retrieved subjects are not 
used. Hence, it is expected that up to 30% of data will be missing at week 52. Based on NN9536-
4373, 21.6% missing on-treatment data were observed after 68 weeks for the additional estimand. 
This included missing data not only due to treatment discontinuation, but also due to initiation of 
other anti-obesity therapies (<1%). For trial NN9536-4734 slightly higher missing on-treatment 
data is expected due to subjects initiating glucose-lowering medication (<1%). In NN9536-4373 it 
was seen that the treatment difference in mean changes for body weight was slightly higher and 
standard deviation was slightly lower for the additional estimand (using on-treatment data) than for 
the primary estimand (using in-trial data).  
Finally, based on the extension phase of NN9536-4373 it is expected that 76% of subjects attending 
the end of treatment visit at week 52 will also attend the end of trial visit at week 80. Therefore, a 
sample size of 201 randomised subjects is expected to give 130 subjects attending the end of trial 
visit at week 80. 
9.3 
Populations for analyses 
The following populations and observation periods are defined: 
Population 
Description 
Full analysis set  
Full analysis set (FAS): All subjects randomised. Exclusion of data from analyses should be 
used restrictively, and normally no data should be excluded from the FAS. Subjects will be 
analysed according to the randomised treatment 
Safety analysis set 
All subjects randomly assigned to trial treatment and who take at least 1 dose of trial 
product. Subjects are analysed according to the treatment they actually received. 
 
Observation period 
Description 
In-trial 
The time period where the subject is assessed in the trial. The in-trial observation period for 
a subject begins on the date of randomisation and ends at the first of the following dates 
(both inclusive): 
 
‘End of trial’ visit 
 
withdrawal of consent 
 
last contact with subject (for subjects lost to follow-up) 
 
death 
In-trial (main phase) 
The time period where the subject is assessed in the main phase of the trial. The in-trial 
(main phase) observation period for a subject begins on the date of randomisation and ends 
at the first of the following dates (both inclusive): 
 
safety visit 
 
withdrawal of consent 
 
last contact with subject (for subjects lost to follow-up) 
 
death 
On-treatment 
The time period where subjects are treated with trial product. A time-point is considered as 
“on-treatment” if any dose of trial product has been administered within the prior 2 weeks 
(14 days). The on-treatment period is defined as all times which are considered on-
treatment. In general, the on-treatment period will therefore be from the date of first trial 
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product administration to date of last trial product administration excluding potential off-
treatment time intervals triggered by at least two consecutive missed doses. 
For the evaluation of AEs and potential pregnancies, the lag time for each on-treatment time 
interval is 5 weeks (35 days). 
Any observation excluded from the analysis database will be documented before database lock with 
the reason for exclusion provided. Efficacy endpoints will be analysed using the FAS; safety 
endpoints will be analysed using the safety analysis set (SAS). 
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. The in-trial (main 
phase) period defines the patient years of observation (PYO) during the main phase of the trial as 
the total time duration in the period. 
9.4 
Statistical analyses 
9.4.1 
General considerations 
The statistical analysis plan (SAP) will be finalised prior to breaking the blind to treatment 
assignment, and it will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and confirmatory secondary endpoints. 
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. 
9.4.2 
Primary endpoints 
The primary endpoints are change in body weight (%) and reversal to normoglycaemia, both from 
baseline (week 0) to end of treatment (week 52) as listed in Section 3.2.1. 
All tests are tests of superiority of semaglutide s.c. 2.4 mg once-weekly to semaglutide placebo. 
Analyses addressing the primary estimand 
The following statistical analyses and imputation method are designed to address the primary 
estimand. 
The analysis model for change in body weight (%) will be a linear regression (ANCOVA), 
assuming unequal variances with randomised treatment as factor and baseline body weight (kg) as 
covariate. The estimated treatment difference between semaglutide s.c. 2.4 mg once-weekly and 
semaglutide placebo will be reported together with the associated two-sided 95% confidence 
interval (CI) and corresponding p-value. 
The statistical model for the reversal to normoglycaemia endpoint is a logistic regression using 
randomised treatment as factor and baseline HbA1c (%) and FPG (mmol/L) as covariates. The 
estimated odds ratio (OR) between semaglutide s.c. 2.4 mg once-weekly and semaglutide placebo 
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will be reported together with the associated two-sided 95% confidence interval and corresponding 
p-value.  
All available data at week 52 are used and missing values at week 52 will be imputed and the 
endpoint will be derived from the imputed values. The imputation approach for the primary analysis 
is a multiple imputation similar to the one described by McEvoy et al.61 For subjects in the 
semaglutide s.c. 2.4 mg once-weekly and the semaglutide placebo groups, missing measurements at 
week 52 for non-retrieved subjects are imputed using assessments from retrieved subjects in each 
treatment group. The timing of last available observation during the on-treatment period (LAO-OT) 
will be included in the imputation model as a continuous covariate. Missing measurements at week 
52 for subjects on randomised treatment (at week 52) are imputed by sampling from available 
measurements at week 52 from subjects on randomised treatment in the relevant randomised 
treatment arms. Details of the multiple imputation approach are provided in the SAP.  
Analysis addressing the additional estimand 
The additional estimand for change in body weight (%) will be assessed using a mixed model for 
repeated measurements (MMRM) approach. Week 52 assessments for retrieved subjects are not 
used in this analysis. The MMRM will use assessments only from subjects who are taking the 
randomised treatment until end of treatment or until first discontinuation of randomised treatment or 
initiation of glucose-lowering medication or other anti-obesity therapies (weight management drugs 
or bariatric surgery). The MMRM will be fitted using change and the same factors and covariate as 
for the primary analysis all nested within visit. An unstructured covariance matrix for measurements 
within the same subject will be employed, assuming that measurements for different subjects are 
independent.  
The additional estimand for the reversal to normoglycaemia endpoint will be analysed according to 
the following procedure: 
1) HbA1c (%) will be analysed in an MMRM using assessments only from subjects who are 
taking the randomised treatment until end of treatment or until first discontinuation of 
randomised treatment or initiation of glucose-lowering medication or other anti-obesity 
therapies (weight management drugs or bariatric surgery). The MMRM will be fitted using 
randomised treatment as factor and baseline HbA1c (%) as covariate nested within visit. An 
unstructured covariance matrix for measurements within the same subject will be employed, 
assuming that measurements for different subjects are independent. 
2) FPG (mmol/L) will be analysed in the same MMRM as for HbA1c (%), but with FPG 
(mmol/L) as outcome and baseline FPG (mmol/L) as covariate.  
3) For subjects with missing HbA1c (%) and/or FPG (mmol/L) at week 52, individual values 
will be predicted from the MMRM analyses and used to classify each subject as 
normoglycaemic or not. This classification will then be analysed using a logistic regression 
model with randomised treatment as factor and baseline HbA1c (%) and FPG (mmol/L) as 
covariates. 
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9.4.3 
Secondary endpoints 
9.4.3.1 
Confirmatory secondary endpoint 
Not applicable for this trial. 
9.4.3.2 
Supportive secondary endpoints 
For details on analyses of additional supportive secondary endpoints, please refer to the SAP.  
9.4.4 
Exploratory endpoints 
For details on analyses of exploratory endpoints, please refer to the SAP. 
9.4.5 
Other safety analyses 
All safety analyses will be made on the safety analysis set. For further description of other safety 
analyses, please refer to the SAP. 
9.5 
Interim analyses  
Not applicable for this trial. 
9.6 
Data monitoring committee  
Not applicable for this trial. 
9.7 
Reporting of the main part of the trial 
A database lock is planned after completion of the ‘end of trial visit’ (week 80) of the extension 
phase. One (1) clinical trial report (CTR) will be prepared including the main and  the extension 
phase of the trial.  
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10 Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and trial oversight considerations 
10.1.1 
Regulatory and ethical considerations 
 This trial will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki62 and applicable ICH Good Clinical Practice (GCP) Guideline63 
 Applicable laws and regulations 
 The protocol, informed consent form, investigator’s brochure (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 site is allowed to start screening subjects, written notification from Novo Nordisk must 
be received. 
 The investigator will be responsible for: 
 
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB/IEC 
and/or regulatory authorities 
 
notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
 
providing oversight of the conduct of the trial at the site and adherence to requirements of 
ICH guidelines, the IRB/IEC, and all other applicable local regulations 
 
ensuring submission of the CTR synopsis to the IRB/IEC 
 
reporting any potential serious breaches to the sponsor immediately after discovery 
10.1.2 
Financial disclosure 
Investigators and sub-investigators will provide Novo Nordisk with sufficient, accurate financial 
information as requested to allow Novo Nordisk to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and one 
year after completion of the trial. 
10.1.3 
Informed consent process 
 The investigator or his/her representative will explain the nature of the trial to the subject and 
answer all questions regarding the trial. 
 The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial.  
 Subjects must be informed that their participation is voluntary. 
 Subjects must be informed about their privacy rights.  
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 Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines63, Declaration of Helsinki62 and the IRB/IEC 
or site. 
 The medical record must include a statement that written informed consent was obtained before 
any trial-related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial-related activity. 
 The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task to a medically qualified person, in accordance with local 
requirements. 
 Subjects must be re-consented to the most current version of the informed consent forms during 
their participation in the trial. 
 A copy of the informed consent forms must be provided to the subject. 
10.1.4 
Information to subjects during trial 
The site will be offered a communication package for the subject during the conduct of the trial. 
The package content is issued by Novo Nordisk. The communication package will contain written 
information intended for distribution to the subjects. The written information will be translated and 
adjusted to local requirements and distributed to the subject at the discretion of the investigator. The 
subject may receive a “welcome to the trial letter” and a “thank you for your participation letter” 
after completion of the trial. Further, the subject may receive other written information during the 
trial.  
All written information to subjects must be sent to IRB/IEC for approval/favourable opinion and to 
regulatory authorities for approval or notification according to local regulations. 
10.1.5 
 Data protection 
 Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only. No direct 
identifiers from the subject are transferred to Novo Nordisk. 
 The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements.  
 The subject must be informed about his/her privacy rights, including that his/her personal trial-
related data will be used by Novo Nordisk in accordance with local data protection law. The 
disclosure of the data must also be explained to the subject.  
 The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. 
United Kingdom: see local requirements in Appendix 7 (Section 10.7). 
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10.1.6 
Committees structure 
10.1.6.1 
Novo Nordisk safety committee 
Novo Nordisk will perform ongoing safety surveillance. If new safety signals are identified, these 
will be evaluated by an internal safety committee. The safety committee may recommend 
unblinding of any data for further analysis, and in this case an internal trial independent ad hoc 
group will be established in order to maintain the blinding of the trial personnel. 
10.1.7 
Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov 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)64, the Food and Drug Administration Amendment 
Act (FDAAA)65, European Commission Requirements1, 66, 67 and other relevant recommendations or 
regulations. If a subject request 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 (LSFT) + 52 weeks corresponding to ‘end of treatment’ visit 
(visit 12). If the last subject is withdrawn early, the PCD is considered the date when the last subject 
would have completed ‘end of treatment’ visit. The PCD determines the deadline for results 
disclosure at clinicaltrials.gov according to FDAAA. 
10.1.8 
Data quality assurance 
10.1.8.1 
Case report forms 
 Novo Nordisk or designee is responsible for the data management of this trial including quality 
checking of the data. 
 All subject data relating to the trial will be recorded on eCRFs unless transmitted electronically 
to Novo Nordisk or designee (e.g. laboratory data and electronic PROs). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.  
 The following will be provided as paper CRFs: 
 
Pregnancy forms 
 The following will be provided as paper CRFs to be used when access to the eCRF is revoked or 
the eCRF is temporarily unavailable:  
 
AE forms  
 
Safety information forms  
 
Technical complaint forms (also to be used to report complaints on trial product not yet 
allocated to a subject) 
 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 
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date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
 The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.  
10.1.8.2 
Monitoring 
 The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor with 
signed and dated printouts. In addition, the relevant site staff should be available for discussions 
at monitoring visits and between monitoring visits (e.g. by telephone).  
 Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
 Monitoring will be conducted using a risk-based approach including risk assessment, 
monitoring plans, centralised monitoring (remote assessment of data by Novo Nordisk) and 
visits to sites.  
 Monitors will review the subject’s medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF.  
10.1.8.3 
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database.  
10.1.9 
Source documents 
 All data entered in the eCRF must be verifiable in source documentation other than the CRF. 
 For the WLQ-25 and EQ-5D-3L, data will be recorded directly into a tablet and will be 
considered source data. 
 Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
 Data reported on the paper CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available.  
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 It must be possible to verify subject’s medical history in source documents, such as subject’s 
medical record. 
 The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested, and who was contacted. 
 Definition of what constitutes source data can be found in a source document agreement at each 
site. There will only be one source document defined at any time for any data element. 
10.1.10 
Retention of clinical trial documentation 
 Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk.  
 The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, eCRF 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 site. 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. 
Canada and Spain: see local requirements in Appendix 7 (Section 10.7). 
10.1.11 
Trial and site closure 
Novo Nordisk reserves the right to close the site or terminate the trial at any time for any reason at 
the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the investigator must 
inform the subjects promptly and ensure appropriate therapy and follow-up. The investigator and/or 
Novo Nordisk must also promptly inform the regulatory authorities and IRBs/IECs and provide a 
detailed written explanation. 
Sites will be closed upon trial completion. A site is considered closed when all required documents 
and trial supplies have been collected and a site closure visit has been performed. 
The investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a site by Novo Nordisk or investigator may include but are not 
limited to: 
 failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
 inadequate recruitment of subjects by the investigator 
 discontinuation of further trial product development. 
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10.1.12 
Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the site. If any tasks are delegated, the investigator must 
maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects.  
A qualified physician, who is an investigator or a sub investigator for the trial, must be responsible 
for all trial-related medical decisions.  
The investigator 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 of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires), 
a new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
10.1.13 
Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence.  
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible. Novo Nordisk accepts liability in accordance with Appendix 7 (Section 10.7). 
10.1.14 
Publication policy 
The information obtained during the conduct of this trial is considered confidential and may be used 
by or on behalf of Novo Nordisk for regulatory purposes as well as for the general development of 
the trial product. All information supplied by Novo Nordisk in connection with this trial shall 
remain the sole property of Novo Nordisk and is to be considered confidential information. 
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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 CTRs for this trial. 
One investigator will be appointed by Novo Nordisk to review and sign the CTRs (signatory 
investigator) on behalf of all participating investigators.  
10.1.14.1 
Communication of results 
Novo Nordisk commits to communicate and disclose results of trials regardless of outcome. 
Disclosure includes publication of a manuscript in a peer-reviewed scientific journal, abstract 
submission with a poster or oral presentation at a scientific meeting or disclosure by other means.  
The results of this trial will be subject to public disclosure on external web sites according to 
international and national regulations. Novo Nordisk reserves the right to defer the release of data 
until specified milestones are reached, for example when the CTR is available. This includes the 
right not to release the results of interim analyses, because the release of such information may 
influence the results of the entire trial. 
At the end of the trial, one or more scientific publications may be prepared collaboratively by the 
investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or 
communication for up to 60 days to protect intellectual property. 
In all cases, the trial results will be reported in an objective, accurate, balanced and complete 
manner, with a discussion of the strengths and limitations. In the event of any disagreement on the 
content of any publication, both the investigators’ and Novo Nordisk opinions will be fairly and 
sufficiently represented in the publication. 
10.1.14.2 
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 Editors.68 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
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Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
10.1.14.3 
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
10.1.14.4 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. 
Individual investigators will have their own research subjects' data and will be provided with the 
randomisation code after results are available. 
 
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10.2 
Appendix 2: Clinical laboratory tests 
 The tests detailed in Table 10-1 will be performed by the central laboratory with the exception 
of urine human chorionic gonadotropin (hCG) pregnancy test. 
 Additional tests may be performed at any time during the trial as determined necessary by the 
investigator or required by local regulations. Only laboratory samples specified in the protocol 
should be sent to the central laboratory for analysis; if additional laboratory sampling is needed, 
e.g. to follow up on AEs, this must be done at a local laboratory. 
 The central laboratory will communicate to the investigator abnormal values of parameters not 
requested in the protocol but identified by the laboratory equipment and/or their processes 
according to their lab SOPs. These data will not be transferred to the trial database. The 
investigator should review such values for AEs and report these according to this protocol. 
 The investigator must review all laboratory results for concomitant illnesses and AEs. 
 Laboratory samples will be destroyed no later than at finalisation of the CTR except for the 
biosamples for future research. 
Table 10-1 
Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Glucose metabolism  
Visit 1, 3, 5, 8, 9, 12, 14, 15 
Visit 2, 3, 5, 8, 9, 12, 14, 15 
 
 HbA1c 
 Fasting plasma glucose (FPG) 
Lipids 
Visit 3, 9, 12, 15 
 Triglycerides 
 Total cholesterol 
 High density lipoprotein (HDL) cholesterol 
 Low density lipoprotein (LDL) cholesterol 
 Very low density lipoprotein (VLDL) cholesterol 
Pregnancy Testing 
Visit 1, 3, 5, 7, 8, 9, 10, 11, 12, P13 
 Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)1 
Biosamples for future research2 
Visit: 3 
Visit: 3, 5, 8, 12, 15 
Visit: 3, 5, 8, 9, 12, 14, 15 
 
 Whole blood (DNA)  
 Plasma 
 Serum, Plasma, whole blood (RNA) 
Notes: 
1Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
2Subjects must sign and date a separate informed consent form before samples are collected 
Table 10-2 
Outliers 
In the event of HbA1c ≥ 6.5% (≥48 mmol/mol) or FPG ≥ 126 mg/dL (7.0 mmol/L) any time during the trial a 
repeated measurement must be taken within four weeks at central laboratory in order to diagnose diabetes.  
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Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
 
Contact details for SAE reporting can be found in the investigator trial master file. 
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10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information 
Definitions 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
If fertility is unclear (e.g. amenorrhea in adolescents or athletes), and a menstrual cycle cannot be 
confirmed before first dose of trial treatment, additional evaluation should be considered. 
Females in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Females with one or more of the following: 
 
Documented total hysterectomy 
 
Documented bilateral salpingectomy 
 
Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above (e.g. 
Müllerian agenesis, androgen insensitivity), investigator discretion should be applied in determining 
trial enrolment. 
3. Postmenopausal female: 
 A postmenopausal state is defined as amenorrhoea for 12 months without an alternative medical 
cause.  
 Females ≥ 50 years of age can be considered postmenopausal (irrespective of treatment with a 
hormonal contraception or hormone replacement therapy (HRT)) if they have both: 
 
Amenorrhoea and 
 
Documentation of 2 high follicle stimulating hormone (FSH) measurements in the 
postmenopausal range and one of these was observed ≥1 year prior to screening. 
 Females ≥ 60 years of age can be considered postmenopausal. 
Females on HRT and whose menopausal status is in doubt are considered of childbearing potential 
and will be required to use one of the highly effective contraception methods.  
Note: Documentation regarding categories 1-3 can come from the site staff’s review of subject’s 
medical records, medical examination or medical history interview. 
Contraception guidance 
Male subjects  
No contraception measures are required for male subjects as the risk of teratogenicity/fetotoxicity 
caused by transfer of semaglutide in seminal fluid is unlikely. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they agree to use methods of 
contraception consistently and correctly as described in table below: 
Table 10-3 
Highly effective contraceptive methods 
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Collection of pregnancy information Female subjects who become pregnant  
 Investigator will collect pregnancy information on any female subject who becomes pregnant 
while participating in this trial. 
 Information will be recorded on the appropriate form and submitted to Novo Nordisk within 14 
calendar days of learning of a subject's pregnancy (see Figure 10-2). 
 Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate which will be forwarded to Novo Nordisk 
within 14 calendar days. Generally, follow-up will not be required for longer than 1 month 
beyond the delivery date. 
 Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure. 
 While pregnancy itself is not considered to be an AE or SAE, any adverse event in connection 
with pregnancy or elective termination of a pregnancy for medical reasons will be reported as an 
AE or SAE. If relevant, consider adding ‘gestational’, ‘pregnancy related’ or a similar term 
when reporting the AE/SAE. 
 Pregnancy outcome should be documented in the subject's medical record. Abnormal pregnancy 
outcome (e.g. spontaneous abortion, foetal death, stillbirth, congenital anomalies and ectopic 
pregnancy) is considered an SAE. 
 Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the IMP by the investigator will be reported to Novo Nordisk as described in 
Section 10.3. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting.  
 
Figure 10-2 Decision tree for determining the forms to complete with associated timelines 
for pregnancy. 
 
Any female subject who becomes pregnant while participating in the trial will discontinue IMP. 
 
Maternal form 1b 
  14 calendar days after birth
Maternal form 1a
  14 calendar days
After birth/
termination 
of pregnancy
No additional 
action
Normal outcome 
Maternal form 2   14 calendar days
Paternal form*1   14 calendar days
Abnormal outcome 
Pregnancy 
verified
*1 Further information collected on Paternal form for male partners of 
female subjects requires signing of specific informed consent.
AE/SAEs in connection with the pregnancy and in the foetus/newborn 
should follow the timelines in Figure 10.1.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
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10.6 
Appendix 6: Retention of human biosamples for future research  
In countries where applicable, the study will involve collection of human biosamples for future 
research to be stored in a central laboratory facility. 
Human biosamples (also in some cases known as human biospecimen or human biological 
materials) are samples that have been taken from the human body during life. It includes:  
 Primary cells containing fluids of human origin (whole blood)  
 Cell free fluids of primary human origin (serum and plasma)  
 Extracts or derivatives of the above, when derived by purification (DNA, RNA, proteins, 
membranes, microsomes and other cellular substructures).  
Table 10-4 
Samples to be collected 
Sample 
Visit 
Tubes/aliquots per visit 
Whole blood (DNA)  
3  
1 tube  
Whole blood (RNA) 
3, 5, 8, 9, 12, 14, 15 
1 tube 
Serum 
3, 5, 8, 9, 12, 14, 15 
5 aliquots 
Plasma,  
3, 5, 8, 9, 12, 14, 15 
5 aliquots 
Plasma  
3, 5, 8, 12, 15 
1 tube 
 
The biosamples will be stored at a central laboratory, at a central storage facility or an analysing 
laboratory contracted by Novo Nordisk for up to 15 years after end of trial. Only relevant Novo 
Nordisk employees, consultants, auditors, research organisations or laboratories working for or 
collaborating with Novo Nordisk as well as storage facility employees will be able to access the 
stored biosamples and associated data. The biosamples may be transferred to other countries for 
analysis and will be destroyed at the latest 15 years after end of trial. 
The analyses of the biosamples for future research are not intended to identify participant-specific 
findings, but to understand and predict response to semaglutide as well as understanding obesity, 
prediabetes and related conditions on a population level. Analysis will be done on the biosamples 
and associated data (data relating to the test results or results from the main study). 
Novo Nordisk will ensure that third party collaborators live up the regulations on data protection, 
see Appendix 1 (Section 10.1). 
The participant may request the stored biosamples for future research to be destroyed by 
withdrawing the designated informed consent at any timepoint during and after the trial. For 
samples that have already been analysed, the results can still be used for scientific research and will 
not be removed from the datafile. 
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10.7 
Appendix 7: Country-specific requirements  
For Denmark: 
Section 5.2 Exclusion criterion no. 11 
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
 combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable) 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomised partner 
 sexual abstinence 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) is not considered a highly effective birth control. 
For Canada: 
Appendix 1 Section 10.1.10 Retention of clinical trial documentation 
Part C, Division 5 of the Food and Drug Regulations [C.05.012] requires a 25 years retention period 
For Spain: 
Appendix 1 Section 10.1.10 Retention of clinical trial documentation 
25 years according to the new Spanish Royal Decree 1090/2015 
Section 5.2 Exclusion criterion no. 11 
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
 combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable) 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomised partner 
 sexual abstinence 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) is not considered a highly effective birth control. 
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For Finland 
Section 5.2 Exclusion criterion no. 11 
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
 combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable) 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomised partner 
 sexual abstinence 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) is not considered a highly effective birth control. 
Collection of human biosamples for future research (Section 8.10) will not be performed for 
subjects from Finland. 
For United Kingdom 
Section 5.2 Exclusion criterion no. 11 
Contraceptive measures considered adequate include highly effective contraceptive methods in 
accordance with the CTFG (Clinical Trial Facilitation Group). Such methods include: 
 combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal) 
 progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable or implantable) 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomised partner 
 sexual abstinence 
A combination of male condom with either cap, diaphragm or sponge with spermicide (double 
barrier methods) is not considered a highly effective birth control. 
Section 5.2 Exclusion criterion no. 12 and Section 7.1 Discontinuation of trial treatment 
Simultaneous participation in a trial with the primary objective of evaluating an approved or non-
approved investigational medicinal product for prevention or treatment of COVID-19 disease or 
postinfectious conditions is not allowed.  
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Appendix 1 Section 10.1.5 Data protection 
Protocol text: “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.” In the UK the IRB/IEC do not have access 
to the patients’ medical records. 
 
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10.8 
Appendix 8: Abbreviations  
ADA 
American Diabetes Association 
AE 
adverse event  
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance  
AST 
aspartate aminotransferase   
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CTFG 
Clinical Trial Facilitation Group 
CTR 
clinical trial report 
DFU 
directions for use 
DUN 
dispensing unit number 
EASD 
The European Association for the Study of Diabetes 
eCRF 
electronic case report form 
EQ-5D-3L  
EuroQol five dimensions three level 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
U.S. Food and Drug Administration Amendments Act 
FPG 
fasting plasma glucose 
FSH  
follicle-stimulating hormone 
GCP  
Good Clinical Practice 
GLP-1  
glucagon-like peptide-1 
HbA1c 
glycated haemoglobin 
hCG 
human chorionic gonadotropin  
HDL 
high density lipoproteins 
HRT  
hormone replacement therapy 
IB  
investigator’s brochure 
ICH  
International Council for Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IEC  
independent ethics committee 
IMP  
investigational medicinal product 
IRB  
institutional review board 
IUD 
intrauterine device  
IUS 
intrauterine hormone-releasing system  
IWRS  
interactive web response system 
LAO-OT  
last available observation during the on-treatment period  
LDL  
low density lipoprotein 
LSFT 
last subject first treatment 
MEN2  
multiple endocrine neoplasia type 2 
MMRM 
mixed model for repeated measurements  
MTC 
medullary thyroid cancer  
NYHA 
New York Heart Association  
OR 
odds ratio  
PCD 
primary completion date 
PRO 
patient-reported outcome 
PYE 
patient years of exposure  
PYO 
patient years of observation  
RA 
receptor agonist 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
s.c. 
subcutaneous 
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SD 
standard deviation 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
T2D 
type 2 diabetes 
TMM 
trial materials manual  
UNL 
upper normal limit 
VAS 
visual analogue scale 
VLDL 
Very low-density lipoprotein 
WLQ-25 
Work Limitations Questionnaire 25-item version 
WOCBP 
woman of childbearing potential 
 
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10.9 
Appendix 9: Protocol amendment history 
Protocol version 2.0 (13 July 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the council of the European Union.1 
Overall rationale for preparing protocol version 2.0 
This version of the protocol was prepared to include a clarification in Section 8.3 of reporting of 
serious adverse events in the extension phase of the trial. Furthermore, a clarification of the time-
period for evaluation of subjects’ treatment intensity regarding lipid-lowering and antihypertensive 
medication has been included (Section 8). A specification of the primary analysis of change in body 
weight has been included. An overview of all updates is presented in the table below: 
Section # and name 
Description of change 
Brief rationale 
1.2 Flowchart 
Section 8.3 (Adverse events and 
serious adverse events) 
Reporting of SAEs in the extension 
phase 
To comply with EU guideline2 
Section 8 (Trial assessments and 
procedures) 
Update of time frame for evaluation of 
treatment intensity of antihypertensive 
and lipid-lowering medication 
For clarification. 
Section 9 (statistical considerations) 
Inclusion of assumption on unequal 
variances in the primary analysis of 
change in body weight 
Based on recommendation from 
FDA 
Section 10.7 (Country-specific 
requirements) 
Specification that human biosamples for 
future research will not be collected 
from subjects from Finland 
Country-specific requirement 
from Finland 
Protocol version 3.0 (08 February 2022) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the council of the European Union.1 
Overall rationale for preparing protocol version 3.0 
This version of the protocol was prepared to delete a requirement for recording date of T2D onset in 
the CRF as presented in the table below: 
Section # and name 
Description of change 
Brief rationale 
Section 10.2 (Clinical laboratory 
tests) 
Deletion of the requirement to record 
the date of T2D onset in the CRF  
This information is not needed 
for the purpose of the 
exploratory endpoints on 
progression to T2D 
 
 
 
 
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11 References 
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
European Commission. Detailed guidance on the collection, verification and presentation of 
adverse event/reaction reports arising from clinical trials on medicinal products for human 
use (‘CT-3’)(2011/C 172/01). 11 Jun 2011. 
3. 
NCD Risk Factor Collaboration. Trends in adult body-mass index in 200 countries from 
1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 
million participants. Lancet. 2016;387(10026):1377-96. 
4. 
Finkelstein EA, DiBonaventura M, Burgess SM, Hale BC. The costs of obesity in the 
workplace. J Occup Environ Med. 2010;52(10):971-6. 
5. 
Kelly T, Yang W, Chen CS, Reynolds K, He J. Global burden of obesity in 2005 and 
projections to 2030. Int J Obes (Lond). 2008;32(9):1431-7. 
6. 
Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in 
the United States, 2011-2012. JAMA. 2014;311(8):806-14. 
7. 
Stevens GA, Singh GM, Lu Y, Danaei G, Lin JK, Finucane MM, et al. National, regional, 
and global trends in adult overweight and obesity prevalences. Popul Health Metr. 
2012;10(1):22. 
8. 
Van Nuys K, Globe D, Ng-Mak D, Cheung H, Sullivan J, Goldman D. The association 
between employee obesity and employer costs: evidence from a panel of U.S. employers. 
Am J Health Promot. 2014;28(5):277-85. 
9. 
Wang YC, Pamplin J, Long MW, Ward ZJ, Gortmaker SL, Andreyeva T. Severe Obesity In 
Adults Cost State Medicaid Programs Nearly $8 Billion In 2013. Health Aff (Millwood). 
2015;34(11):1923-31. 
10. 
Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with 
overweight and obesity using standard body mass index categories: a systematic review and 
meta-analysis. JAMA. 2013;309(1):71-82. 
11. 
le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L, et al. 3 years of 
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9.1.1
Protocol Attachment
Protocol Attachment I is located in the Trial Master File.
If applicable, Protocol Attachment II is also located in the Trial Master File.
Content: Global key staff and Country key staff.
Date:
Novo Nordisk
Version:
Status:
Semaglutide 2.4 mg once-weekly
Study ID: NN9536-4734 (pre-diabetes)
Clinical Study Report
Appendix 9.1.1
02 November 2023
1.0
Final
CONFIDENTIAL