Renal Mode of Action of Semaglutide in Patients With Type 2 Diabetes and Chronic Kidney Disease
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2, Chronic Kidney Disease
Sponsor: Novo Nordisk A/S

Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT04865770 
Sponsor trial 
ID: 
NN9535-4662 
Official title of 
study: 
REMODEL - Renal mode of action of semaglutide in patients with type 2 
diabetes and chronic kidney disease 
Document 
date: 
21 April 2022 

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
Status: 
Final 
Page: 
1 of 89 
Protocol
Protocol title: REMODEL - Renal mode of action of semaglutide in patients with type 2 
diabetes and chronic kidney disease  
Substance name: once-weekly semaglutide s.c. 
Universal Trial Number: U1111-1248-7912 
EudraCT Number: 2020-000828-19 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
1
 .
-
 |
1
 |
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
. 
Trial phase: 3b/4 

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
Status: 
Final 
Page: 
2 of 89 
Protocol amendment summary of changes table 
DOCUMENT HISTORY 
Document version 
Date 
Applicable in country(-ies) and/or 
site(s)  
Protocol version 3.0 
21 April 2022 
All 
Protocol version 2.0 
29 January 2021 
All 
Original protocol version 1.0 
07 September 2020 
All 
Protocol version 3.0 (21 April 2022) 
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, 
because it is considered to have impact on the conduct of the trial. 
Overall rationale for preparing protocol, version 3.0: 
The overall rationale for the changes implemented in the amended protocol is to update inclusion 
criteria 6, 7 and 8, as it is expected to beneficially impact on recruitment without compromising the 
study integrity or subject safety. Changes to the content of the protocol are presented in the table 
below. 
In addition, minor editorial changes were made in Sections 1.2, 4.2, 5.1, 5.4, 8.1.1, 8.1.2, 8.1.4, and 
in Appendix 2, 8 and 9 to increase consistency and clarity. 
Based on evaluation by Novo Nordisk and input from an external Expert Panel, the changes 
introduced will have no impact on efficacy endpoints or subject safety. 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Changes to key inclusion criteria 
To align wording with inclusion criteria 
in section 5.1  
Section 1.2 Flowchart 
Visit window for the end of trial visit 
(V12) has been changed from ±7 days to 
+7 days.
To correct a typo. Based on semaglutide 
half-life the end of trial visit cannot be 
earlier than 5 weeks after end of 
treatment.  
On site random spot urine collection 
added as a separate row in the flowchart. 
For clarification purposes only, to clearly 
differentiate the urine collections (first 
morning void spot urine, on site random 
spot urine, and 24-hour urine). 
Section 4.2 Scientific 
rationale for trial design 
Wording slightly updated to align with 
changes in inclusion criteria in section 
5.1. 
To align wording with inclusion criteria 
in section 5.1  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
2
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
3 of 89 
 
Section # and name 
Description of change 
Brief rationale 
Section 5.1 Inclusion criteria  Inclusion criterion 6: 
• For subjects in the non-biopsy 
population: The lower limit for eGFR 
has been changed to ≥ 30 mL/min/ 
1.73 m2. 
• For subjects in the biopsy sub-
population the value is kept at ≥40 
mL/min/ 1.73 m2.   
• For subjects in the non-biopsy 
population, lowering the eGFR to 30 
ml/min is not expected to influence 
MRI endpoints. It is also not likely to 
impact subject safety nor significantly 
alter the subject population in the trial 
but is expected to beneficially affect 
recruitment.  
• For subjects in the biopsy sub-
population, the lower limit for eGFR 
is kept unchanged to ensure subject 
safety.  
Inclusion criterion 7: 
The lower limit for UACR has been 
changed to ≥ 20 mg/g. 
Changing the lower limit for UACR to ≥ 
20 mg/g will not impact the subject 
safety nor alter the subject population in 
the trial significantly but is expected to 
beneficially affect recruitment.  
Inclusion criterion 8: 
Criterion updated to allow inclusion of 
subjects for whom treatment with RAAS 
blockers is contraindicated or not 
tolerated. 
To align with wording in trial NN9535-
4321 (FLOW, a large CVOT 
investigating the effect of semaglutide in 
subjects with T2D and CKD) and to 
allow for the possibility that some 
subjects do not tolerate RAAS blockers. 
This is expected to beneficially affect 
recruitment but not impact subject safety 
nor alter the subject population in the 
trial. 
Section 5.4 Screen failures 
Wording updated to put more emphasis 
on the investigator’s evaluation on when 
it makes medical sense to rescreen a 
subject. Reference to specific inclusion 
criteria (5, 6 and/or 7) has been removed. 
Rescreening of previous screen failures is 
still only allowed twice. 
To accommodate that it can make 
medical sense to re-screen a subject that 
screen fails on other changeable or 
fluctuating inclusion/ exclusion criteria 
than inclusion criteria 5, 6 and/ or 7. This 
is expected to ease the screening and 
recruitment process.  
A sentence added to specify that subjects 
who are rescreened are required to sign a 
new informed consent.  
To clarify expectations related to when a 
subject is rescreened and to align with 
new protocol template text.  
Section 8.1.1 Magnetic 
resonance imaging 
Plasma glucose updated to blood glucose. 
To clarify, as the glucose measurements 
are performed with BG meters at site. 
Wording slightly updated to clarify 
investigator responsibilities related to 
radiology assessment.  
For clarification purposes only. 
Section 8.1.2 Kidney biopsy 
Wording slightly updated to clarify 
investigator responsibilities related to 
histopathologic report.  
For clarification purposes only. 
Section 8.1.4 Urine 
collection 
A paragraph describing on site random 
spot urine has been added 
Text added for clarification purposes 
only, to clearly differentiate the urine 
collections (first morning void spot 
urine, on site random spot urine, and 24-
hour urine). 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
3
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
4 of 89 
 
Section # and name 
Description of change 
Brief rationale 
Section 10.2, Appendix 2 
Clinical laboratory tests 
Table 10-1 Protocol-
required efficacy laboratory 
assessments 
Renal function: 
Laboratory parameters related to first 
morning void spot urine and on site 
random spot urine split into separate 
rows in the table. 
Biomarkers: 
Urine changed to: On site random spot 
urine. 
For clarification purposes only. 
Section 10.8 Appendix 8 
Mitigations to ensure 
subject safety and data 
integrity during 
epidemics/pandemics 
Visit window for the end of trial visit 
(V12) has been changed from ±7 days to 
+7 days. 
On site random spot urine collection 
added as a separate row in the flowchart. 
To align with changes in the flowchart 
(Section 1.2).  
Section 10.9, Appendix 9 
Country-specific 
requirements 
Country-specific requirements added for 
Denmark. 
Denmark has been included in the study.  
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
4
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
5 of 89 
 
Table of Contents    
Page 
Protocol amendment summary of changes table ........................................................................................... 2 
Table of Contents.............................................................................................................................................. 5 
1 Protocol summary ....................................................................................................................................... 9 
1.1 
Synopsis .............................................................................................................................................. 9 
1.2 
Flowchart .......................................................................................................................................... 12 
2 Introduction ............................................................................................................................................... 15 
2.1 
Trial rationale .................................................................................................................................... 15 
2.2 
Background ....................................................................................................................................... 15 
2.3 
Benefit-risk assessment ..................................................................................................................... 16 
2.3.1 
Risk assessment ................................................................................................................. 17 
2.3.2 
Benefit assessment ............................................................................................................. 20 
2.3.3 
Overall benefit-risk conclusion ......................................................................................... 21 
3 Objectives and endpoints .......................................................................................................................... 21 
3.1 
Primary, secondary and exploratory objective(s).............................................................................. 21 
3.1.1 
Primary objective ............................................................................................................... 21 
3.1.2 
Secondary objectives ......................................................................................................... 21 
3.1.3 
Exploratory objectives ....................................................................................................... 21 
3.2 
Primary, secondary and exploratory endpoint(s) .............................................................................. 21 
3.2.1 
Primary endpoints .............................................................................................................. 22 
3.2.2 
Secondary endpoints .......................................................................................................... 22 
3.2.2.1 
Supportive secondary endpoints .................................................................... 22 
3.2.3 
Exploratory endpoint(s) ..................................................................................................... 22 
4 Trial design ................................................................................................................................................ 22 
4.1 
Overall design ................................................................................................................................... 22 
4.2 
Scientific rationale for trial design .................................................................................................... 23 
4.3 
Justification for dose ......................................................................................................................... 24 
4.4 
End of trial definition ........................................................................................................................ 24 
5 Trial population ......................................................................................................................................... 24 
5.1 
Inclusion criteria ............................................................................................................................... 24 
5.2 
Exclusion criteria .............................................................................................................................. 25 
5.2.1 
Biopsy subpopulation exclusion criteria ............................................................................ 26 
5.3 
Lifestyle considerations .................................................................................................................... 27 
5.3.1 
Meals and dietary requirements ......................................................................................... 27 
5.4 
Screen failures ................................................................................................................................... 27 
5.5 
Randomisation criteria ...................................................................................................................... 27 
6 Treatments ................................................................................................................................................. 28 
6.1 
Treatments administered ................................................................................................................... 28 
6.2 
Preparation/handling/storage/accountability ..................................................................................... 29 
6.3 
Measures to minimise bias: randomisation and blinding .................................................................. 30 
6.4 
Treatment compliance ....................................................................................................................... 31 
6.5 
Concomitant medication ................................................................................................................... 31 
6.5.1 
RAAS blocking agent ........................................................................................................ 32 
6.5.2 
Anti-hyperglycaemic agents .............................................................................................. 32 
6.5.3 
Data capture of concomitant medications.......................................................................... 33 
6.6 
Dose modification ............................................................................................................................. 33 
6.7 
Treatment after end of trial ............................................................................................................... 33 
7 Discontinuation of trial treatment and subject discontinuation/withdrawal ....................................... 33 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
5
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
6 of 89 
 
7.1 
Discontinuation of trial treatment ..................................................................................................... 34 
7.1.1 
Temporary discontinuation of trial treatment .................................................................... 35 
7.2 
Subject discontinuation/withdrawal from the trial ............................................................................ 35 
7.2.1 
Replacement of subjects .................................................................................................... 35 
7.3 
Lost to follow-up............................................................................................................................... 35 
8 Trial assessments and procedures............................................................................................................ 36 
8.1 
Efficacy assessments ......................................................................................................................... 36 
8.1.1 
Magnetic resonance imaging ............................................................................................. 36 
8.1.2 
Kidney biopsy .................................................................................................................... 37 
8.1.2.1 
Requirements for the kidney biopsy .............................................................. 38 
(a) 
Requirements for the kidney biopsy operator ........................................ 38 
(b) 
Pre-biopsy requirements ........................................................................ 38 
(c) 
Post-biopsy regimen and information .................................................... 39 
8.1.3 
Clinical efficacy laboratory assessments ........................................................................... 40 
8.1.4 
Urine collection ................................................................................................................. 40 
8.2 
Safety assessments ............................................................................................................................ 41 
8.2.1 
Physical examinations ....................................................................................................... 41 
8.2.2 
Vital signs .......................................................................................................................... 41 
8.2.3 
Eye examination ................................................................................................................ 42 
8.2.4 
Self-measured plasma glucose ........................................................................................... 42 
8.2.5 
Clinical safety laboratory assessments .............................................................................. 43 
8.3 
Adverse events and serious adverse events ....................................................................................... 43 
8.3.1 
Time period and frequency for collecting AE and SAE information ................................ 43 
8.3.2 
Method of detecting AEs and SAEs .................................................................................. 44 
8.3.3 
Follow-up of AEs and SAEs ............................................................................................. 44 
8.3.4 
Regulatory reporting requirements for SAEs .................................................................... 44 
8.3.5 
Pregnancy .......................................................................................................................... 44 
8.3.6 
Cardiovascular and death events ....................................................................................... 45 
8.3.7 
Technical complaints ......................................................................................................... 45 
8.4 
Treatment of overdose ...................................................................................................................... 45 
8.5 
Pharmacokinetics .............................................................................................................................. 45 
8.6 
Pharmacodynamics ........................................................................................................................... 46 
8.7 
Genetics ............................................................................................................................................ 46 
8.8 
Biomarkers ........................................................................................................................................ 46 
8.8.1 
RNA transcriptome research ............................................................................................. 46 
9 Statistical considerations .......................................................................................................................... 47 
9.1 
Statistical hypotheses ........................................................................................................................ 47 
9.2 
Sample size determination ................................................................................................................ 47 
9.3 
Populations for analyses ................................................................................................................... 48 
9.4 
Statistical analyses ............................................................................................................................ 48 
9.4.1 
General considerations ...................................................................................................... 48 
9.4.2 
Primary endpoints .............................................................................................................. 49 
9.4.3 
Secondary endpoints .......................................................................................................... 51 
9.4.3.1 
Supportive secondary endpoints .................................................................... 51 
9.4.4 
Exploratory endpoints........................................................................................................ 52 
9.4.5 
Other safety analyses ......................................................................................................... 52 
9.4.6 
Other analyses ................................................................................................................... 52 
9.4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling .................................. 52 
9.5 
Interim analyses ................................................................................................................................ 52 
9.6 
Data monitoring committee .............................................................................................................. 52 
9.7 
Reporting of the main part of the trial ............................................................................................... 52 
10 Supporting documentation and operational considerations.................................................................. 52 
10.1 Appendix 1: Regulatory, ethical, and trial oversight considerations ................................................ 52 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
6
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
7 of 89 
 
10.1.1 
Regulatory and ethical considerations ............................................................................... 52 
10.1.2 
Financial disclosure ........................................................................................................... 53 
10.1.3 
Informed consent process .................................................................................................. 53 
10.1.4 
Information to subjects during trial ................................................................................... 54 
10.1.5 
Data protection .................................................................................................................. 54 
10.1.6 
Committees structure ......................................................................................................... 55 
10.1.6.1 
Novo Nordisk safety committee..................................................................... 55 
10.1.7 
Dissemination of clinical trial data .................................................................................... 55 
10.1.8 
Data quality assurance ....................................................................................................... 55 
10.1.8.1 
Case report forms ........................................................................................... 55 
10.1.8.2 
Monitoring ..................................................................................................... 56 
10.1.8.3 
Protocol compliance ....................................................................................... 56 
10.1.9 
Source documents .............................................................................................................. 56 
10.1.10 Retention of clinical trial documentation .......................................................................... 57 
10.1.11 Trial and site closure.......................................................................................................... 57 
10.1.12 Responsibilities .................................................................................................................. 57 
10.1.13 Indemnity statement .......................................................................................................... 58 
10.1.14 Publication policy .............................................................................................................. 58 
10.1.14.1 
Communication of results .............................................................................. 59 
10.1.14.2 
Authorship ...................................................................................................... 59 
10.1.14.3 
Site-specific publication(s) by investigator(s)................................................ 60 
10.1.14.4 
Investigator access to data and review of results ........................................... 60 
10.2 Appendix 2: Clinical laboratory tests................................................................................................ 61 
10.3 Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, follow-up, 
and reporting ..................................................................................................................................... 64 
10.3.1 
Definition of AE ................................................................................................................ 64 
10.3.2 
Definition of an SAE ......................................................................................................... 65 
10.3.3 
Description of AEs requiring additional data collection ................................................... 66 
10.3.4 
Recording and follow-up of AE and/or SAE ..................................................................... 66 
10.3.5 
Reporting of SAEs ............................................................................................................. 69 
10.4 Appendix 4: Contraceptive guidance and collection of pregnancy information ............................... 70 
10.5 Appendix 5: Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .................................................................................................................... 74 
10.5.1 
Definition of technical complaint ...................................................................................... 74 
10.5.2 
Recording and follow-up of technical complaints ............................................................. 74 
10.5.3 
Reporting of technical complaints ..................................................................................... 75 
10.6 Appendix 6: Retention of human biosamples ................................................................................... 76 
10.7 Appendix 7: Severe hypoglycaemic episodes ................................................................................... 77 
10.8 Appendix 8: Mitigations to ensure subject safety and data integrity during 
epidemics/pandemics (e.g. COVID-19) ............................................................................................ 78 
10.8.1 
Site visits ........................................................................................................................... 78 
10.8.2 
Assessments ....................................................................................................................... 78 
10.8.3 
Alternative dispensing methods of trial product ................................................................ 78 
10.8.4 
Minimum assessments to be performed during lockdown ................................................ 79 
10.9 Appendix 9: Country-specific requirements ..................................................................................... 81 
10.10 Appendix 10: Abbreviations ............................................................................................................. 83 
10.11 Appendix 11: Protocol amendment history ...................................................................................... 85 
11 References .................................................................................................................................................. 88 
 
Protocol attachment I Global list of key staff and relevant departments and suppliers 
Protocol attachment II Country list of key staff and relevant departments 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
7
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
8 of 89 
 
1 
Protocol summary 
1.1 
Synopsis 
Rationale: 
In the SUSTAIN 6 trial, once-weekly (OW) subcutaneous (s.c.) semaglutide showed a significant 
reduction in the risk of new or worsening nephropathy. To confirm the renal benefit suggested by 
SUSTAIN 6, the FLOW trial (NN9535-4321) was initiated, a pivotal phase 3b trial investigating 
kidney outcomes. The aim of the current trial (the REMODEL trial) is to explore the impact of 
semaglutide on the underlying kidney-related mechanisms hypothesised to be involved in the 
kidney protective effect of semaglutide in patients with type 2 diabetes (T2D) and chronic kidney 
disease (CKD). Non-invasive MRI methods will be used, along with urine- and blood-based 
sampling, kidney biopsies and RNA sequencing to assess changes in the kidney after 52 weeks of 
treatment with semaglutide compared to placebo. 
Objectives and endpoints: 
The primary objective:  
• To investigate the effect of OW semaglutide s.c. versus placebo on renal inflammation and 
haemodynamics, as measured by MRI in patients with T2D and CKD. 
The secondary objective: 
• To investigate the effect of OW semaglutide s.c. versus placebo on renal oxidative stress, 
natriuresis, albumin excretion and kidney function in subjects with T2D and CKD.  
The following primary endpoints are derived from the MRI scan: 
Endpoint title 
Time frame 
Unit 
Change in kidney oxygenation (cortex), BOLD MRI (R2*)  
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
Change in kidney oxygenation (medulla), BOLD MRI (R2*)  
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
Change in global kidney perfusion (MRI)  
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
Change in kidney inflammation (cortex), T1 mapping (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
Change in kidney inflammation (medulla), T1 mapping (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
BOLD: blood oxygenation-level dependent; MRI: magnetic resonance imaging 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
8
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
9 of 89 
 
The following are key secondary endpoints: 
Endpoint title 
Time frame 
Unit 
Change in gene expression assessed by single nucleus RNA 
sequencing (kidney biopsy) 
From baseline (week 0) to 
end of treatment (week 52)  log2 fold-change 
Change in glomerular basement membrane width (kidney 
biopsy) 
From baseline (week 0) to 
end of treatment (week 52)  nm 
Change in ADC (cortex) (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
Change in ADC (medulla) (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  Ratio 
Change in natriuresis (urinary sodium excretion) (urinalysis) 
From baseline (week 0) to 
end of treatment (week 52)   mmol/l 
Change in albumin excretion rate (urinalysis) 
From baseline (week 0) to 
end of treatment (week 52)   mg/24 h 
Change in kidney function (creatinine clearance) (urinalysis) 
From baseline (week 0) to 
end of treatment (week 52)   ml/min/1.73 m2 
ADC: apparent diffusion coefficient. 
Overall design: 
This is a multi-centre, international, randomised, double-blinded, parallel-group, placebo-controlled 
trial comparing OW semaglutide 1.0 mg s.c. versus placebo, both added to standard-of-care 
treatment (including antidiabetic medication, CKD medication and CV medication) in subjects with 
T2D and CKD. Subjects will be randomised 2:1 to receive either OW semaglutide or placebo. 
Key inclusion criteria: 
• Male or female. 
• Age above or equal to 18 years at the time of signing informed consent. 
• Diagnosed with T2D ≥180 days prior to the day of screening. 
• HbA1c ≤9.0% (≤75 mmol/mol). 
• Depending on biopsy/non-biopsy population: 
a. For subjects in the non-biopsy population: Serum creatinine-based eGFR ≥ 30 and 
≤75 mL/min/1.73 m2 (CKD-EPI). 
b. For subjects in the biopsy sub-population: Serum creatinine-based eGFR ≥ 40 and 
≤75 mL/min/1.73 m2 (CKD-EPI). 
• UACR ≥20 and <5000 mg/g. 
• Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone system 
(RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or 
angiotensin II receptor blocker (ARB)) unless such treatment is contraindicated or not tolerated. 
Treatment dose must be stable for at least 28 days prior to screening. 
Key exclusion criteria: 
• Use of any glucagon-like peptide 1 receptor agonist (GLP-1 RA) within 30 days prior to 
screening. 
• A prior solid organ transplant or awaiting solid organ transplant. 
• Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
• Presence or history of malignant neoplasms (other than basal or squamous cell skin cancer, in 
situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of 
screening. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
9
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
10 of 89 
 
• Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune 
kidney diseases including glomerulonephritis or congenital urinary tract malformations. 
• Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and V2. Pharmacological pupil-dilation is a requirement unless using a digital fundus 
photography camera specified for non-dilated examination. 
• Treatment with systemic anti-inflammatory or immunosuppressant drugs within 90 days prior to 
screening. Stable treatment with acetylsalicylic acid for prevention of cardiovascular events and 
occasional use of propionic acid derivatives drugs (e.g. ibuprofen) is allowed. 
• Any contraindication for MRI according to standard checklist used in clinical routine, including 
claustrophobia or metallic foreign bodies, metallic implants, internal electrical devices, or 
permanent makeup/tattoos that cannot be declared MR compatible.  
• Combination use of an ACE inhibitor and an ARB. 
Number of subjects:  
In this trial, 105 subjects will be randomly assigned to trial product.  
Treatment groups and duration: 
The total duration of trial participation for each subject will be: 
• up to 6 weeks for screening and pre-treatment assessments 
• 52 weeks of treatment 
• 5 weeks follow-up 
Trial products are: 
• Active trial product: semaglutide 1.34 mg/mL solution for injection in pre-filled PDS290 pen-
injector. One pre-filled pen contains 2 mg semaglutide in 1.5 mL solution. 
• Reference product: semaglutide placebo, solution for injection in 1.5 mL pre-filled PDS290 
pen-injector. 
Data monitoring committee: No
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
10
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
      
Date: 
21 April 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN9535-4662 
      
Version: 
3.0 
Page: 
11 of 89 
 
1.2 
Flowchart 
Procedure 
Protocol 
section 
Information 
Screening 
Pre-treatment 
period 
Randomisation 
Treatment period 
End of 
treatment 
End of trial 
 Visit number 
 
V0 
V1a 
V2b 
V3 
V4 
P5 
V6 
P7c 
V8 
V9 
V10 
V11d 
V12 
 Timing of Visit (Weeks) 
 
Minimum 3 days 
prior to V1 
Prior to V2 and up to 
6 weeks prior to V3 
Up to 5 weeks 
prior to V3 
0 
1 
2 
4 
8 
12 
26 
39 
52 
End of 
treatment + 
5 weeks 
 Visit Window (Days) 
 
 
 
- 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7c 
+7 
Informed consent and demographye 
10.1.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteriaf 
5.1, 5.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation criteria and randomisation 
5.5, 6.3 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
6.5 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant illness/medical history  
8.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Tobacco and nicotine products useg 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Childbearing potentialh 
10.4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
8.3.5 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
Physical examination 
8.2.1 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Height 
8.2.1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Body weight 
8.2.1 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Blood pressure 
8.2.2 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Pulse 
8.2.2 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Eye examinationi 
8.2.3 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
MRI Scan 
8.1 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Kidney biopsyj 
8.1 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments 
8, 10.2 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
VV-TMF-5179642|1.0|NN9535 -NN9535-4662
  Protocol  v3.0|11 of 89

Protocol 
      
Date: 
21 April 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN9535-4662 
      
Version: 
3.0 
Page: 
12 of 89 
 
Procedure 
Protocol 
section 
Information 
Screening 
Pre-treatment 
period 
Randomisation 
Treatment period 
End of 
treatment 
End of trial 
 Visit number 
 
V0 
V1a 
V2b 
V3 
V4 
P5 
V6 
P7c 
V8 
V9 
V10 
V11d 
V12 
 Timing of Visit (Weeks) 
 
Minimum 3 days 
prior to V1 
Prior to V2 and up to 
6 weeks prior to V3 
Up to 5 weeks 
prior to V3 
0 
1 
2 
4 
8 
12 
26 
39 
52 
End of 
treatment + 
5 weeks 
 Visit Window (Days) 
 
 
 
- 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7c 
+7 
24-hour urine collectionk 
10.2 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
First morning void collectionl 
8.1.4 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
On site random spot urine collection 
8.1.4 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Biosamples for future analysism 
10.6 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Adverse event 
8.3, 10.3 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Severe hypoglycaemic episodes 
10.7 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensing 
6 
 
 
 
X 
 
 
X 
  
X 
X 
X 
 
 
Attend visit following dietary requirementsn 
5.3.1 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Training in devices 
6.1 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
a. The investigator must confirm subject eligibility based on all inclusion and exclusion criteria assessed at V1 (including the eye examination) before the subject can initiate the pre-
treatment period (V2).   
b. Assessments at V2 must be done in the period between V2 and V3. V2 is included to ensure that eligibility has been settled, while treatment with trial drug has not yet been initiated.   
c. The P7 visit should include a reminder of dose escalation from 0.5 to 1.0 mg. 
d. The MRI scan and kidney biopsy (for subjects who participate in the biopsy subpopulation) can be performed up to 28 days before V11. For subjects who permanently discontinue 
treatment early, MRI and kidney biopsy should be performed as presented in Section 8.1.1 and 8.1.2, respectively.  
e. Demography consists of date of birth, sex, ethnicity and race (according to local regulation). 
f. Date of informed consent will be captured in CRF during V1. 
g. Tobacco use is defined as smoking at least one cigarette or equivalent daily. 
h. Only applicable for women of childbearing potential; Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
VV-TMF-5179642|1.0|NN9535 -NN9535-4662
  Protocol  v3.0|12 of 89

Protocol 
      
Date: 
21 April 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN9535-4662 
      
Version: 
3.0 
Page: 
13 of 89 
 
i. The V1 eye examination can be performed and evaluated 90 days prior to V1 or in the period between V1 and V2 (see Section 8.2.3). The V11 eye examination may be performed on a 
separate day up to 28 days before V11. 
j. Kidney biopsies to be performed only in a subset of the population, see Section 4.1. Kidney biopsy should be performed after the MRI scan scheduled at the same visit has been approved. 
k. Subjects must have collected 24-hour urine prior to the site visit, see Section 8.1.4 for details.  
l. Subjects must have collected first morning urine samples two days before and one day before the visit; for V1, subjects must additionally collect a first morning urine sample on the day of 
the visit. See Section 8.1.4 for details. 
m. Only applicable for subjects that have provided informed consent for biobanking.  
n. Applicable for the days prior to and the day of the MRI scan (and biopsy, for subjects in the biopsy subpopulation).
VV-TMF-5179642|1.0|NN9535 -NN9535-4662
  Protocol  v3.0|13 of 89

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
14 of 89 
 
 
2 
Introduction 
Semaglutide is a GLP-1 analogue developed by Novo Nordisk for the treatment of T2D and other 
diseases. Once weekly semaglutide s.c. has received marketing approval by the U.S. FDA, the 
European Commission and several other countries (Ozempic®, OW semaglutide s.c.).2, 3 In the US, 
OW semaglutide s.c. is also indicated for reduction of MACE in adults with T2D and established 
CV disease.2 Semaglutide is currently being investigated for the treatment of CKD in subjects with 
T2D.  
2.1 
Trial rationale 
A statistically significant 36% reduction in the secondary 4-component composite endpoint of new 
or worsening nephropathy was observed for treatment with OW semaglutide s.c. versus placebo in 
subjects with T2D and high risk of CV events in the pre-approval CVOT SUSTAIN 6 (NN9535-
3744).4 The 4-component composite endpoint was comprised of 1) death due to renal disease, 
2) continuous renal-replacement therapy, 3) new onset of persistent macroalbuminuria and 
4) persistent doubling of serum creatinine level. The results of the 4-component endpoint were 
primarily driven by a reduction in events of new onset of persistent macroalbuminuria in the 
semaglutide group. 
To confirm the renal benefit suggested by SUSTAIN 6, the FLOW trial (NN9535-4321) has been 
initiated. The FLOW trial is a pivotal phase 3b trial, aiming to demonstrate that OW semaglutide 
s.c. 1 mg delays the progression of renal impairment and lowers the risk of renal and CV mortality 
compared to placebo, both added to standard-of-care, in subjects with T2D and CKD. The primary 
endpoint in the FLOW trial is time to the first occurrence of: 
• Onset of persistent ≥ 50% reduction in eGFR (CKD-EPI) compared with baseline 
• Onset of persistent eGFR (CKD-EPI) < 15 mL/min/1.73 m2 
• Initiation of chronic renal replacement therapy (dialysis or kidney transplantation) 
• Renal death 
• CV death 
The renal mode of action of semaglutide is not well established. There are a number of proposed 
direct and indirect mechanisms, including a reduction in inflammation and oxidative stress,  and 
changed haemodynamics (direct mechanisms) as well as via improvement of glycaemic control, 
blood pressure and body weight (indirect mechanisms). The aim of the current trial is to explore the 
impact of semaglutide on kidney-related parameters hypothesised to be involved in the kidney 
protective effect of semaglutide in subjects with T2D and CKD.  
2.2 
Background 
CKD is a frequent and severe microvascular complication of diabetes. Diabetes is the single leading 
cause of ESKD, requiring either chronic dialysis treatment or kidney transplantation. Up to 40% of 
patients with T2D develop some degree of CKD, and these patients have severely increased 
cardiovascular morbidity and mortality.5  
Blocking the RAAS with ACE inhibitors or ARBs is recommended to reduce the progression of 
CKD.6 Additionally, treatment with SGLT-2 inhibitors holds the potential to decrease CKD 
progression rates.7 Despite optimal standard of care, a major unmet medical need to improve the 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
14
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
15 of 89 
 
 
treatment of CKD in patients with T2D persists; semaglutide holds the potential to fill in parts of 
this gap. While the FLOW trial will provide such clarification, knowledge of the underlying 
mechanism of semaglutide’s effect in the kidneys remains unknown, and investigation is warranted. 
The pathogenesis of CKD progression within T2D is complex. Kidney hypoxia, inflammation, 
oxidative stress and haemodynamic changes play critical roles and a vicious circle gradually results 
in fibrosis and loss of kidney function.8 Current knowledge indicates that the expected kidney 
protective effect of GLP-1 is caused only to a minor extent by indirect mechanisms including 
improved glycaemic control, systolic blood pressure reduction and weight loss,9, 10 suggesting that 
one or more of the direct mechanisms mentioned above may play a key role. Only few, small non-
clinical and clinical studies have focused on the direct renal MoA of GLP-1. These studies have 
primarily assessed the acute phase following GLP-1 treatment in the setting of normal kidney 
function with or without diabetes. GLP-1 RA therapy has been shown to reduce systemic markers 
of inflammation in humans,11 and the kidney specific marker of inflammation and macrophage 
activation MCP-1 was significantly reduced by liraglutide in a mice study (data on file). Moreover, 
in a recent publication, semaglutide was found to downregulate multiple inflammatory genes.12 
Changes in renal haemodynamics have been inconsistent in different studies and seem to depend on 
baseline renal function,13-17 whereas change in oxidative stress is only sparsely elucidated. GLP-1 
therapy consistently induces natriuresis in the acute phase18 as well as modulates the RAAS system 
by suppressing angiotensin II and renin.13-15, 17 The impact of these findings are unclear and the 
current trial will investigate the impact of semaglutide on kidney inflammation, kidney oxidative 
stress, renal haemodynamics and natriuresis in patients with T2D and CKD, who are treated with 
standard of care for T2D, CVD and CKD. This trial will therefore support and expand the scientific 
understanding of the results of the FLOW trial.  
Detailed information for OW semaglutide s.c. is available in the current edition of the IB and in the 
local labels for Ozempic®.   
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 of OW semaglutide 
s.c may be found in the investigator’s brochure or prescribing information/ summary of product 
characteristics.2, 3  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
15
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
16 of 89 
 
 
2.3.1 
Risk assessment 
Table 2-1 
Potential risks of clinical significance 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
 
Trial treatment(s) (semaglutide)  
Gastrointestinal 
disorders 
Consistent with other GLP-1 RAs, the 
most frequent adverse events (AEs) with 
semaglutide are gastrointestinal (nausea, 
vomiting and diarrhoea). In general, 
these reactions are mild or moderate in 
severity, of short duration, and dose 
dependent.   
 
In subjects treated with GLP-1 RAs, 
nausea, vomiting and diarrhoea may lead 
to significant dehydration. This should 
be considered when treating subjects 
with impaired renal function as it may 
cause a deterioration of renal function.  
Clinical trials have shown that a low starting 
dose and gradual dose escalation mitigates 
the risk of developing gastrointestinal 
symptoms.  
 
Subjects with GI AEs are recommended to 
drink plenty of fluids, unless medically 
contraindicated, to avoid volume depletion. 
Hypoglycaemia 
There is a low risk of hypoglycaemic 
episodes when semaglutide is used as 
monotherapy. Subjects treated with 
semaglutide in combination with 
sulphonylurea or insulin may have an 
increased risk of hypoglycaemia. 
The risk of hypoglycaemia can be lowered 
by reducing the dose of sulphonylurea 
and/or insulin when initiating treatment with 
semaglutide. See Section 6.5. 
 
Diabetic retinopathy 
complications 
In a 2-year clinical trial with s.c. 
semaglutide (NN9535-3744) involving 
3,297 subjects with T2D, 
high CV risk, long duration of diabetes 
and poorly controlled blood glucose, 
EAC-confirmed events of diabetic 
retinopathy complications occurred in 
more subjects treated with s.c. 
semaglutide (3.0%) 
compared to placebo (1.8%). The 
absolute risk increase for diabetic 
retinopathy complications was larger 
among subjects with a history of diabetic 
retinopathy at baseline. In the subjects 
who did not have a documented history 
of diabetic retinopathy the number of 
events were similar for s.c. semaglutide 
and placebo. In the other clinical trials up 
to 1 year involving 4,807 subjects with 
T2D, AEs related to diabetic retinopathy 
were reported in similar proportions of 
subjects treated with s.c. semaglutide 
(1.7%) and comparators (2.0%). 
Rapid improvement in glucose control has 
been associated with a temporary worsening 
of diabetic retinopathy, but other 
mechanisms cannot be excluded. Long-term 
glycaemic control decreases the risk of 
diabetic retinopathy. These subjects should 
be monitored closely and treated according 
to clinical guidelines.  
Allergic reactions 
As with all protein-based 
pharmaceuticals, treatment with 
semaglutide may evoke allergic 
reactions, including serious allergic 
reactions such as anaphylactic reactions 
and angioedema. 
As a precaution, subjects with known or 
suspected hypersensitivity to semaglutide or 
related products will not be enrolled in this 
trial. In addition, subjects will be instructed 
to contact the site staff as soon as possible 
for further guidance if suspicion of a 
hypersensitivity reaction to the trial product 
occurs. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
16
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
17 of 89 
 
 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
 
Acute pancreatitis 
Acute pancreatitis has been observed 
with the use of GLP-1 RAs. In the 
completed phase 3 trials with 
semaglutide s.c. and oral semaglutide, 
both the event rate and the proportion of 
subjects experiencing confirmed 
pancreatitis were similar with 
semaglutide and comparator. Few events 
were confirmed; the events occurred 
throughout the trial periods and the 
overall rates were similar to the rates 
reported in background populations 
Subjects should be informed of the 
characteristic symptoms of acute pancreatitis 
and if pancreatitis is suspected, semaglutide 
should be discontinued. If confirmed, 
semaglutide should not be restarted. 
For details on discontinuation of treatment, 
see Sections 7.1 and 7.1.1 
Neoplasms (malignant 
and non-malignant) 
Patients with T2D, as well as patients 
with overweight or obesity, have an 
increased risk of certain types of cancer. 
There is no evidence from clinical trials 
that GLP-1-based therapies increase the 
risk of neoplasms. However, in the 
semaglutide s.c. as well as oral 
semaglutide phase 3a trials, the 
proportion of subjects with neoplasms 
(malignant and non-malignant) were 
slightly higher with semaglutide than 
with comparator. The number of subjects 
exposed to semaglutide s.c. or oral 
semaglutide for a longer period is 
considered insufficient for a thorough 
assessment of the risk of neoplasms. 
Subjects with presence or history of 
malignant neoplasm (other than basal or 
squamous cell skin cancer, in-situ 
carcinomas of the cervix, or in situ prostate 
cancer) within 5 years prior to the day of 
screening will not be enrolled in this trial. 
Pancreatic cancer 
Patients with T2D have an increased risk 
of certain types of cancer such as 
pancreatic cancer. There is currently no 
support from non-clinical studies, 
clinical trials or post-marketing data that 
GLP-1 based therapies increase the risk 
of pancreatic cancer. However, 
pancreatic cancer has been classified as a 
potential class risk for all marketed GLP-
1 RAs by regulatory agencies. There is 
no indication of an increased relative risk 
in the semaglutide treatment groups vs. 
comparator, including placebo. The rates 
of EAC-confirmed events of pancreatic 
cancer were consistently low across 
trials. 
Subjects with presence or history of 
malignant neoplasm (other than basal or 
squamous cell skin cancer, in situ 
carcinomas of the cervix, or in situ prostate 
cancer) within 5 years prior to the day of 
screening will not be enrolled in this trial. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
17
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
18 of 89 
 
 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
 
Medullary thyroid cancer 
Thyroid C-cell tumours were seen in 
mouse and rat carcinogenicity studies 
after daily exposure to semaglutide for 
2 years. The rodent C-cell tumours are 
caused by a non-genotoxic, specific 
GLP-1 receptor mediated mechanism to 
which rodents are particularly sensitive. 
No C-cell tumours were observed in 
monkeys after 52 weeks exposure up to 
52-fold above the clinical plasma 
exposure at 14 mg/day. The GLP-1 
receptor is not expressed in the normal 
human thyroid, and therefore the clinical 
relevance of the findings is considered to 
be low. 
To mitigate this risk, subjects with a family 
or personal history of medullary thyroid 
carcinoma or multiple endocrine neoplasia 
type 2 (MEN2) are excluded from clinical 
trials with semaglutide. 
Trial procedures 
COVID-19: Risk of 
COVID-19 infection in 
relation to participation 
in trial 
Subjects may be exposed to the risk of 
COVID-19 transmission and infection in 
relation to site visits if an outbreak is 
ongoing in the given country or 
region/state. 
The risk of COVID-19 transmission in 
relation to site visits is overall considered to 
be low. To minimize the risk as much as 
possible, the following measures have been 
taken: 
• 
Cautious subject recruitment planning 
ensures controlled subject enrollment in 
countries where the COVID-19 
pandemic is evaluated to be sufficiently 
under control, and at sites where health 
care resources are evaluated to be 
adequate. 
• 
The number of physical on-site visits 
has been limited to the extent possible, 
without risking the scientific value of 
the trial. Phone visits have to the extent 
possible replaced on-site visits. 
• 
On-site visits will be well prepared and 
as short as possible. Physical contact 
between subjects and site staff will be 
limited to the extent possible, and 
protective measures will be 
implemented, if deemed necessary by 
the investigator. 
MRI 
All medical imaging examinations are 
carried out using a scanner where the 
subject lies on a bed that is moved into 
the scanner so that the head is inside the 
scanner tunnel. This procedure may be 
perceived as unpleasant for people 
suffering from claustrophobia. Further, 
the MRI examination involves the use of 
strong magnetic field but does not 
involve radiation exposure. No contrast 
agent will be used in this trial. 
To minimize the risk of claustrophobia and 
risks associated with the magnetic field, 
local guidelines will be followed, and the 
following subjects have been excluded from 
the trial:  
• 
subjects who might experience 
claustrophobia  
• 
subjects with metal implants of certain 
types (e.g. pacemakers and cochlear 
implants) or permanent makeup that 
cannot be declared MR compatible. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
18
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
19 of 89 
 
 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
 
Kidney biopsy 
A kidney biopsy is an invasive 
procedure, which may cause mild to 
severe complications. Refer to the biopsy 
SI/IC for additional details.     
A number of initiatives will be taken to 
minimize the risk for kidney biopsy 
complications and to ensure proper and 
immediate handling should they appear:  
• 
Only nephrologists, invasive 
radiologists or other HCPs with 
extensive experience in performing 
kidney biopsies will perform the 
procedure.  
• 
Local biopsy guidelines should be 
strictly adhered to including: 
o fasting before the biopsy procedure 
o sufficiently regulated blood pressure    
o pausing of relevant concomitant 
medication in advance of the biopsy 
procedure 
o monitoring of vital signs before and 
after the biopsy procedure 
o imaging guided biopsy procedure 
o post-biopsy clinical observation 
o post-biopsy precautions       
Other 
Pregnancy and fertility 
Studies in animals have shown 
reproductive toxicity. There are limited 
data from the use of semaglutide in 
pregnant women. 
Semaglutide should not be used during 
pregnancy. Women of childbearing potential 
are required to use highly effective 
contraceptive methods when participating in 
this trial (see Appendix 4, Table 10-3). If a 
subject wishes to become pregnant, or 
pregnancy occurs, semaglutide should be 
discontinued (please see Section 7.1 and 
8.3.5 for further guidance). The effect of 
semaglutide on fertility in humans is 
unknown.  
2.3.2 
Benefit assessment 
In clinical trials, semaglutide has provided superior long-term glycaemic control in subjects with 
T2D and clinically relevant reductions in body weight as compared to commonly used marketed 
glucose lowering products and to placebo. The CV outcome trial SUSTAIN 6 established the CV 
safety of semaglutide and reported a clinically relevant CV risk reduction with semaglutide 
compared to placebo when added to standard-of-care.19 
During the current trial, all subjects will be treated within a regimen anticipated to be better than or 
equal to the treatment they receive at the time of entry into the trial. It is expected that all subjects 
will benefit from participation through frequent, close contact with investigators and other site staff 
who will ensure that subjects are treated according to recommended standard-of-care for T2D, CKD 
and CV risk management, and disease development and progression will be closely monitored and 
treated. To ensure all subjects, including those receiving placebo, have adequate glycaemic control, 
investigators are encouraged to optimise treatment with anti-hyperglycaemic medications (GLP-1 
RAs and SGLT-2 inhibitors excluded) throughout the trial in accordance with local clinical practice. 
All subjects in this trial will receive trial product and auxiliary supplies free of charge. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
19
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
20 of 89 
 
 
2.3.3 
Overall benefit-risk conclusion 
Data from the clinical development programme for semaglutide has not revealed any safety issues 
that would outweigh the benefits of participation in this trial. The trial population will consist of 
T2D subjects with CKD. Assessment of diabetes and CKD and appropriate attention to the 
standard-of care treatment will be provided throughout the trial. It is therefore concluded that the 
potential benefits from trial participation will outweigh the potential risks for the semaglutide as 
well as the placebo treated subjects.  
More detailed information about the known and expected benefits and risks and expected AEs of 
semaglutide may be found in the investigator’s brochure or the locally approved label for 
Ozempic®. 
Considering the measures taken to minimise risk to subjects participating in this trial, the potential 
risks identified in association with OW semaglutide s.c. are justified by the anticipated benefits that 
may be afforded to subjects with T2D and CKD. 
3 
Objectives and endpoints 
3.1 
Primary, secondary and exploratory objective(s) 
3.1.1 
Primary objective 
 
To investigate the effect of OW semaglutide s.c. versus placebo on renal inflammation and 
haemodynamics, as measured by MRI in subjects with T2D and CKD. 
3.1.2 
Secondary objectives 
To investigate the effect of OW semaglutide s.c. versus placebo on renal oxidative stress, 
natriuresis, albumin excretion and kidney function in subjects with T2D and CKD.  
3.1.3 
Exploratory objectives 
To explore the effect of OW semaglutide s.c. versus placebo on circulating and urinary biomarkers 
in subjects with T2D and CKD.  
3.2 
Primary, secondary and exploratory endpoint(s) 
For each assessment, the baseline is defined as the latest observed measurement at or before the 
randomisation visit (V3). 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
20
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
21 of 89 
 
 
3.2.1 
Primary endpoints 
The following primary endpoints are derived from the MRI scan. 
Endpoint title 
Time frame 
Unit 
Change in kidney oxygenation (cortex), BOLD MRI (R2*)  
From baseline (week 0) to 
end of treatment (week 52)  ratio 
Change in kidney oxygenation (medulla), BOLD MRI (R2*)  
From baseline (week 0) to 
end of treatment (week 52)  ratio  
Change in global kidney perfusion (MRI)  
From baseline (week 0) to 
end of treatment (week 52)  ratio 
Change in kidney inflammation (cortex), T1 mapping (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  ratio 
Change in kidney inflammation (medulla), T1 mapping (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  ratio 
BOLD: blood oxygenation-level dependent; MRI: magnetic resonance imaging 
3.2.2 
Secondary endpoints 
3.2.2.1 
Supportive secondary endpoints 
Endpoint title 
Time frame 
Unit 
Change in gene expression assessed by single nucleus RNA 
sequencing (kidney biopsy) 
From baseline (week 0) to 
end of treatment (week 52)  log2 fold-change 
Change in glomerular basement membrane width (kidney 
biopsy) 
From baseline (week 0) to 
end of treatment (week 52)  nm 
Change in ADC (cortex) (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  ratio  
Change in ADC (medulla) (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  ratio  
Change in mean RARI (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  ratio  
Change in mean arterial flow (MRI) 
From baseline (week 0) to 
end of treatment (week 52)  ratio 
Change in natriuresis (urinary sodium excretion) (urinalysis) 
From baseline (week 0) to 
end of treatment (week 52)   mmol/l 
Change in albumin excretion rate (urinalysis) 
From baseline (week 0) to 
end of treatment (week 52)   mg/24 h 
Change in kidney function (creatinine clearance) (urinalysis) 
From baseline (week 0) to 
end of treatment (week 52)   ml/min/1.73 m2 
ADC: apparent diffusion coefficient; RARI : renal artery resistive index  
3.2.3 
Exploratory endpoint(s) 
Exploratory endpoints will be defined in the SAP, and include additional outcomes from the MRI 
scans, morphometric outcomes from kidney biopsies, 24-hour urine, circulating and urinary 
biomarkers, and clinical parameters. 
4 
Trial design 
4.1 
Overall design 
This is a multi-centre, international, randomised, double-blinded, parallel-group, placebo-controlled 
trial comparing OW semaglutide s.c. versus placebo, both added to standard-of-care treatment 
(including antidiabetic medication, CKD medication and CV medication) in subjects with T2D and 
CKD. The total treatment duration will be 52 weeks with a follow-up period of 5 weeks. The trial 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
21
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
22 of 89 
 
 
will include a subpopulation (aiming for 45 subjects or more) undergoing kidney biopsies at 
baseline and end of treatment. Subjects will be invited to participate in the biopsy subpopulation at 
sites with the capacity to perform kidney biopsy. The full population (including the biopsy 
subpopulation) will be randomised 2:1 to semaglutide or placebo, respectively. Standard dose 
escalation (every 4 weeks) will be applied, until the maximum dose of 1 mg semaglutide or placebo 
is reached. A schematic illustration of the trial design is shown in Figure 4-1. 
Figure 4-1 
Trial design 
 
4.2 
Scientific rationale for trial design 
Previous data has suggested that GLP-RAs are associated with improvements in renal 
inflammation, haemodynamics, natriuresis, oxidative stress and the RAAS.9-16 However, most 
studies have focused on the acute phase response and been hampered by limited sample size, non-
CKD populations and lack of methods to assess the effect on a molecular level.  
The REMODEL trial will include subjects with T2D and pre-existing CKD. Subjects who will 
undergo biopsy will have a minimum baseline eGFR of 40 ml/min/1.73 m2 to ensure the safety of 
the subjects as well as interpretability of the biopsies due to limited fibrosis. Subjects who will not 
undergo biopsy will have a minimum baseline eGFR of 30 ml/min/1.73 m2. Overall, subjects will 
have a UACR ≥20 mg/g; however, in >50% of the trial population, subjects will have a UACR 
≥100 mg/g, which is indicative of existing renal damage and significant risk of disease progression. 
This will also ensure a similar population to the FLOW trial. Maximum HbA1c will be 9.0% to 
minimise the potential impact on inflammatory measures seen following dramatic improvements in 
glycaemic control.20 A treatment duration of 52 weeks allows for a thorough assessment of the 
chronic effects of semaglutide treatment, and it ensures the possibility to correlate changes in renal 
inflammation, oxygenation, haemodynamics and gene expression with changes in markers of 
kidney damage (e.g. albuminuria) and kidney function (e.g. eGFR). Frequent visits and assessments 
during early trial conduct also allows for assessment of the acute effects of semaglutide treatment. 
A pre-treatment visit (V2) will ensure that the baseline measurements for MRI scan and kidney 
biopsy are performed before treatment with trial drug is initiated. 
SGLT-2 inhibitors have been shown to reduce progression of CKD;7 and therefore randomisation 
will be stratified by concomitant treatment with SGLT-2 inhibitors at baseline to ensure 
representative use in both treatment groups. For the biopsy subpopulation as well as for the total 
population, there will be a 50% cap on the number of subjects treated with an SLGT-2 inhibitor. To 
0.25 mg
0.25 mg
Follow-up 
(5 weeks)
Treatment period
(52 weeks)
Screening and 
Pre-treatment 
(Up to 6 weeks)
N=105
Randomisation 2:1
0.5 mg
0.5 mg
1.0 mg OW semaglutide s.c. 
1.0 mg OW placebo s.c. 
Week -6
Week 0
Randomisation
Week 4
Week 8
Week 52 
Information
Week 57 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
22
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
23 of 89 
 
 
reduce possible bias with SGLT-2 inhibitor treatment, a stable dose of SGLT-2 inhibitor for a 
minimum of 90 days is required at screening, while initiation of SGLT-2 inhibitors will not be 
allowed during the trial. For subjects treated with an SGLT-2 inhibitor at baseline, dose changes 
during the trial are allowed, however discontinuation is discouraged unless for safety reasons. Dose 
modification of SGLT-2 inhibitors is considered acceptable because there is no clear dose-response 
for the kidney-protective effect of SGLT-2 inhibitors.21-23 These restrictions on SGLT-2 inhibitor 
treatment are considered ethically acceptable, as other treatments for hyperglycaemia or co-
morbidities can be introduced (except GLP-1 RAs) or adjusted throughout the trial based on 
individual needs and at the investigator’s discretion. 
To ensure unbiased assessment of the effects and underlying mechanisms of semaglutide on 
kidneys, the trial is randomised, double-blinded and placebo-controlled. 
4.3 
Justification for dose 
A dose of OW semaglutide s.c. 1 mg was chosen similar to the FLOW trial. This dose has been 
tested for glycaemic control in subjects with T2D in a comprehensive phase 3a programme and 
shown to have a positive benefit-risk balance. The SUSTAIN 6 data indicates that the 1 mg dose 
provides a slower decline in kidney function compared to the 0.5 mg dose, with a comparable AE 
profile. For information regarding dose modifications, see Section 6.6. 
In order to lower the risk of gastrointestinal AEs, a dose-escalation regimen is applied, in 
accordance with the prescribing information.2, 3  For further information on the dose-escalation, see 
Section 6.1. 
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 (V12, ‘end of trial’ according to the flowchart). 
The end of the trial is defined as the date of the last 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. 
Inclusion and exclusion criteria are also referred to as eligibility criteria. 
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. 
3. Age above or equal to 18 years at the time of signing informed consent. 
4. Diagnosed with T2D ≥180 days prior to the day of screening. 
5. HbA1c ≤9.0% (≤ 75 mmol/mol). 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
23
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
24 of 89 
 
 
6. Depending on biopsy/non-biopsy population: 
a. For subjects in the non-biopsy population: Serum creatinine-based eGFR ≥30 and 
≤75 mL/min/1.73 m2 (CKD-EPI).a 
b. For subjects in the biopsy sub-population: Serum creatinine-based eGFR ≥ 40 and 
≤75 mL/min/1.73 m2 (CKD-EPI).a 
7. UACR ≥20 and <5000 mg/g.a, b 
8. Treatment with maximum labelled or tolerated dose of a RAAS blocking agent including an 
ACE inhibitor or an angiotensin II receptor blocker (ARB) unless such treatment is 
contraindicated or not tolerated. Treatment dose must be stable for at least 28 days prior to 
screening. 
a. At the time of sample collection, the subject must be in usual health condition as evaluated by the investigator.  
b. Present in 2 out of 3 first morning void urine samples taken at individual, consecutive days prior to V1 (screening). 
Screening UACR is defined as the median value of the 3 first morning void urine samples. 
5.2 
Exclusion criteria  
The following are general exclusion criteria for all enrolled subjects. Subjects in the biopsy sub-
population have additional exclusion criteria, see Section 5.2.1. 
Subjects are excluded from the trial if any of the following criteria apply: 
1. Known or suspected hypersensitivity to trial product(s) or related products. 
2. Previous participation in this trial. Participation is defined as randomisation. 
3. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing 
potential and not using a highly effective contraceptive method (see Appendix 4 [10.4] for 
further guidance). For country specific requirements see Appendix 9 (10.9). 
4. Receipt of any investigational medicinal product within 60 days before the day of the screening 
visit. 
5. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or 
compliance with the protocol. 
6. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic 
attack within 180 days prior to the day of screening. 
7. Planned coronary, carotid or peripheral artery revascularisation. 
8. Chronic heart failure classified as being in New York Heart Association (NYHA) ≥ Class III at 
screening. 
9. Presence or history of malignant neoplasms (other than basal or squamous cell skin cancer, in 
situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of 
screening. 
10. Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune 
kidney diseases including glomerulonephritis or congenital urinary tract malformations. 
11. Use of any GLP-1 receptor agonist within 30 days prior to screening. 
12. Use of finerenone within 30 days prior to screening. 
13. Personal or first-degree relative(s) history of multiple endocrine neoplasia type 2 (MEN2) or 
medullary thyroid carcinoma (MTC). 
14. Chronic or intermittent haemodialysis or peritoneal dialysis. 
15. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus 
examination performed within the past 90 days prior to screening or in the period between 
screening and V2. Pharmacological pupil-dilation is a requirement unless using a 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
24
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
25 of 89 
 
 
digital fundus photography camera specified for non-dilated examination. 
16. Treatment with systemic anti-inflammatory or immunosuppressant drugs within 90 days prior to 
screening. Stable treatment with acetylsalicylic acid for prevention of cardiovascular events and 
occasional use of propionic acid derivatives drugs (e.g. ibuprofen) is allowed. 
17. Inadequately treated blood pressure, defined, as systolic ≥180 mmHg or diastolic 
≥110 mmHg at screening.a 
18. Any contraindication for MRI according to standard checklist used in clinical routine, including 
claustrophobia or metallic foreign bodies, metallic implants, internal electrical devices, or 
permanent makeup/tattoos that cannot be declared MR compatible.  
19. Abdominal height in the supine position >35 cm (>13.8 inch). Abdominal height should be 
measured as the vertical distance from the back to tallest point on the abdomen while the subject 
is lying flat on his/her back. 
20. A prior solid organ transplant or awaiting solid organ transplant. 
21. Combination use of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin II 
receptor blocker (ARB). 
22. Depending on baseline SGLT-2 inhibitor use: b. 
a. For subjects not treated with an SGLT-2 inhibitor at baseline: 
Treatment with an SGLT-2 inhibitor within 90 days of screening 
b. For subjects treated with an SGLT-2 inhibitor at baseline: 
Stable dose of SGLT-2 inhibitor for less than 90 days prior to screening  
a. For patients in the biopsy subpopulations, blood pressure requirements in advance of the kidney biopsy will be more 
stringent (see Section 8.1.2.1(b)). 
b. See Section 4.2 on baseline SGLT-2 inhibitor use. 
5.2.1 
Biopsy subpopulation exclusion criteria 
Subjects are excluded from the biopsy subpopulation if any of the following criteria apply 
(however, these subjects may still be eligible for the non-biopsy population of the trial): 
1. Not expected to fulfil all of the biochemical, imaging and clinical requirements on the day of the 
biopsy (see Section 8.1.2.1(b) for details). 
2. Any condition with a single kidney. 
3. Evidence of bleeding disorder or complications from previous bleeding episodes. 
4. Use of aspirin, NSAID, other anti-platelet therapy, fish oil, gabapentin or other drugs that can be 
associated with bleeding and which cannot be safely stopped for a sufficient time period before 
and after the biopsy   
• anti-platelet agents (e.g. clopidogrel, aspirin) to be stopped for at least 7 days prior to biopsy 
• regular NSAID to be stopped for at least 4 days prior to biopsy 
• other agents associated with bleeding should be paused at the investigator’s discretion, and 
avoided if possible 
5. Use of chronic anticoagulation (e.g. novel oral anticoagulants [NOAC] or warfarin) that cannot 
be safely stopped for a sufficient time period before and after the biopsy. 
6. Unwilling to receive blood transfusion (if needed). 
7. Allergy to iodinated contrast, or if allergic, then alternative contrast-free imaging approaches 
must be available at the biopsy site in case an intervention for bleeding is needed. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
25
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
26 of 89 
 
 
5.3 
Lifestyle considerations 
5.3.1 
Meals and dietary requirements 
Subjects must follow these dietary requirements before the MRI scan visits according to the 
flowchart: 
• drinking 250 mL (8.5 oz) of water within one hour before the MRI scan. 
• avoid excess intake of sodium during the 3 days before the MRI scan.   
• abstaining from caffeine, nicotine, alcohol and protein-rich meals within 6 hours of the MRI 
scan. 
If the subject has not been following the dietary requirements, the subject should be called in for a 
new visit within the visit window to have the MRI scan performed. 
For subjects in the biopsy subpopulation, subjects must adhere to local site regulations for fasting 
before the kidney biopsy visits. 
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 and randomisation 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. 
A screen failure session must be made in IWRS. 
Subjects who do not meet the criteria for participation in this study may be re-screened twice if the 
investigator assesses it is reasonable to expect that potential changeable or fluctuating in- or 
exclusion criteria may change, e.g., biochemical parameters. Previously randomised subjects cannot 
be re-screened. Subjects who are re-screened are required to sign a new informed consent form and 
provided with a new subject ID. A new screening session must be made in the IWRS.  
If the subject has failed any of the inclusion criteria related to laboratory parameters, re-sampling is 
not allowed, unless subject is re-screened. However, in case of technical issues (e.g. haemolysed or 
lost), re-sampling is allowed for the affected parameters. 
5.5 
Randomisation criteria 
First dose must only be administered after baseline assessments related to primary and/or secondary 
endpoints are completed. 
To be randomised, all randomisation criteria must be answered "yes". 
1. No initiations of the following medications between screening and randomisation: anti-
inflammatory drugs, immunosuppressants, finerenone, GLP-1 RAs or SGLT-2 inhibitors. 
2. No disorder having arisen since screening that, in the investigator’s opinion, might jeopardise 
subject’s safety or compliance with the protocol. 
3. Acceptable image acquisition at V2 for MRI scan as judged by the centralised imaging core 
laboratory. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
26
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
27 of 89 
 
 
4. Kidney biopsy performed at V2 (applicable only for the biopsy subpopulation). 
5. Stable dose of RAAS blocking agent between screening and randomisation. 
6 
Treatments 
6.1 
Treatments administered 
Investigational medicinal products (IMP) 
The investigational medicinal products (trial products) provided by Novo Nordisk are listed in 
Table 6-1. The trial products are packed blinded and are visually identical. 
Table 6-1 
Investigational medicinal product provided by Novo Nordisk A/S 
Information about the use of the PDS290 pen-injector for semaglutide and placebo can be found in 
the DFU. 
Dose escalation 
Subjects will initiate once weekly treatment with 0.25 mg semaglutide/placebo at randomisation. 
Following 4 weeks of treatment, the dose will be escalated to 0.5 mg and maintained for another 
4 weeks until escalating to the target dose of 1 mg semaglutide/placebo as shown in Table 6-2. The 
4-week dose escalation intervals are applied in order to lower the risk of GI AEs. The investigator 
should remind subjects when to escalate dose; not all dose escalations are scheduled to occur at site 
visits. 
Table 6-2 
Trial periods and treatment groups 
Trial periods 
Screening 
Dose 1 
Dose 2 
Maintenance 
Follow-up 
Duration of each period 
Up to 6 
weeks 
4 weeks 
4 weeks 
44 weeks 
5 weeks 
Treatment 
N 
 
Semaglutide s.c. OW 
70 
- 
0.25 mg 
0.5 mg 
1 mg 
- 
Placebo s.c. OW 
35 
- 
0.25 mg 
0.5 mg 
1 mg 
- 
N: number of subjects, OW: once weekly, s.c.: subcutaneous. 
Subjects should remain on the 1 mg dose level until the end of treatment visit; however, dose 
reductions and extensions of dose escalation intervals are allowed e.g. if treatment with trial product 
is associated with unacceptable AEs or due to other circumstances. Treatment with trial product 
should be intensified towards the target dose of 1 mg if/when deemed safe at the discretion of the 
investigator. Continued maintenance treatment at the 0.25 mg dose level is not acceptable. Subjects 
who discontinue trial product permanently will be withdrawn from the trial, see Section 7. Date and 
dose need to be recorded in the eCRF when trial product is initiated and changed.  
Trial product name: 
Semaglutide B 1.34 mg/ml  
Semaglutide placebo 
Dosage form 
Solution for injection 
Solution for injection 
Route of administration  
Subcutaneous 
Subcutaneous 
Recommended dosing (mg) 
0.25, 0.5, 1 
0.25, 0.5, 1 
Dosing instructions 
Once weekly 
Once weekly 
Packaging 
1.5 ml pre-filled PDS290 pen-injector 1.5 ml pre-filled PDS290 pen-injector 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
27
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
28 of 89 
 
 
Instructions for the subject 
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, see 
Section 1.2). If the investigator finds it relevant, the DFU can also be given at other visits during the 
trial. Training is the responsibility of the investigator or delegate. 
Subjects will be instructed to inject the trial product s.c. once weekly in the abdomen, thigh, or 
upper arm. The injection site can be changed without dose adjustment. The investigator may choose 
to observe the subject when administering the first dose.  
The injection can be administered at any time of the day irrespective of meals, but on the same day 
of the week. The day of weekly administration can be changed if necessary, as long as the time 
between two doses is at least 2 days (≥48 hours) or in accordance with the local label. After 
selecting a new dosing day, once weekly dosing should be continued. 
Auxiliary supplies 
Auxiliary supplies are provided by Novo Nordisk: 
• needles for the PDS290 pen-injector (maximum needle length: 6 mm) 
• directions for use (DFU) for the prefilled PDS290 pen-injector 
• blood glucose (BG) meters including lancets, test strips, control solutions and instructions for 
use 
Only needles provided by Novo Nordisk may be used for administration of trial product. Auxiliary 
supplies should be provided at the first dispensing visit and again during the trial as relevant. 
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. Information on in-use conditions and in-use time will be 
available on the trial product label and in the TMM. 
Each trial site will be supplied with sufficient trial products for the trial on an on-going basis, 
controlled by IWRS. Trial product will be distributed to the trial sites according to screening and 
randomisation. 
The following requirements must be followed: 
• 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. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
28
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
29 of 89 
 
 
• The investigator or designee is responsible for drug accountability and record maintenance (i.e. 
receipt, accountability and final disposition records). 
• Drug accountability must be performed in the IWRS by registering pen-injectors as returned 
(either used/partly used, or unused) or as lost. 
• The investigator or designee must instruct the subject in what to return at next visit. 
• The investigator or designee must instruct the subject on how to manage the in-use time of 
dispensed products. 
• 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. 
• All returned, expired or damaged trial products (for technical complaint samples, see 
Appendix 5 [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. 
6.3 
Measures to minimise bias: randomisation and blinding 
All subjects will be centrally screened and randomised using an IWRS and assigned to the next 
available treatment according to randomisation schedule. Trial product will be dispensed/allocated 
at the trial visits summarised in the flowchart. 
At screening (V1), each subject will be assigned a unique 6-digit subject number, which will remain 
the same throughout the trial. Each site is assigned a 3-digit number and all subject numbers will 
start with the site number. 
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 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation. The person breaking the blind must print the "code break 
confirmation" notification generated by the IWRS, sign and date the document. If IWRS is not 
accessible at the time of blind break, the IWRS helpdesk should be contacted. Contact details are 
listed in Attachment I. The subject will continue on trial product if there are no safety concerns at 
the discretion of the investigator 
Randomisation will be stratified by: 
• SGLT-2 inhibitor treatment at baseline (yes versus no)  
• participation in the biopsy subpopulation (yes versus no)  
• MRI field strength (1.5 T versus 3.0 T) 
In the overall population, as well as the biopsy subpopulation, the number of subjects on SGLT-2 
inhibitor treatment at baseline will be capped at 50%, see Section 4.2 for details.   
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
29
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
30 of 89 
 
 
The number of subjects with screening UACR <100 mg/g will be capped at 50% of the overall 
population. Screening UACR is defined as the median value of the 3 first morning void urine 
samples. 
6.4 
Treatment compliance 
Drug treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to encourage subject compliance. 
When subjects self-administer trial product(s) at home, compliance with trial product administration 
will be assessed and the assessment documented in source documents at each visit where 
information is available. If any suspicion of non-compliance arises, the site must enter into a 
dialogue with the subject, re-emphasizing the importance of compliance and uncover barriers to 
compliance. This dialogue must be documented. Compliance will be assessed by cross checking the 
following sources and comparing these to the expected use:  
• Drug accountability information; counting returned trial product, visual inspection of pens  
• Discussion with subjects 
Treatment start and stop dates will be recorded in the CRF. 
Missed doses 
If one semaglutide dose is missed, it should be administered as soon as possible and within 5 days 
after the missed dose. If more than 5 days have passed, the missed dose should be skipped, and the 
next dose should be administered on the regularly scheduled day. In either case, subjects can then 
resume their regular once-weekly dosing schedule. A missed dose should not affect the scheduled 
dosing day of the week. 
If 2–3 consecutive doses of trial product are missed, the subject should be encouraged to 
recommence the treatment if considered safe as per the investigator’s discretion and if the subject 
does not meet any of the discontinuation criteria (Section 7.1). The trial product should be 
continued as early as the situation allows. The missed doses should not affect the scheduled dosing 
day of the week. The start dose for re-initiation of trial product is at the investigator’s discretion.  
If ≥4 consecutive doses of trial product are missed, the investigator should consult Novo Nordisk to 
decide if the subject can continue treatment. Previous dose and gastrointestinal adverse reactions 
should be taken into consideration when evaluating whether to repeat dose escalation in case 
treatment is resumed. 
If doses are missed blood glucose should be more closely monitored if judged necessary by the 
investigator. 
6.5 
Concomitant medication 
Semaglutide/placebo will be added on top of standard-of-care treatment. Changes to standard-of 
care medications will be allowed during trial conduct to optimise recommended standard-of-care. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
30
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
31 of 89 
 
 
Additional anti-hyperglycaemic, CV, and CKD medications may be added or changed during the 
trial at the discretion of the investigator and in accordance with local treatment guidelines and 
policies. Investigators are encouraged to optimise standard-of-care treatment for T2D, CKD, and 
CV risk management according to local treatment practice.  
Subjects are not allowed to receive continuous treatment with systemic anti-inflammatory drugs 
>14 days. Stable treatment with acetylsalicylic acid for prevention of cardiovascular events and 
occasional use of propionic acid derivatives drugs (e.g. ibuprofen) is allowed. Refer to Section 7.1. 
Anti-hyperglycaemic, CV and CKD standard-of-care treatment is considered background treatment 
and will not be provided by Novo Nordisk A/S. 
6.5.1 
RAAS blocking agent 
At screening, subjects are required to be treated with a stable, maximum labelled or tolerated dose 
of a RAAS blocking agent (an ACE inhibitor or an ARB) as standard-of-care treatment for CKD in 
T2D. The maximum labelled dose will be assessed by the investigator in accordance with local 
label and guidelines. Treatment dose must be stable for at least 28 days prior to screening and kept 
stable between screening and randomisation. 
6.5.2 
Anti-hyperglycaemic agents 
Initiating GLP-1 RAs or SGLT-2 inhibitors (for subjects not on SGLT-2 inhibitors at baseline) is 
not allowed during the entire trial, refer to Section 7.1. For subjects on SGLT-2 inhibitor treatment 
at baseline (capped at maximum 50% of subjects), dose modification of the SGLT-2 inhibitor is 
considered acceptable, however discontinuing SGLT-2 inhibitor treatment during the trial is 
discouraged, except for safety reasons; these subjects are allowed to re-initiate SGLT-2 inhibitor 
treatment following temporary termination, at the investigator’s discretion. For subjects on SGLT-2 
inhibitor treatment at baseline, treatment dose must be stable for at least 90 days prior to screening. 
It is recommended that the investigator ensures that subjects taking sulphonylurea or insulin 
perform adequately frequent blood glucose monitoring to ensure subject safety during trial product 
initiation and dose escalation. A reduction in the dose of sulphonylurea or insulin should be 
considered to reduce the risk of hypoglycaemia. 
To mitigate risk of hypoglycaemia, consider cautiously lowering the dose of insulin and 
sulphonylurea when initiating treatment and/or escalating dose of trial product. General 
recommendations in patients with high risk of hypoglycaemia, well controlled HbA1c (e.g. <8% 
[64 mmol/mol]) and/or advanced CKD (e.g. eGFR <45 mL/min/1.73 m2) are to reduce the insulin 
(basal and especially prandial) dose by approximately 20% or more, while 50% dose reduction or 
pausing of sulphonylurea may be considered. Exact dose reduction should be individualized at the 
investigator´s discretion. Close monitoring of blood glucose levels during initiation and dose 
escalation of trial product is important, with further adjustments as appropriate based on changes in 
blood glucose. 
The reduced dose of insulin/sulphonylurea should be maintained or gradually increased towards 
baseline doses during the titration period at the investigator´s discretion based on blood glucose 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
31
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
32 of 89 
 
 
measurements. Dose increase of concomitant anti-diabetic therapy should be commenced once 
target dose of the trial product has been reached to ensure optimal glycaemic control. 
6.5.3 
Data capture of concomitant medications 
For randomised subjects, the following medications (not including trial product) that the subject is 
receiving at the time of screening (V1) or receives during the trial must be recorded in eCRF: 
• medication to treat T2D  
• medication to treat CKD 
• medication to treat or prevent CV disease 
• medication administered in relation to AEs listed in Section 8.3 
The medication must be recorded in the eCRF along with dates of administration including start and 
stop dates or continuation and related AE number when applicable. For anti-hyperglycaemic 
medication, including SGLT-2 inhibitors if not administered as anti-hyperglycaemic medication, 
and for RAAS blocking agents (ACE inhibitors and ARBs), the total daily dose needs to be 
included in the eCRF.  
Changes in concomitant medication must be recorded at each visit. Dose changes (lasting 2 weeks 
or more) should be captured as a new concomitant medication with the new dose and relevant start 
and stop date. If a change is due to an AE or serious adverse event (SAE), then this must be 
reported according to Section 8.3. 
6.6 
Dose modification 
Not applicable for this trial. Refer to Section 6.1 for description of dose escalation. 
6.7 
Treatment after end of trial 
When discontinuing trial product at the end of treatment visit, the subject should be transferred to a 
suitable marketed product at the discretion of the investigator. Considering the long half-life of 
semaglutide and to avoid over-exposure to GLP-1 RA and interference with safety data collection, 
initiating GLP-1 RAs should be avoided between the end of treatment visit (V11) and the end of 
trial visit (V12). All other medications are allowed during the follow-up period, although it is 
discouraged that subjects who are not treated with an SGLT-2 inhibitor at screening also do not 
initiate SGLT-2 inhibitor treatment until after the end of trial visit (V12). 
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 the subjects who discontinue trial product attend the end of treatment 
visit (V11) as soon as possible, and the end of trial visit (V12) 5 weeks after last treatment. Subjects 
must be educated about the continued scientific importance of their data, even if they discontinue 
trial product early. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
32
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
33 of 89 
 
 
7.1 
Discontinuation of trial treatment 
The trial product must be discontinued, if any of the following applies for the subject: 
1. Safety concern as judged by the investigator 
2. Confirmation 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 triala 
6. Treatment with another GLP-1 RAb  
7. Treatment with an SGLT-2 inhibitor (applicable only for subjects not on SGLT-2 inhibitor 
treatment at baseline)b 
8. Treatment with finerenoneb 
9. Continuous treatment with systemic anti-inflammatory or immunosuppressant drugs >14 days. 
Stable treatment with acetylsalicylic acid for prevention of cardiovascular events and occasional 
use of propionic acid derivatives drugs (e.g. ibuprofen) is allowed.   
10. Continuous maintenance treatment of trial product with a dose lower than 0.5 mg.  
a. Simultaneous participation in a COVID-19 vaccine trial is allowed without discontinuing trial product. 
b. Initiation of GLP-1 RAs, SGLT-2 inhibitors and/or finerenone is not allowed in the trial. Subjects treated with GLP-1 
RAs, SGLT-2 inhibitors and/or finerenone for > 30 days will be discontinued from the trial and the V11 MRI and 
kidney biopsy should not be performed. Subjects treated with GLP-1 RAs, SGLT-2 inhibitors and/or finerenone for ≤30 
days must discontinue treatment with the disallowed medication, and the V11 MRI and kidney biopsy should only be 
performed if possible within the visit window and after washout (5 half-lives) of the disallowed medication. 
For subjects who are discontinued for any reason, a Novo Nordisk medical expert should be 
consulted to determine in collaboration with the investigator, whether the discontinuation will be 
permanent or temporary (see Section 7.1.1). Subjects who discontinue trial product permanently 
will be discontinued from the trial. 
As soon as possible after the decision to permanently discontinue trial product, the subject should 
attend the end of treatment visit (V11), followed by the end of trial visit (V12) 5 weeks after 
treatment discontinuation. A treatment discontinuation session must be made in the IWRS. The 
primary reason for discontinuation of trial product must be specified in the end of trial form in the 
eCRF, and final drug accountability must be performed.  
For subjects who discontinue before week 26 (V9), the end of treatment (V11) MRI scan and 
kidney biopsy should not be performed. Subjects who discontinue between V5 and V6 (both 
inclusive) should have the V6 MRI scan performed.  
If a patient intends to become pregnant, trial product must be discontinued at least 5 weeks before 
the contraceptive method is stopped. If a patient becomes pregnant unintentionally, trial product 
must be discontinued immediately during pregnancy and during breast feeding. 
If the subject does not wish to attend scheduled site visits, efforts should be made to have the 
remaining visits converted to phone contacts. If a subject is unwilling to attend any of the remaining 
visits, information about the attempts to follow up with the subject must be documented in the 
subject’s medical record. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
33
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
34 of 89 
 
 
7.1.1 
Temporary discontinuation of trial treatment 
If a subject has discontinued trial product temporarily, the guide for missed doses should be 
followed (Section 6.4). In such cases a treatment discontinuation session should not be made in the 
IWRS. 
In case of suspicion of acute pancreatitis, the trial product should promptly be interrupted. 
Treatment discontinuation session should not be made in IWRS before diagnosis of acute 
pancreatitis is confirmed.  
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 (V11) and the end of 
trial visit (V12). See the flowchart for data to be collected. For subjects who discontinue before 
week 26 (V9), the end of treatment (V11) MRI scan and kidney biopsy should not be performed. 
Subjects who discontinue between V5 and V6 (both inclusive) should have the V6 MRI scan 
performed.  
Final drug accountability must be performed even if the subject is not able to come to the site. A 
treatment discontinuation session must be made in the IWRS. 
If the subject withdraws consent, Novo Nordisk may retain and continue to use any data collected 
before such a withdrawal of consent. 
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 CRF. 
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 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
34
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
35 of 89 
 
 
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 Appendix 1 (10.1.3). 
• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all inclusion and randomisation criteria and none of the exclusion criteria. 
• The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
• At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant 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.  
• The investigator must ensure to keep regular contact with each subject throughout the entire 
trial, and always have updated contact information. Even if a visit is missed and it is not 
possible to reschedule, every effort to have all subjects followed for the primary endpoint and 
AEs must be made.  
• To secure optimal data quality and reduce risk of missing or repeating assessments, the 
investigator should remind the subjects of upcoming trial visits and requirements for these e.g. 
via a telephone call or a text message.  
• Review of laboratory reports, MRI scans and kidney biopsy reports (where applicable) must be 
documented either on the documents or in the subject's medical records.  
• Repeat samples may be taken for technical issues and unscheduled samples or assessments may 
be taken for safety reasons. Please refer to Appendix 2 (10.2) for further details on laboratory 
samples. 
• The investigator must confirm subject eligibility based on all inclusion and exclusion criteria 
assessed at the screening visit (V1) (including the eye examination) before the subject can 
attend the pre-treatment visit (V2). All V2 assessments must be evaluated before the subject can 
be randomised at V3. 
8.1 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart. 
8.1.1 
Magnetic resonance imaging 
The MRI scans will be performed at selected MRI units and images will be analysed by a 
centralised imaging core laboratory. For standardisation purposes the imaging core laboratory will 
train the MRI units as applicable, and the imaging core laboratory will do centralised blinded 
(blinded to treatment allocation) image analysis.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
35
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
36 of 89 
 
 
Information on the imaging processes and analysis will be described in the documents prepared by 
the imaging core laboratory. Results from the imaging analyses will be electronically transferred 
directly from the centralised imaging core laboratory to Novo Nordisk.  
To account for the impact of circadian rhythm, the three MRI scans should be performed at the 
same time of the day (± 2 hours). On the day of each MRI scan, the subject should have blood 
glucose measured and documented in the eCRF. Blood glucose should be measured shortly before 
the MRI scan, and the subject should avoid food and carbohydrate-containing beverages between 
the measurement of blood glucose and the MRI scan. If the first MRI scan at any visit does not pass 
quality control checks, an additional MRI scan should be performed once more only. The imaging 
site should use the same approved MR scanner for all scheduled MRI scans. 
An MRI scan should be performed for all subjects during the V2 pre-treatment period. A subject 
cannot be randomised without an acceptable MRI scan as judged by the centralised imaging core 
laboratory.  
The end of treatment MRI can be performed up to 28 days before V11 (if the subject has remained 
on trial product), or as soon as possible after treatment discontinuation. If trial product is 
permanently discontinued before V9 (week 26), the end of treatment MRI should not be performed. 
If the subject permanently discontinues treatment during week 3 (the week leading up to the V6 
(week 4) MRI assessment), a V6 MRI should be performed as soon as possible after treatment 
discontinuation.  
The investigator must ensure that a standard radiology assessment of the MR images is performed 
by a qualified radiologist. In case of any incidental findings, the investigator must assess if any 
adverse event reporting is required (please refer to Section 8.3). It is the responsibility of the 
investigator to refer the subject to further examination and treatment based on the incidental 
findings as medically indicated. Continued trial participation or discontinuation must be considered 
by the investigator.  
To calibrate the MRI, the imaging core laboratory will test the imaging protocol in healthy 
volunteers. This test will check the MRI settings and the quality of the images generated. Novo 
Nordisk will not have access to any data generated from the MRI examination on the healthy 
volunteers and these subjects are therefore not considered part of the trial. 
8.1.2 
Kidney biopsy 
The kidney biopsies will be performed in a subpopulation of subjects. The aim is for 45 subjects or 
more to have kidney biopsies performed.  
Kidney biopsies will be analysed for histopathology, morphometry and snRNAseq at a centralised 
kidney biopsy laboratory. 
All subjects in the biopsy subpopulation should have acceptable MRI acquisition before performing 
the kidney biopsy scheduled for the same visit. The end of treatment biopsy can be performed up to 
28 days before V11 (if the subject has remained on trial product), or as soon as possible after 
treatment discontinuation. If trial product is permanently discontinued before week 26 (V9), the 
kidney biopsy at V11 (week 52) should not be performed. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
36
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
37 of 89 
 
 
In case conclusive evaluation of pre-randomisation biopsy or end of treatment biopsy is not possible 
due to technical issues with the biopsy sample, the subject should not be asked to have another 
kidney biopsy performed. The investigator will be notified if a subject’s pre-treatment biopsy is not 
usable for subsequent analysis. These subjects should not undergo the V11 biopsy. 
The histopathologic assessment will be performed after processing of the kidney biopsy. A report 
based on the histopathological assessment will be send to the investigator. It is the responsibility of 
the investigator to inform the trial subject and to take appropriate action should the outcome of the 
report indicate a need for further examinations. In case of any incidental findings, the investigator 
must assess if any adverse event reporting is required (please refer to Section 8.3).  
Kidney samples will be stored until CTR, except for subjects who have consented to biobanking 
(see Appendix 6 [10.6]). 
8.1.2.1 
Requirements for the kidney biopsy  
Local site clinical practice procedures should be followed as the underlying basis for the kidney 
biopsy procedure and post-biopsy regimen. Tissue handling and transportation of the kidney biopsy 
will be described in a kidney biopsy manual. 
The below requirements are minimum requirements; in case of stricter requirements defined in local 
site procedures, the stricter requirements should be followed.  
(a) Requirements for the kidney biopsy operator 
Kidney biopsies must be performed at sites with extensive experience with this procedure and 
subsequent post-biopsy observation regimen. The kidney biopsy procedure must be performed by a 
highly experienced nephrologist or intervention radiologist.  
The biopsy operators must be credentialed (e.g. Licensed Independent Providers), and meet the 
following minimum requirements: 
• minimum experience of 35 kidney biopsies over a 2-year period within the past 5 years, with at 
least 25 kidney biopsies as the primary operator  
• an overall major complication rate (complications requiring acute or subacute intervention) of 
less than 10%, as assessed at the discretion of the operator’s institution 
(b) Pre-biopsy requirements 
In advance of the biopsy, the subject must fulfil the following minimum biochemical, imaging and 
clinical requirements. These must be documented in source data files. 
Biochemical requirements 
Biochemical requirements must be assessed locally in advance of the biopsy procedure and in 
accordance with local site clinical practice procedures. If the requirements are not immediately met, 
re-tests can be done in accordance with local site clinical practice procedures.  
The following minimum requirements must be met and documented: 
• Blood urea nitrogen ≤80 mg/dL (≤28.6 mmol/L) 
• eGFR (creatinine-based, according to CKD-EPI formula) ≥40 mL/min/1.73 m2 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
37
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
38 of 89 
 
 
• INR (international normalised ratio) ≤1.4 
• Haemoglobin (Hgb) ≥10 mg/dL (≥6.2 mmol/L) 
• Platelet count ≥100,000/µL 
• aPTT/PTT  ≤35 s 
• in WOCBP: negative pregnancy test  
Imaging requirements 
Imaging (ultrasound or CT scan) requirements must be assessed locally in advance of the biopsy 
procedure and in accordance with local site clinical practice procedures.  
The following minimum requirements must be met and documented: 
• 2 kidneys (i.e., subjects with single kidney are excluded from the trial) 
• Kidney cortex ≥1 cm (both kidneys) 
• Kidney length ≥8 cm (both kidneys) 
• Absence of any anatomical abnormalities that, at the operator’s discretion, would render the 
kidney biopsy unsafe 
Clinical requirements 
Clinical requirements must be assessed locally in advance of the biopsy procedure and in 
accordance with local site clinical practice procedures.  
The following minimum requirements must be met and documented: 
• No evidence of urinary tract infection  
• Systolic blood pressure ≤150 mmHg and diastolic blood pressure ≤100 mmHg on the day of the 
biopsy 
• Blood pressure lowering medication may be given to achieve required blood pressure at the 
clinical discretion of the investigator. 
• Absence of any disorder or condition that, at the operator’s discretion, would render the kidney 
biopsy unsafe 
• Fasting requirements, in accordance with local site clinical practice procedures. 
(c) Post-biopsy regimen and information 
Post-biopsy observation should be performed according to local site clinical practice procedures. 
The patient should be kept for on-site observation for at least 8 hours following the procedure.  
Local clinical practice procedures should specify the following: 
• Timing and frequency for monitoring of pulse, blood pressure and symptoms (including pain 
and swelling) 
• Timing for strict bedrest and mobilisation 
• Timing and frequency for testing of blood haemoglobin (and haematocrit, if tested) 
• Requirements for observation of post-biopsy void, including assessment for haematuria 
The biopsy site must have a setup in place for observation, monitoring and potential interventions 
for biopsy complications, including: 
• Kidney imaging  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
38
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
39 of 89 
 
 
• Consultation with a surgeon or interventional radiologist, in case haematuria, falling serum 
haemoglobin or other symptoms suggest a haematoma, 
• Embolization or surgical intervention in case of excessive bleeding 
Before discharge, subjects must receive instructions for home care according to local site clinical 
practice procedures. The instructions must include a telephone number to call for questions or to 
report new symptoms, as well as instructions not to lift heavy objects and to avoid strenuous 
activities after discharge. 
8.1.3 
Clinical efficacy laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (10.2), must be conducted 
in accordance with the flowchart and the laboratory manual. 
8.1.4 
Urine collection 
First morning void spot urine 
Subjects must collect first morning void urine samples in accordance with the flowchart. Urine must 
be collected in the containers which are to be provided at the previous visit. The investigator should 
remind the subject to collect first morning void samples e.g. via a telephone call or a text message.  
For the applicable visits, subjects must collect 2 first morning void samples: Two days before and 
on the day before the visit. For the screening visit (V1), subjects must also collect the first morning 
void sample on the day of the visit. 
If the subject has not collected the required first morning void urine samples, the subject must be 
asked to provide new samples (within the visit window) to replace the missed samples. 
On site random spot urine 
Subjects must collect on site random spot urine samples in accordance with the flowchart. Urine 
must be collected in a container, which will be provided at the applicable visit. The urine collection 
is independent of time of the day. 
24-hour urine 
Subjects must collect 24-hour urine samples in accordance with the flowchart. Urine must be 
collected in the container which is to be provided at the previous visit. The investigator should 
remind the subject to start collecting 24-hour urine e.g. via a telephone call or a text message. 
Subject must be instructed to keep the 24-hour urine samples refrigerated at home if possible, and 
cooled during transit to site in the provided cooler bag. 
The first morning void should be collected as described above. For the following 24 hours after the 
first void, all urine (including the first morning void of the following day) must be collected in the 
container. Collection of 24-hour urine should end on the day of the visit. 
If the subject has not collected the required 24-hour urine samples, the subject must be asked to 
provide a new 24-hour urine sample within the visit window. For the randomisation visit (V3), the 
first dose of trial medication must be postponed until 24-hour urine has been collected.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
39
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
40 of 89 
 
 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in the flowchart. Time period and 
frequency for collecting AEs and SAEs are described in Section 8.3.1. 
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. 
The following concomitant illness/medical history should be reported in the eCRF: 
• T2D including date of diagnosis 
• History of neuropathy 
• History of kidney disease  
• History of CV disease  
• History of eye diseases 
• History of pancreatitis 
• History of gallbladder diseases 
• History of neoplasms 
• Other relevant concomitant illness/medical history 
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.  
8.2.1 
Physical examinations 
A physical examination will include assessments of the  
• General appearance 
• Thyroid gland 
• Respiratory system 
• Cardiovascular system 
• Abdomen 
• Extremities 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Body measurements will also be measured and recorded as specified in the flowchart: 
• Height, without shoes 
• Body weight, without shoes and only wearing light clothing 
8.2.2 
Vital signs 
• Pulse, systolic and diastolic blood pressure will be assessed. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
subject in a quiet setting without distractions (e.g. no use of television, cell phones). 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
40
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
41 of 89 
 
 
• Blood pressure and pulse measurements will be assessed sitting with a completely automated 
device. Manual techniques must be used only if an automated device is not available. 
• Blood pressure will consist of 3 systolic and diastolic blood pressure measurements with 
intervals of at least 1–2 minutes. An additional fourth blood pressure measurement must be 
performed if the first two readings on systolic or diastolic blood pressure differ by >10 mmHg.  
• The mean systolic and diastolic blood pressure values are calculated based on the last 2 
systolic and diastolic blood pressure measurements, respectively. The mean pulse value is 
calculated based on the last 2 pulse measurements. 
• Record the last 2 systolic and the last 2 diastolic blood pressure measurements in the eCRF. 
The eCRF will calculate the mean of the last 2 systolic blood pressure measurements and the 
mean of the last 2 diastolic blood pressure measurements.  
• Pulse will be measured in connection to the blood pressure measurements.  
• Record the pulse for the last 2 blood pressure measurements in the eCRF. The eCRF will 
calculate the mean of the last 2 pulse measurements. 
8.2.3 
Eye examination 
Subjects with uncontrolled and potentially unstable diabetic retinopathy or maculopathy are not 
eligible as this indicates retinopathy that has recently progressed to a level that requires intervention 
or is approaching intervention but has yet to be brought under control.  
Results of an eye examination performed by an ophthalmologist or another suitably qualified health 
care provider (e.g. optometrist) must be available and evaluated by the investigator before V2 to 
assess eligibility. The eye examination should be performed as a fundus photography (e.g. 2-field 
60 degree or better, colour or red-free) or by slit-lamp biomicroscopy examination (e.g. using a pre-
corneal or corneal contact lens examination). Pharmacological pupil-dilation is a requirement unless 
using a digital fundus photography camera specified for non-dilated examination. 
If the subject had such an eye examination performed within 90 days prior to screening, the 
investigator may base his/her evaluation upon the results of that examination. The examination must 
be repeated before V2 if the subject has experienced worsening of visual function since the last 
examination. If the applicable eye examination was performed before the subject signed the 
informed consent form, it must be documented that the reason for performing the examination was 
not related to this trial. 
After V2, an eye examination performed according to above must be performed as per protocol 
flowchart. The investigator should indicate the outcome of each eye examination. Relevant findings 
prior to randomisation must be recorded as concomitant illness/medical history. Relevant findings 
occurring after randomisation should be reported only if it is an SAE, please refer to Section 8.3. 
8.2.4 
Self-measured plasma glucose 
Subjects will be provided with a BG meter including auxiliaries as well as instructions for use. The 
subjects will be instructed in how to use the device and this will be repeated as needed. The 
investigator will advise the individual subject of when the self-measured plasma glucose values 
should be measured at the discretion of the investigator. The measurements are meant to support the 
investigator’s treatment decisions when optimising glycaemic control.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
41
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
42 of 89 
 
 
8.2.5 
Clinical safety laboratory assessments 
All protocol-required laboratory assessments, as defined in Appendix 2 (10.2), must be conducted 
in accordance with the laboratory manual and the protocol flowchart. 
8.3 
Adverse events and serious adverse events 
The investigator is responsible for detecting, documenting, recording and following up on all the 
events listed below:  
• SAEs 
• AEs leading to discontinuation of trial product 
• Severe hypoglycaemic episodes 
• Selected types of AEs (SAEs and non-SAEs) requiring additional data collection (Table 8-1) 
The definition of AEs and SAEs can be found in Appendix 3 (10.3), along with a description of 
AEs requiring additional data collection. 
Some AEs require additional data collection on a specific event form. The relevant events are listed 
below in Table 8-1. 
Table 8-1 
AEs requiring additional data collection (serious and non-serious AEs) 
Event type  
AE requiring additional data collection 
Medication error 
Specific event form 
Misuse and abuse of IMP 
Specific event form 
Neoplasms (malignant and non-malignant) 
Specific event form 
A detailed description of the events mentioned in the above table can be found in Appendix 3 
(10.3). 
Severe hypoglycaemic episodes 
Severe hypoglycaemic episodes require data collection on a severe hypoglycaemic episode form. 
Non-serious severe hypoglycaemic episodes do not require an AE form to be filled in. If the severe 
hypoglycaemic episode fulfils the criteria for an SAE, then, in addition to the severe hypoglycaemic 
episode form, an AE form and a SIF must be filled in, please see Appendix 3 (10.3). 
For more information on severe hypoglycaemic episodes, please refer to Appendix 7 (10.7). 
Non-serious, non-severe hypoglycaemic episodes are not collected in this trial. 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All events specified in Section 8.3 (for events related to pregnancy, see Appendix 4 [10.4]) must be 
collected and reported. Events must be collected from the screening visit (V1) and until the end of 
trial visit (V12), at the time points specified in the flowchart.  
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 (10.3). All SAEs must be recorded and reported to Novo Nordisk 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
42
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
43 of 89 
 
 
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 (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 (10.3).  
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to Novo Nordisk 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, IRB/IEC, and investigators. This also includes 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 pregnancy outcome. 
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 
(10.4). 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
43
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
44 of 89 
 
 
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 (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 
There is no specific antidote for overdose with semaglutide. In the event of an overdose, appropriate 
supportive treatment should be initiated according to the subject´s clinical signs and symptoms. 
Overdoses of up to 4 mg in a single dose have been reported in clinical trials. The most commonly 
reported adverse reaction was nausea. All subjects recovered without complications. 
A prolonged period of observation and treatment for these symptoms may be necessary, taking into 
account the long half-life of semaglutide of approximately one week. 
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 (10.3) for further details 
In the event of an overdose, the investigator should closely monitor the subject for overdose-related 
AE/SAE. 
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 IB for OW semaglutide 
s.c. 
8.5 
Pharmacokinetics 
• Single blood samples for measuring plasma concentration of semaglutide will be drawn on 
visits specified in Appendix 2 (10.2) 
• The exact timing of obtaining the PK sample must be recorded on the laboratory form. In 
addition, dose details (date, time and dose) will be collected for the last 2 doses before each visit 
with PK samples. The investigator must ensure that the correct information is collected, e.g. by 
asking the subject to note the dosing details after injection, instructing the subject to dose at the 
same time each day, or by calling the subject on the planned day of dosing. 
• PK samples may be taken at any time in relation to trial product administration. 
• Blood samples for PK assessments must be collected, handled and shipped according to the 
description in the laboratory manual supplied by the central laboratory. The bioanalysis of 
semaglutide PK will be performed by a special laboratory. Semaglutide PK samples will be 
stored at the special laboratory responsible for PK until final CTR, in case Novo Nordisk 
requests further analysis of the PK samples. Details of the bioanalysis will be outlined in a 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
44
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
45 of 89 
 
 
bioanalytical study plan issued by the special laboratory. Bioanalysis of plasma samples for 
semaglutide will be carried out using a validated LC-MS/MS assay. 
8.6 
Pharmacodynamics 
Not applicable for this trial. 
8.7 
Genetics 
Not applicable for this trial. 
8.8 
Biomarkers 
Collection and storage of serum, plasma, urine and kidney tissue for future research (biobanking) is 
part of this trial. Participation in the biobank component is optional and requires separate informed 
consent. Subjects who do not wish to participate in the biobank component may still participate in 
the trial. For the biobank, samples will be collected according to the flowchart and stored for future 
analyses. 
Storage of kidney tissue is only applicable to subjects who consent to both kidney biopsy and 
biobanking. No additional biopsy will be performed, and no additional biopsy core will be acquired 
from the planned biopsies; only potential surplus kidney tissue sample will be stored. 
Sampling must be recorded in the CRF. The samples are collected for the purpose of allowing 
future analyses of biomarkers at a later point in time when new knowledge or improved 
measurement techniques may have become available. The analyses may include biomarkers 
currently known or discovered in the future.  
Analyses of biomarkers may include analysis of hormones, metabolites or other nongenetic markers 
with the purpose of understanding how semaglutide cardiometabolic parameters.  
Circulating and urinary samples need to be frozen and should be sent in batches to the central 
laboratory. The analyses are likely to be performed after the trial has come to an end, and results 
will therefore not be part of the CTR. The biobank samples may be stored up to 15 years after end 
of trial at secure central biorepositories. For further details on retention of human samples for 
subjects who consented to biobanking, see Appendix 6 (10.6).  
Clinical laboratory assessments for efficacy and safety are described in Sections 8.1.3 and 8.2.5, 
respectively. 
8.8.1 
RNA transcriptome research  
Tissue samples from the kidney biopsies will be used for snRNAseq.  
Kidney biopsies are described in Section 8.1.2.  
Information on the sequencing process will be described in the documents prepared by the kidney 
biopsy core laboratory.  
The analysis of snRNAseq data is described in Section 9.4.3.1 and in the bioinformatics analysis 
plan. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
45
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
46 of 89 
 
 
9 
Statistical considerations  
9.1 
Statistical hypotheses 
The trial is explorative, and no confirmatory hypothesis testing is planned. Analyses and p-values 
from statistical models are considered descriptive in nature. No adjustment for multiple testing will 
be performed, except separately in connection with analyses of gene expression data where methods 
for controlling false discovery rates will be applied as needed.  
9.2 
Sample size determination  
Due to the exploratory nature of this trial, the sample size has been determined in a more heuristic 
manner, by arguing that the trial would be able to detect changes in R2* that are considered 
clinically important. This sample size is also considered sufficient for the analyses of the remaining 
primary endpoints.  
Specifically, the trial is designed to have at least 80% marginal power to detect a relative treatment 
difference of 10% for R2* cortex and medulla, respectively, after 52 weeks treatment. This 
treatment difference is considered clinically relevant but is hypothetical, as no previous studies have 
assessed whether semaglutide changes renal tissue oxygenation. However, relative differences in 
R2* of this magnitude (~5-15%) have been observed in various intervention studies of short 
duration.24-26  
Limited data is available on the variation of R2* (cortex as well as medulla) in a diabetic CKD 
population. In a large trial in CKD patients, the CV for R2* cortex varied between 0.11 and 0.15 
depending on time of assessments, whereas the CV for R2* medulla varied between 0.09 and 
0.11.27 In the proposed analysis where baseline is included as a covariate the CV should be smaller. 
CVs of 0.09, 0.12, 0.15 have been examined in the power calculations seen below. The power 
calculation is for each endpoint based on a two-sided test at the 5% significance level, with no 
adjustment for multiplicity. 
Table 9-1 
R2* (cortex or medulla): Number of subjects with primary endpoint data needed 
to obtain 80% marginal power based on 2:1 randomisation 
CV 
Treatment ratio 
1.05 
1.10 
1.15 
0.09 
123 
36 
18 
0.12  
216 
60 
30 
0.15 
333 
90 
45 
There is no correction for multiplicity in the power calculation 
Hence, with a CV of e.g. 0.15 and 90 subjects with primary endpoint data, the trial will with 80% 
power be able to detect a treatment ratio of 1.10 corresponding to a relative treatment difference of 
10%, see Table 9-1. 
Based on “Multiparametric Renal Magnetic Resonance Imaging: Validation, Interventions, and 
Alterations in Chronic Kidney Disease”,28 the CV of global kidney perfusion is assumed to be 0.8, 
whereas the CV of T1 mapping is assumed to be 0.06 and 0.05 for cortex and medulla, respectively.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
46
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
47 of 89 
 
 
With data from 90 subjects, the detectable treatment ratio corresponding to 80% marginal power is 
then 1.56 for global kidney perfusion and 1.04 for T1 mapping (cortex as well as medulla). The 
expected treatment ratios between semaglutide and placebo are not known. However, in Cox et al, 
2017 28 the ratio of the estimated means in global cortical perfusion for healthy subjects versus 
CKD patients was approximately 2.8, whereas the ratio between the estimated means in T1 
mapping in CKD patients versus healthy subjects was approximately 1.09 (cortex) and 1.02 
(medulla). Hence, for two of the endpoints these treatment ratios are well above the detectable 
treatment ratios presented above. Due to the explorative nature of the trial, this is considered 
acceptable. 
Based on the above, 90 subjects with primary endpoint data is needed.  Assuming approximately 
15% of randomised subjects will have missing data (mainly due to treatment discontinuation prior 
to the week 39 visit (V10)), 105 subjects will be randomly assigned to trial product. 
9.3 
Populations for analyses 
The following populations are defined: 
Population 
Description 
Randomised 
All subjects randomised. 
Full analysis set (FAS) 
All subjects randomly assigned to trial treatment and who take at least 1 dose of trial 
product. 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 
treatment they actually received.  
Safety analysis set (SAS) 
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. 
Analyses of efficacy endpoints will be analysed based on the full analysis set and safety will be 
analysed based on the safety analysis set.  
9.4 
Statistical analyses 
The first draft of the statistical analysis plan (SAP) will be finalised prior to first subject first visit 
(FSFV), and it will include a more technical and detailed description of the statistical analyses 
described in this section. Any changes will be documented in the change-log. 
This section provides a description of the planned statistical analyses of the primary endpoints and a 
short summary of the analyses of gene-expression data. All analyses of gene-expression data will be 
described in detail in a separate bioinformatics analysis plan prepared by Bioinformatics & Data 
Mining, Novo Nordisk, which will be finalised prior to database lock. 
9.4.1 
General considerations 
The comparison presented from a statistical analysis will be semaglutide versus placebo. 
The randomisation is stratified by use of SGLT-2 inhibitors at baseline (yes/no), MRI field strength 
(1.5/3.0 T), as well as whether subjects participate in the biopsy subpopulation (yes/no). 
Stratification for biopsy subpopulation is done purely for administrative reasons, to balance the 
subpopulation treatment allocation and not because subpopulation membership is expected to be 
associated with the outcome. Accordingly, it will not be accounted for in the statistical analyses.29 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
47
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
48 of 89 
 
 
When the term ‘stratification’ factor is applied it refers to use of SGLT-2 inhibitors at baseline 
(yes/no) and MRI field strength (1.5/3.0 T). 
9.4.2 
Primary endpoints 
The primary endpoints are derived from the MRI scan. They are defined as the ratio of baseline to 
week 52 in:  
• kidney oxygenation (cortex), R2* (no unit) 
• kidney oxygenation (medulla), R2* (no unit) 
• global kidney perfusion (no unit) 
• kidney inflammation (cortex), T1 mapping (no unit)  
• kidney inflammation (medulla), T1 mapping (no unit) 
Primary analysis, if all subjects had adhered to the randomised treatment, without initiation 
of disallowed medication 
The aim of the analysis is for each of the endpoints to estimate the treatment ratio between 
semaglutide and placebo after 52 weeks of treatment if all subjects had adhered to the randomised 
treatment of semaglutide/placebo, without initiation of disallowed medication.    
The following intercurrent events are considered: 
• Permanent discontinuations of treatment prior to the week 39 visit:  
• When subjects discontinue treatment, the end of treatment visit (V11) will be scheduled as 
soon as possible thereafter. Unless subjects have discontinued treatment prior to the week 26 
visit (V9), the MRI scan and biopsy will be performed. However, data collected for subjects 
who discontinue treatment prior to the week 39 visit (V10) will not be applied in the 
analysis. For this intercurrent event a hypothetical strategy is applied, and data will be 
imputed as described below. 
• Permanent discontinuation of treatment at or after the week 39 visit: 
• Data collected after this intercurrent event will be used in the analysis as week 52 
assessments. 
• Maintenance treatment at 0.5 mg or 1 mg semaglutide/placebo is not reached: 
• A continued maintenance treatment at the 0.25 mg semaglutide/placebo is not allowed. 
Subjects who cannot tolerate a dose of at least 0.5 mg as a maintenance dose should 
discontinue treatment and data will be handled as described above.  
• Initiation of GLP-1 RA, SGLT-2 inhibitor (only for subjects not on SGLT-2 at baseline) and/or 
finerenone: 
• Initiation of GLP-1 RAs, SGLT-2 inhibitors and/or finerenone is not allowed. Data collected 
after these intercurrent events from subjects that fulfil discontinuation criteria 6, 7, or 8 will 
not be used in the analysis, regardless of continued trial participation.  
• Discontinuation or change of dose of SGLT-2 inhibitors (only for subjects on SGLT-2 inhibitors 
at baseline): 
• Discontinuation of SGLT-2 inhibitors is discouraged unless due to safety reasons. Change of 
dose of SGLT-2 inhibitors is allowed during the trial, because this is expected to have little 
effect on the MRI and biopsy endpoints. Therefore, data collected after these intercurrent 
events will be applied in the analysis.  
Change from baseline analyses will be done on log scale based on the FAS. The log treatment 
differences will be back transformed in order to obtain treatment ratios for reporting. Imputation of 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
48
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
49 of 89 
 
 
missing data (either truly missing or omitted from analysis due to the hypothetical strategy) will be 
handled by multiple imputations assuming that the missing data are missing at random (MAR). 
Missing data will be imputed using observed data within the same actual treatment group. It is 
thereby assumed that the likely values of what the missing data would have been if available are 
best described by information from subjects who receive the same actual treatment. 
A sequential regression approach for imputing missing values at planned visits will be implemented 
for each endpoint starting with V6 and continuing to the planned end of treatment visit at week 52 
(V11). For each actual treatment group an analysis of covariance (ANCOVA) model will be used to 
impute missing values at the planned post-baseline visits. The model will include region and 
stratification factors as categorical effects and baseline and, (when applicable) the post-baseline 
value prior to the visit in question as covariates. A total of 500 copies of the dataset will be 
generated. 
An ANCOVA with actual treatment, region and the stratification factors as categorical effects and 
the endpoint baseline value as a covariate will for each endpoint be used to estimate the treatment 
difference on the log scale at week 52 for each of the 500 complete data sets generated as part of the 
imputation of missing values. Rubin’s rule will be used to combine the estimates, which will then 
be backtransformed in order to draw inference on the relative scale.  
The estimated treatment ratio between semaglutide and placebo will be presented together with the 
associated two-sided 95% confidence interval and a two-sided p-value. Due to the explorative 
nature of the trial, no adjustment for multiplicity is made. 
Sensitivity analysis, delta-adjustment 
The aim of the analysis is to assess the sensitivity of results to the missing at random assumption. 
The analysis address if discontinued subject had adhered to the treatment regimen but would have 
responded less favourably than adherent subjects. 
The delta adjustment analysis is based on the FAS. In this analysis, subjects from the semaglutide 
group with missing observations will be given a penalty (a delta value), i.e., it is assumed that 
subjects with missing observations who are treated with semaglutide will have less favourable 
outcomes than subjects with observed values who are treated with semaglutide.  
The 500 complete datasets created for the primary analysis will be re-used for the delta adjustment 
analysis. For each of these datasets, a penalty is added to the imputed log-change from baseline at 
week 52 for subjects with actual treatment semaglutide, followed by performing the ANCOVA 
applied for the primary analysis. A range of penalties will be applied to assess the impact on the 
results. 
Additional analysis, while on treatment after week 26 if all subjects had adhered to the 
randomised treatment at least until week 26, without initiation of disallowed medication 
The aim of the analysis is to estimate the treatment ratio between semaglutide and placebo while on 
treatment after week 26 if all subjects had adhered to the randomised treatment at least until week 
26, without initiation of disallowed medication. 
The following intercurrent events are considered: 
• Permanent discontinuations of treatment prior to the week 26 visit (V9):  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
49
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
50 of 89 
 
 
• For subjects who discontinue treatment prior to the week 26 data, the final MRI scan and 
biopsy will not be performed. For this intercurrent event a hypothetical strategy is applied, 
and data will be imputed from the ‘while-on treatment after week 26’ values. 
• Permanent discontinuation of treatment at or after the week 26 visit: 
• Data collected after this intercurrent event will be used in the analysis. A while on treatment 
strategy is applied. 
• Maintenance treatment at 0.5 mg or 1 mg semaglutide/placebo is not reached: 
• A continued maintenance treatment at the 0.25 mg semaglutide/placebo is not allowed. 
Subjects who cannot tolerate a dose of at least 0.5 mg as a maintenance dose should 
discontinue treatment and data will be handled as described above.  
• Initiation of GLP-1 RA, SGLT-2 inhibitor (only for subjects not on SGLT-2 at baseline) and/or 
finerenone: 
• As for the primary analysis, data collected after these intercurrent events from subjects that 
fulfil discontinuation criteria 6, 7, or 8 will not be used in the analysis, regardless of 
continued trial participation. 
• Discontinuation or change of dose of SGLT-2 inhibitors (only for subjects on SGLT-2 inhibitors 
at baseline): 
• As for the primary analysis, data collected after these intercurrent events will be applied in 
the analysis.  
The analysis will, as the primary analysis, be done on log scale based on the FAS. The imputation 
of missing values will be further described in the SAP.   
9.4.3 
Secondary endpoints 
9.4.3.1 
Supportive secondary endpoints 
Relative change in gene expression as fold change from kidney biopsy generated snRNAseq 
A secondary endpoint is the fold change values derived from the changes in the gene expression 
within relevant cell types comparing different conditions. In order to achieve this, first, a 
dimensionality reduction and clustering of the abundance data will be performed. Annotation of 
clusters will be done manually or via a state-of-the-art classification tool. In order to accurately 
annotate cell types and ensure comparability with existing studies, available data sets will be 
compared (or integrated) with the REMODEL data. After successful annotation of cell types, 
differences in cell type composition between placebo and semaglutide can be explored using 
differential abundance testing. For all cell types of interest, changes in gene expression within that 
cell type but between the different comparisons can be explored. In order to test for significance, 
state-of-the-art methods accounting for sample variation (pseudo-bulk, linear mixed models) will be 
used. Subsequent analysis could include trajectory inference and analysis of gene dynamics. 
All analyses of the single nucleus RNA sequencing of cells from the kidney biopsies will be 
described in detail in the bioinformatics analysis plan. 
Remaining supportive secondary endpoints 
For details on the analyses of all other supportive endpoints, please refer to the SAP. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
50
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
51 of 89 
 
 
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. The standard safety assessments (AEs, 
safety laboratory parameters, vital signs, etc.) will be reported descriptively; including any notable 
changes of clinical interest in laboratory parameters. 
9.4.6 
Other analyses 
The primary endpoints may be affected by differences in blood glucose. Exploratory analyses will 
therefore be performed to evaluate the association between the pre-scan plasma glucose levels and 
the primary endpoints. 
For other analyses, please refer to the SAP.  
9.4.6.1 
Pharmacokinetic and/or pharmacodynamic modelling 
PK modelling based on the data from the current trial may be carried out, e.g. as a joint analysis of 
PK data from multiple trials. Other exploratory PK/PD and exposure-response analyses for this trial 
may be performed if deemed relevant. If PK and/or PK/PD modelling is performed, it will be 
carried out by Quantitative Clinical Pharmacology, Novo Nordisk, and the results will be reported 
separately from the CTR.  
Individual drug concentration data will be tabulated in the CTR. 
9.5 
Interim analyses  
No interim analysis is planned for this trial. 
9.6 
Data monitoring committee  
Not applicable for this trial. 
9.7 
Reporting of the main part of the trial 
Not applicable for this trial. 
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: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki30 and applicable ICH Good Clinical Practice (GCP) 
Guideline31 
o Applicable laws and regulations  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
51
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
52 of 89 
 
 
• The analysis of kidney biopsies (snRNAseq and histopathology assessments), which are solely 
analysed by laboratories at Michigan University, are exploratory in nature, and hence not 
considered fully GCP-applicable. The rights, safety and well-being of the subject will be 
protected, and data integrity will be assured. 
o The lab responsible for snRNAseq is heading the NIH-funded (National Institute of 
Health) KPMP (kidney precision medicine project). 
o The lab responsible for the histopathology assessments is CLIA-certified (Clinical 
Laboratory Improvement Act) and CAP-accredited (College of American 
Pathologists). 
• 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: 
o providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities 
o notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
o ensuring submission of the CTR synopsis to the IRB/IEC 
o 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. 
For US sites: Verification under disclosures per Code of Federal Regulations (CFR) of Financial 
Conflict of Interest. 
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.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
52
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
53 of 89 
 
 
• 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.  
• Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines31, Declaration of Helsinki30 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. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
53
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
54 of 89 
 
 
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. 
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),32 the Food and Drug Administration Amendment 
Act (FDAAA),33 European Commission Requirements1, 34, 35 and other relevant recommendations or 
regulations. If a subject requests to be included in the trial via the Novo Nordisk e-mail contact at 
these web sites, Novo Nordisk may disclose the investigator’s contact details to the subject. As a 
result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The PCD is the last assessment of the primary endpoint, and is for this trial last subject first 
treatment (LSFT) + 52 weeks corresponding to visit 11. If the last subject is withdrawn early, the 
PCD is considered the date when the last subject would have completed the end of treatment visit 
(V11). 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 electronic CRFs unless transmitted 
electronically to Novo Nordisk or designee (e.g. laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing the 
CRF.  
• The following will be provided as paper CRFs: 
o Pregnancy forms 
• The following will be provided as paper CRFs to be used when access to the CRF is revoked or 
the CRF is temporarily unavailable:  
o AE forms  
o Safety information forms 
o 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 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
54
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
55 of 89 
 
 
• 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 CRF must be verifiable in source documentation other than the CRF. 
• If source data is entered directly in a paper CRF, each data entry or clear series of data entries 
must be signed and dated separately by the trial staff making the entry. 
• 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.  
• It must be possible to verify subject’s medical history in source documents, such as subject’s 
medical record. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
55
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
56 of 89 
 
 
• 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, electronic CRF (eCRF) and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems 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. 
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. 
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 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
56
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
57 of 89 
 
 
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. This also 
includes ensuring that no indirect sharing of user credentials for IT systems used in this study takes 
place (e.g., by not sharing IT equipment with others in a way where user credentials have the 
possibility of being shared). 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.  
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. 
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. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
57
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
58 of 89 
 
 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One or more investigator will be appointed by Novo Nordisk to review and sign the CTR (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.36 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
58
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
59 of 89 
 
 
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. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
59
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
60 of 89 
 
 
10.2 
Appendix 2: Clinical laboratory tests 
• The tests in Table 10-1 and Table 10-2 will be performed by the central laboratory with the 
exception of F2-isoprostanes per unit creatinine and semaglutide plasma concentration, which 
will be performed by the special laboratory, and urine pregnancy tests, which will be performed 
locally (at trial sites or at home). 
• Descriptions of laboratory supplies and procedures for obtaining, handling and transportation of 
samples will be available in the laboratory manual provided to sites. 
• 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.  
o For subjects who consent to biobanking, human biosamples for future research will 
be stored as described in Appendix 6 (10.6). 
• Laboratory results that could unblind the trial (e.g. PK data) will not be reported to the trial sites 
until the trial has been unblinded.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
60
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
61 of 89 
 
 
Table 10-1 
Protocol-required efficacy laboratory assessments 
Laboratory 
assessments 
Parameters 
Visit 
Renal function 
Serum/plasma:  
• Creatinine 
• Creatinine-based eGFR, calculated per CKD-EPI equation 
• Cystatin C 
• Cystatin C-based eGFR, calculated per CKD-EPI equation 
V1, V3, V4, V6, V8, V9, 
V10, V11, V12 
 
First morning void spot urine:  
• Urinary albumin-to-creatinine ratio (UACR) 
UACR: 
V1, V3, V4, V6, V8, V9, 
V10, V11, V12 
On site random spot urine: 
• Sodium and fractional sodium excretion 
Sodium and fractional 
sodium excretion: 
V3, V6, V8, V11 
24-hour urine:  
• Volume 
• Creatinine clearance 
• Albumin excretion rate 
• Sodium excretion rate 
• pH 
V3, V6, V8, V11 
Biomarkers 
Serum/plasma:  
Inflammation: 
• High-sensitivity C-reactive Protein (hs-CRP) 
• Interleukin 6 (IL-6) 
• Soluble Tumour Necrosis Factor Receptor-1 (sTNFR1) 
• Soluble Tumour Necrosis Factor Receptor-2 (sTNFR2) 
• Tumour Necrosis Factor Alpha (TNF-α) 
• uric acid 
Renal injury: 
• Fibrinogen 
On site random spot urine: 
Inflammation: 
• Monocyte Chemoattractant Protein-1 (MCP-1) 
Renal injury: 
• Kidney Injury Molecule-1 (KIM-1) 
• Neutrophil Gelatinase-associated Lipocalin (NGAL) 
Oxidative stress:  
• F2-isoprostanes per unit creatinine 
• 8-oxo-2’-deoxyguanosine (8-OHdG) 
hs-CRP: 
V1, V3, V4, V6, V8, V9, 
V10, V11, V12 
 
All other biomarkers 
(serum/plasma and on site 
random spot urine): 
V3, V6, V8, V11 
Glucose 
metabolism  
• HbA1c 
V1, V3, V4, V6, V8, V9, 
V10, V11, V12 
Lipids 
• Cholesterol 
• HDL cholesterol 
• LDL cholesterol 
• Triglycerides 
V3, V6, V8, V11 
Pharmacokinetics 
• Semaglutide plasma concentrations  
V6, V8, V9, V11 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
61
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
62 of 89 
 
 
Table 10-2 
Protocol-required safety laboratory assessments 
Laboratory 
assessments 
Parameters 
Visit 
Haematology 
• Haemoglobin 
• Haematocrit  
V3, V6, V8, V11 
Biochemistry 
• Albumin 
• Potassium 
• Sodium 
• Calcium 
• Albumin-corrected calcium 
• Urea 
• Bicarbonate 
V3, V6, V8, V11 
Pregnancy Testing 
• Highly sensitive serum or urine human chorionic 
gonadotropin (hCG) pregnancy test (as needed for 
WOCBP)a 
V1, V3, V11, V12 
a. Local urine testing will be standard unless serum testing is required by local regulation or IRB/IEC. 
WOCBP: woman of child-bearing potential.
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
62
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
63 of 89 
 
 
10.3 
Appendix 3: Adverse events: Definitions and procedures for recording, evaluation, 
follow-up, and reporting 
10.3.1 
Definition of AE 
AE definition 
An AE is any untoward medical occurrence in a clinical trial subject that is temporally associated 
with the use of an investigational medicinal product (IMP), whether or not considered related to 
the IMP. 
An AE can therefore be any unfavourable and unintended sign, including an abnormal laboratory 
finding, symptom or disease (new or exacerbated) temporally associated with the use of an IMP. 
 
Events meeting the AE definition 
• Any abnormal laboratory test results or safety assessments considered clinically significant in 
the medical and scientific judgment of the investigator, including events that have worsened 
from prior to the time point from which AEs are collected 
• Conditions detected or diagnosed after IMP administration even though it may have been 
present prior to the time point from which AEs are collected  
• Exacerbation/worsening of a chronic or intermittent condition including either an increase in 
frequency and/or intensity of the condition 
• Signs, symptoms or the clinical sequelae of a suspected drug-drug interaction 
• Signs, symptoms or the clinical sequelae of a suspected overdose of IMP regardless of intent 
 
A "lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE 
if they fulfil the definition. 
Events NOT meeting the AE definition  
• Conditions present prior to the time point from which AEs are collected and anticipated day-to-
day fluctuations of these conditions, including those identified during screening or other trial 
procedures performed before exposure to IMP.  
Note: Conditions present or occurring prior to the time point from which AEs are collected 
should be recorded as concomitant illness/medical history. 
• Medical or surgical procedures (e.g. endoscopy, appendectomy). The condition that leads to the 
procedure is the AE. 
• Medical or surgical procedures not preceded by an AE or worsening of a known condition. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
63
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
64 of 89 
 
 
10.3.2 
Definition of an SAE 
An SAE is an AE that fulfils at least one of the following criteria: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalisation or prolongation of existing hospitalisation 
• Hospitalisation signifies that the subject has been detained at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the physician’s office 
or outpatient setting. Complications that occur during hospitalisation are AEs. If a complication 
prolongs hospitalisation or fulfils any other seriousness criteria, the event is serious. When in 
doubt as to whether “hospitalisation” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalisation for elective treatment (e.g. elective medical or surgical procedures) of a 
condition that was present prior to the time point from which AEs are collected, and that did 
not worsen, is not considered an AE. 
Note:  
• Hospitalisations for administrative, trial related, social and convenience reasons do not 
constitute AEs and should therefore not be reported as AEs or SAEs.  
• Hospital admissions for medical or surgical procedures, planned before trial inclusion, are not 
considered AEs or SAEs.  
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experience of relatively minor medical significance, 
such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, and accidental trauma 
(e.g. sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical event: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations. This includes important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may jeopardise the subject 
or may require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definition. These events should usually be considered serious and reported as SAEs 
using the important medical event criterion. 
• The following adverse events must always be reported as SAEs using the important medical 
event criterion if no other seriousness criteria are applicable: 
o Suspicion of transmission of infectious agents via the IMP  
o Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x UNL and total bilirubin >2 x UNL where no 
alternative aetiology exists (Hy's law). Please see the box ‘Follow-up of an AE 
and SAE’ in Section 10.3.4. 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
64
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
65 of 89 
 
 
10.3.3 
Description of AEs requiring additional data collection  
Description of AEs requiring additional data collection (on specific event form)  
Adverse events requiring additional data collection 
AEs requiring additional data collection on a specific event form are listed in Table 8-1.  
Medication error 
A medication error is an unintended failure in the IMP treatment process that leads to, or has the 
potential to lead to, harm to the subject, such as:  
• administration of wrong drug:  
Note: Use of wrong DUN is not considered a medication error unless it results in 
administration of wrong drug.  
• wrong route of administration, such as intramuscular instead of subcutaneous  
• accidental administration of a lower or higher dose than intended. The administered dose 
must deviate from the intended dose to an extent where clinical consequences for the trial 
subject were likely to happen as judged by the investigator, although they did not necessarily 
occur. 
Misuse and abuse  
• Situations where the IMP is intentionally and inappropriately used not in accordance with the 
protocol (e.g. overdose to maximise effect) 
• Persistent or sporadic, intentional excessive use of an IMP which is accompanied by harmful 
physical or psychological effects (e.g. overdose with the intention to cause harm) 
Medication error, misuse and abuse must always be reported as an AE (e.g. accidental overdose, 
intentional overdose or other) on a separate AE form, and a medication error, misuse and abuse 
form must be completed. In case of a medication error and/or misuse and abuse resulting in a 
clinical consequence, this must be reported on an additional AE form. 
Neoplasms (malignant and non-malignant)  
• All confirmed neoplasms (both malignant and non-malignant) by histology or other 
substantial clinical evidence 
 
10.3.4 
Recording and follow-up of AE and/or SAE 
AE and SAE recording 
• SAEs and AEs listed in Section 8.3 and AEs/SAEs in connection with pregnancies, must be 
recorded by the investigator in the CRF. The investigator will attempt to establish a diagnosis 
of the event based on signs, symptoms, and/or other clinical information. In such cases, the 
diagnosis (not the individual signs/symptoms) will be documented as the AE/SAE.  
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory and diagnostics reports) related to the 
event. 
• There may be instances when copies of source documents (e.g. medical records) for certain 
cases are requested by Novo Nordisk. In such cases, all subject identifiers, with the exception 
of the subject number, will be redacted on the copies of the source documents before 
submission to Novo Nordisk. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
65
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
66 of 89 
 
 
• For all non-serious AEs, the applicable forms should be signed when the event is resolved or at 
the end of the trial at the latest. For sign-off of SAE related forms, refer to “AE and SAE 
reporting via paper CRF” later in this section. 
• Novo Nordisk products used as concomitant medication: if an AE is considered to have a 
causal relationship with a Novo Nordisk marketed product used as concomitant medication in 
the trial, it is important that the suspected relationship is reported to Novo Nordisk, e.g. in the 
alternative aetiology section on the safety information form. Novo Nordisk may need to report 
this adverse event to relevant regulatory authorities. 
 
Assessment of severity 
The investigator will assess severity for each event reported during the trial and assign it to one of 
the following categories:  
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not 
interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities.  
Note: An AE that is assessed as severe should not be confused with an SAE. Both AEs and 
SAEs can be assessed as severe.  
 
Assessment of causality 
• The investigator is obligated to assess the relationship between IMP and the occurrence of each 
AE/SAE. 
• Relationship between an AE/SAE and the relevant IMP(s) should be assessed as:  
o Probable - Good reason and sufficient documentation to assume a causal 
relationship. 
o Possible - A causal relationship is conceivable and cannot be dismissed. 
o Unlikely - The event is most likely related to aetiology other than the IMP. 
• Alternative aetiology, such as underlying disease(s), concomitant medication, and other risk 
factors, as well as the temporal relationship of the event to IMP administration, will be 
considered and investigated. 
• The investigator should use the investigator’s brochure for the assessment. For each AE/SAE, 
the investigator must document in the medical records that he/she has reviewed the AE/SAE 
and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report. However, it is important that the investigator 
always makes an assessment of causality for every event before the initial transmission of 
the SAE data. 
• The investigator may change his/her opinion of causality, in light of follow-up information, 
and update the causality assessment in the CRF. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
66
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
67 of 89 
 
 
Final outcome 
The investigator will select the most appropriate outcome: 
• Recovered/resolved: The subject has fully recovered, or by medical or surgical treatment the 
condition has returned to the level observed when first documented 
• Recovering/resolving: The condition is improving, and the subject is expected to recover from 
the event. This term may be applicable in cases of chronic conditions, cancer or AEs ongoing 
at time of death (where death is due to another AE).  
Note: For SAEs, this term is only applicable if the subject has completed the follow-up period 
and is expected to recover. 
• Recovered/resolved with sequelae: The subject has recovered from the condition but with 
lasting effect due to a disease, injury, treatment or procedure. If a sequela meets an SAE 
criterion, the AE must be reported as an SAE. 
• Not recovered/not resolved: The condition of the subject has not improved, and the symptoms 
are unchanged, or the outcome is not known.  
Note: This term may be applicable in cases of chronic conditions, cancer or AEs ongoing at 
time of death (where death is due to another AE).  
• Fatal: This term is only applicable if the subject died from a condition related to the reported 
AE. Outcomes of other reported AEs in a subject before he/she died should be assessed as 
“recovered/resolved”, “recovering/resolving”, “recovered/resolved with sequelae” or “not 
recovered/not resolved”. An AE with a fatal outcome must be reported as an SAE. 
• Unknown: This term is only applicable if the subject is lost to follow-up. 
 
Follow-up of AE and SAE 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Novo Nordisk to elucidate the nature 
and/or causality of the AE or SAE as fully as possible (e.g. severe hypersensitivity reactions or 
Hy’s law. Please see seriousness criteria f). This may include additional laboratory tests (e.g. skin 
prick test) or investigations, histopathological examinations, or consultation with other health 
care professionals. 
If a subject dies during participation in the trial or during a recognised follow-up period, the 
investigator should provide Novo Nordisk with a copy of autopsy report including 
histopathology. 
New or updated information will be recorded in the CRF. 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
67
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
68 of 89 
 
 
10.3.5 
Reporting of SAEs 
SAE reporting via electronic CRF 
• Relevant forms (AE and safety information form) must be completed in the CRF.  
• For reporting and sign-off timelines, see Figure 10-1 below. 
• If the CRF is unavailable for more than 24 hours, then the site will use the paper AE form, and 
if the CRF is unavailable for more than 5 calendar days, then the site will use the safety 
information form (see box below). 
• The site will enter the SAE data into the CRF as soon as it becomes available. 
• After the trial is completed, the trial database will be locked, and the CRF will be 
decommissioned to prevent the entry of new data or changes to existing data. If a site receives 
a report of a new SAE from a subject or receives updated data on a previously reported SAE 
after CRF decommission, then the site can report this information on a paper AE and safety 
information form (see box below) or to Novo Nordisk by telephone. 
 
AE and SAE reporting via paper CRF 
• Relevant CRF forms (AE and safety information form) must be forwarded to Novo Nordisk in 
accordance with Section 10.1.5. 
• For SAEs, initial notification via telephone is acceptable, although it does not replace the need 
for the investigator to complete the AE and safety information form within the designated 
reporting timelines (as illustrated in the figure below): 
o AE form within 24 hours 
o Safety information form within 5 calendar days 
o Both forms must be signed within 7 calendar days after first knowledge by the 
investigator. 
• The specific event form for AEs requiring additional data collection within 14 calendar days  
Figure 10-1 Decision tree for determining the event type and the respective forms to 
complete with associated timelines 
AE identified
AE form       hours
SIF     calendar days
Sign off     calendar days
Is the AE serious, or 
non-serious
Is the AE leading to 
discontinuation of trial 
product or listed in table 8-1?
Does the AE require 
additional data 
collection?
Non-serious
Serious
Specific event form
(For SAE:      calendar days)
Yes
• 
Timelines are from the awareness of an AE.
• 
Queries and follow-up requests to be resolved      calendar 
days.
• 
Non-serious AEs with additional data collection: In general data 
must be recorded in the CRF as soon as possible, preferably 
within 5 working days (see Appendix 1).
AE: Adverse Events, SAE: Serious Adverse Events, SIF: Safety 
Information Form, CRF: case report form
AE Form
No additional 
action
No
Yes
No
 
Contact details for SAE reporting can be found in the investigator trial master file. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
68
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
69 of 89 
 
 
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 
11. 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 HRT) if they have both: 
o Amenorrhoea and 
o 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 10-3: 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
69
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
70 of 89 
 
 
Table 10-3 
Highly effective contraceptive methods 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL INCLUDE: 
Highly effective methodsb, d that have low user dependency: 
• Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS)b 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is 
the sole sexual partner of the woman of childbearing potential, and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
 
Highly effective methodsb,d that are user dependent: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
o oral 
o intravaginal 
o transdermal 
o injectable 
• Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the trial treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial 
and the preferred and usual lifestyle of the subject. 
NOTES 
a) Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for those participating in clinical trials. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates 
differ from those when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary 
mode of action. 
d) Contraception should be utilised during the treatment period and for at least 35 days 
(corresponding to time needed to eliminate trial product) after the last dose of trial product.  
In certain cases, it is accepted to use double barrier methods (a condom combined with an occlusive 
cap (e.g. diaphragm) with/without the use of spermicide). This should only be allowed in females 
with: 
• known intolerance to the highly effective methods mentioned in Table 10-3 or where the use of 
any of the listed highly effective contraceptive measures are contraindicated in the individual 
subject, and/or 
• if the risk of initiating treatment with a specific highly effective method outweighs the benefit for 
the female. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
70
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
71 of 89 
 
 
Justification for accepting double barrier method should be at the discretion of the investigator 
taking into consideration his/her knowledge about the female’s medical history, concomitant illness, 
concomitant medication and observed AEs. The justification must be stated in the medical records. 
Pregnancy testing 
• Additional pregnancy testing should be performed during the treatment period, if required 
locally (Appendix 9 [10.9]). 
• WOCBP should only be included after a negative highly sensitive urine pregnancy test (refer to 
Appendix 2 [10.2]). 
• A pregnancy test should be performed at the end of relevant systemic exposure (refer to 
Appendix 2 [10.2]). 
• Pregnancy testing should be performed whenever a menstruation is missed or when pregnancy 
is otherwise suspected. 
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 
Appendix 3 (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.  
• In case of abnormal pregnancy outcome, the male partner will be asked to sign a specific 
informed consent form for further collection of paternal information 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
71
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
72 of 89 
 
 
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
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
72
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
73 of 89 
 
 
10.5 
Appendix 5: Technical complaints: Definition and procedures for recording, 
evaluation, follow-up and reporting 
10.5.1 
Definition of technical complaint 
Technical complaint definition  
A technical complaint is any written, electronic or oral communication that alleges product 
(medicine or device) defects. The technical complaint may be associated with an AE but does not 
concern the AE itself. 
Examples of technical complaints: 
• Problems with the physical or chemical appearance of trial products (e.g. discoloration, particles 
or contamination) 
• Problems with packaging material including labelling 
• Problems related to devices (e.g. to the injection mechanism, dose setting mechanism, push 
button or interface between the pen-injector and the needle) 
Time period for detecting technical complaints  
All technical complaints which occur from the time of receipt of the product at site until the time 
of the last usage of the product must be collected for products predefined on the technical 
complaint form.  
10.5.2 
Recording and follow-up of technical complaints 
Reporting of technical complaints to Novo Nordisk 
Contact details for Customer Complaint Center, please refer to Attachment I. 
Technical complaints must be reported on a separate technical complaint form: 
1. One technical complaint form must be completed for each affected DUN. 
2. If DUN is not available, a technical complaint form for each batch, code or lot number must be 
completed. 
 
Timelines for reporting of technical complaints to Novo Nordisk 
The investigator must complete the technical complaint form in the CRF within: 
• 24 hours if related to an SAE 
• 5 days calendar for all other technical complaints  
If the CRF is unavailable, or when reporting a technical complaint on a trial product that is not 
yet allocated to subject, the information must be provided on a paper form to Customer 
Complaint Center, Novo Nordisk, within the same timelines as stated above. When the CRF 
becomes available again, the investigator must enter the information on the technical complaint 
form in the CRF. 
 
Follow-up of technical complaints  
The investigator is responsible for ensuring that new or updated information will be recorded on 
the originally completed form. 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
73
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
74 of 89 
 
 
Collection, storage and shipment of technical complaint samples 
The investigator must collect the technical complaint sample and all associated parts that were 
packed in the same DUN and notify the monitor within 5 calendar days of obtaining the sample at 
site. The sample and all associated parts must be sent as soon as possible to Customer Complaint 
Center, Novo Nordisk, together with a copy of the completed technical complaint form. The 
technical complaint sample should contain the batch, code or lot number and, if available, the 
DUN. If the technical complaint sample is unobtainable, the reason must be stated on the 
technical complaint form. If several samples are shipped in one shipment, the sample and the 
corresponding technical complaint form should be kept together. 
Storage of the technical complaint sample must be done in accordance with the conditions 
prescribed for the product.  
10.5.3 
Reporting of technical complaints 
Reporting of technical complaints for Novo Nordisk products not included in technical 
complaint form 
Technical complaints on Novo Nordisk products not included in the technical complaint form 
should be reported to local Novo Nordisk. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
74
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
75 of 89 
 
 
10.6 
Appendix 6: Retention of human biosamples 
For patients who consent, the trial will involve collection of human biosamples to be stored in 
central archives for future use as noted in Section 8.8. The following samples will be stored: 
• Plasma (for future analyses of circulating biomarkers) 
• Serum (for future analyses of circulating biomarkers) 
• Urine (for future analyses of urinary biomarkers) 
• Kidney tissue (applicable to subjects who consent to both kidney biopsy and biobanking). No 
additional biopsy will be performed, and no additional biopsy core will be acquired from the 
planned biopsies; only potential surplus kidney tissue sample will be stored. 
As new biomarkers related to the disease and/or safety, efficacy or mechanism of action of 
semaglutide within T2D and CKD may evolve during the conduct of the trial, the analyses of the 
stored biosamples may also include biomarkers that are unknown at present or have not been 
included in the scientific hypotheses at initiation of the trial. 
The samples will be transferred and stored at a secure central biorepository after end of trial and 
until the research project terminates, but no longer than 15 years from end of trial after which they 
will be destroyed. Only Novo Nordisk staff and biorepository personnel will have access to the 
stored samples. 
Subjects may withdraw from the biobank component of the trial at any time, independent of 
participation in the trial. The subject can choose to do so at any given time while in the trial or after 
the end of the trial. If a subject withdraws from the biobank component, all of the subject’s stored 
biosamples will be destroyed. 
Confidentiality and personal data protection will be ensured during storage after the end of trial. 
The subject’s identity will remain confidential and the samples will be identified only by subject 
number, visit number, and trial identification number. No direct identification of the subject will be 
stored together with the samples. 
In the event that the collected biosamples will be used in the future, the investigator will become 
directly informed by Novo Nordisk about the results, if the findings are deemed clinically relevant 
and analytically valid and quantifiable. In such case, a written summary of the findings, including 
listings of subject specific values, will be provided once a firm conclusion from the results has been 
drawn by Novo Nordisk. Potentially, observations of neoplastic diseases, serious hereditary 
diseases, other un-treatable diseases or any other abnormal findings could be part of the 
observations.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
75
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
76 of 89 
 
 
10.7 
Appendix 7: Severe hypoglycaemic episodes 
Only severe hypoglycaemic episodes are to be collected in this trial. 
Severe hypoglycaemia 
Severe hypoglycaemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be 
available during an event, but neurological recovery following the return of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
concentration.37 
Nocturnal hypoglycaemia 
Nocturnal hypoglycaemic episodes: episodes occurring between 00:01 and 05:59 both inclusive. 
Reporting of severe hypoglycaemic episodes   
Reporting of severe hypoglycaemic episodes by BG meters: 
Plasma glucose (PG) should always be recorded in the eCRF when a severe hypoglycaemic episode 
is suspected.  
If the severe hypoglycaemic episode fulfils the criteria for an SAE then, an AE form and a safety 
information form must also be filled in. One AE form and safety information form can cover 
several hypoglycaemic episode forms, if the subject has not recovered between the episodes, see 
Section 8.3. 
Upon onset of a hypoglycaemic episode the subject is recommended to measure PG every 15 
minutes until the PG value is ≥3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in 
accordance with current guidelines.37 
Repeated PG measurements and/or symptoms will by default be considered as one hypoglycaemic 
episode until a succeeding PG value is ≥3.9 mmol/L (70 mg/dL) and/or symptoms have been 
resolved and should be reported as only one hypoglycaemic episode. In case of several low PG 
values within the hypoglycaemic episode, the lowest value is the one that will be reported as the PG 
value for the hypoglycaemic episode, but the start time of the episode will remain as the time for the 
first low PG value and/or symptom. The remaining values will be kept as source data. 
 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
76
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
77 of 89 
 
 
10.8 
Appendix 8: Mitigations to ensure subject safety and data integrity during 
epidemics/pandemics (e.g. COVID-19) 
In case local restrictions due to COVID-19 lead to lockdown of a site, the investigator must contact 
the sponsor (Novo Nordisk) to allow for implementation of the mitigations mentioned in this 
appendix based on mutual agreement.  
The assessments listed in Table 10-4 indicate the minimum requirements that should be performed 
during a lockdown, although investigators should always aim to follow the assessments outlined in 
the protocol flowchart to the extent possible. Implementation of specific mitigations should be 
based on a feasibility assessment at the individual site. 
If local regulations, requirements and/or guidelines have been issued, these must be complied with. 
10.8.1 
Site visits 
• The information visit (Visit 0), screening visit (Visit 1) and randomisation (Visit 3) must always 
be performed as physical on-site visits. If a site is unable to perform these visits on-site, 
screening and randomisation of new subjects at that site should be on hold until on-site visits 
can be conducted. 
• Visit including MRI scans (Visit 2, 6 and 11) and kidney biopsies (Visit 2 and 11) (relevant for 
the biopsy sub-population only) should always be performed as physical on-site visits at 
respective imaging and biopsy sites. 
• Efforts to assess and collect as much data as possible to the flowchart must always be ensured. 
Visit 4, 8, 9, 10 and 12 can however be converted to phone visits, if deemed necessary because 
of the lockdown. Minimum requirements for assessments during a phone visit are shown in 
Table 10-4. Visit 5 and 7 are already phone visits as per protocol. 
• At each visit the investigator must indicate in the eCRF how the visit was performed and specify 
the reason for the preferred assessment method. 
10.8.2 
Assessments 
• Assessments used for the primary and supportive secondary endpoints (i.e. MRI scans, kidney 
biopsies, first morning void spot urine, and 24-hour urine) should be prioritised.  
• First morning void spot urine and 24-hour urine can be shipped to the site if on-site visits are not 
possible. The site is responsible for contracting a suitable courier and costs will be reimbursed 
by Novo Nordisk. It must be documented in medical records that the subject has consented to 
this process, and, if required locally, the subject might have to sign a separate informed consent 
form. 
• Local laboratories or diagnostic facilities can be used for safety laboratory assessments if on-site 
visits cannot be conducted or in case of temporary lockdown of the central laboratory. Such data 
should not be entered in the eCRF. 
10.8.3 
Alternative dispensing methods of trial product 
Alternative dispensing methods of study intervention may be implemented, and details will be 
communicated and documented. The dispensing options will eb based on options and requirements 
at country level and if permitted by local regulations and Novo Nordisk A/S. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
77
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
      
Date: 
21 April 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN9535-4662 
      
Version: 
3.0 
Page: 
78 of 89 
 
 
10.8.4 
Minimum assessments to be performed during lockdown 
Table 10-4 
Minimum requirements that should be performed during a lockdown 
Please see Section 1.2 for the full flowchart. Procedures marked with a black X should be prioritised. If deemed necessary because of the lockdown, procedures marked with a red □ can be 
cancelled and Visit 4, 8, 9, 10 and 12 can be fully converted to phone visits. 
Procedure 
Information 
Screening 
Pre-treatment 
period 
Randomisation 
Treatment period 
End of 
treatment 
End of trial 
 Visit number 
V0 
V1 
V2 
V3 
V4 
P5 
V6 
P7 
V8 
V9 
V10 
V11 
V12 
 Timing of Visit (Weeks) 
Minimum 3 days 
prior to V1 
Prior to V2 and up to 
6 weeks prior to V3 
Up to 5 weeks 
prior to V3 
0 
1 
2 
4 
8 
12 
26 
39 
52 
End of 
treatment + 5 
weeks 
 Visit Window (Days) 
 
 
- 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7c 
+7 
Informed consent and demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation criteria and randomisation 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant illness/medical history  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Tobacco and nicotine products use 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Childbearing potential 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
 
X 
 
X 
 
 
 
 
 
 
 
X 
X 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Height 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Body weight 
 
 
 
X 
 
 
X 
 
□ 
□ 
□ 
X 
□ 
Blood pressure 
 
X 
 
X 
□ 
 
X 
 
□ 
□ 
□ 
X 
□ 
Pulse 
 
X 
 
X 
□ 
 
X 
 
□ 
□ 
□ 
X 
□ 
Eye examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
VV-TMF-5179642|1.0|NN9535 -NN9535-4662
  Protocol  v3.0|78 of 89

Protocol 
      
Date: 
21 April 2022 
Status: 
Final 
Novo Nordisk 
Trial ID: NN9535-4662 
      
Version: 
3.0 
Page: 
79 of 89 
 
 
Procedure 
Information 
Screening 
Pre-treatment 
period 
Randomisation 
Treatment period 
End of 
treatment 
End of trial 
 Visit number 
V0 
V1 
V2 
V3 
V4 
P5 
V6 
P7 
V8 
V9 
V10 
V11 
V12 
 Timing of Visit (Weeks) 
Minimum 3 days 
prior to V1 
Prior to V2 and up to 
6 weeks prior to V3 
Up to 5 weeks 
prior to V3 
0 
1 
2 
4 
8 
12 
26 
39 
52 
End of 
treatment + 5 
weeks 
 Visit Window (Days) 
 
 
- 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7c 
+7 
MRI Scan 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Kidney biopsy 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
Laboratory assessments 
 
X 
 
X 
□ 
 
X 
 
□ 
□ 
□ 
X 
□ 
24-hour urine collection 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
First morning void collection 
 
X 
 
X 
□ 
 
X 
 
□ 
□ 
□ 
X 
□ 
On site random spot urine collection 
 
 
 
X 
 
 
X 
 
□ 
 
 
X 
 
Biosamples for future analysis 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
Adverse event 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Severe hypoglycaemic episodes 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug dispensing 
 
 
 
X 
 
 
X 
  
Xa 
Xa 
Xa 
 
 
Attend visit following dietary requirements 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
Training in devices 
 
 
 
X 
 
 
X 
 
 
□ 
 
 
 
a. Trial product could if possible be dispensed via alternative methods listed in Section 10.8.3. 
VV-TMF-5179642|1.0|NN9535 -NN9535-4662
  Protocol  v3.0|79 of 89

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
80 of 89 
 
 
10.9 
Appendix 9: Country-specific requirements  
Canada 
• Appendix 1, Section 10 (10.1.10): Part C, Division 5 of the Food and Drug Regulations 
[C.05.012] requires a 25 year retention period 
Denmark 
• Section 5.2, exclusion criterion 3; and Appendix 4 (Section 10.4): Contraceptive measures 
considered adequate include highly effective contraceptive methods in accordance with the 
CTFG: Recommendations related to contraception and pregnancy testing in clinical studies. 
This means use of double barrier methods is not applicable for Denmark. 
• Appendix 1 (Section 10.1.5), Data protection: The participant must be informed about 
his/her privacy rights, including that his/her personal study-related data will be used by 
Novo Nordisk in accordance with local data protection law in the given country of data 
handling. 
France 
• Appendix 1, Section 13 (10.1.13): The French Public Health Code article L 1121-10 (law 
n° 2004-806 of 9 August 2004 art. 88 I,IX, Journal Officiel of 11 August 2004. "The sponsor is 
responsible for identification of the harmful consequences of the biomedical the research for the 
person lending himself thereto and for indemnification of his beneficiaries, except in case of 
proof, incumbent on it, that the prejudice is not attributable to his fault or the fault of any 
intervening party, without the sponsor's being entitled to call on acts by a third party or the 
voluntary withdrawal of the person who had initially consented to cooperating in the research." 
• Collection of age is needed for the calculation of eGFR per CDK-EPI.38 
• Collection of race and ethnic origin will not be collected in the eCRF. This will only be 
recorded in the central laboratory requisition form for eGFR calculation. 
Poland 
• Section 5.2, exclusion criteria 3; and Appendix 4 (10.4): Contraceptive measures according to 
the EU CTFG guideline.39 This means use of double barrier methods is not applicable for 
Poland.  
• Indemnity statement: Novo Nordisk carries liability for the Trial exclusively in the scope 
defined by the applicable laws and in particular by the Civil Code and the Pharmaceutical Law 
dated 6 September 2001 (uniform version Journal of Laws of 2008 No. 45 item 271 with 
amendments). In order to support potential claims for liability attributable to the Trial, Novo 
Nordisk and Investigator are covered by the Insurance Policy issued according to applicable 
Polish law.  
Spain 
• Section 5.2, exclusion criteria 3; and Appendix 4 (10.4): Contraceptive measures according to 
the EU CTFG guideline.39 
• Appendix 1, Section 10 (10.1.10): 25 years according to the Spanish Royal Decree 1090/2015. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
80
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
81 of 89 
 
 
USA 
• Section 8.2.3 (eye examinations): Funduscopy/fundusphotography will be performed by the 
investigator or a local ophthalmologist/optometrist according to local practice 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
81
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
82 of 89 
 
 
10.10 Appendix 10: Abbreviations  
ACE 
angiotensin-converting enzyme 
ADC 
apparent diffusion coefficient  
AE 
adverse event 
ANCOVA 
analysis of covariance 
aPTT/PTT 
activated prothromboplastin time / thromboplastin time 
ARB 
angiotensin II receptor blockers 
BG 
blood glucose 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CTFG 
Clinical Trial Facilitation Group  
CTR 
clinical trial report 
CVOT 
cardiovascular outcome trial 
DFU 
directions for use 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
eCRF 
electronic case report form 
ESKD 
end stage kidney disease 
FAS 
full analysis set 
FDA 
U.S. Food and Drug Administration 
FDAAA 
FDA Amendments Act 
GLP-1 
glucagon-like peptide 1 
GLP-1 RA 
glucagon-like peptide 1 receptor agonist 
HbA1c 
glycated haemoglobin 
HDL 
high-density lipoprotein 
HRT 
hormone replacement therapy 
hsCRP 
high-sensitivity C-reactive protein 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IRB 
institutional review board 
IWRS 
interactive web response system 
LDL 
low-density lipoprotein 
LSLV 
last subject last visit 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
82
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
83 of 89 
 
 
MACE 
major adverse cardiovascular event 
MCP-1 
monocyte chemoattractant protein 1 (also known as CCL2) 
MOA 
mode of action 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NSAID 
nonsteroidal anti-inflammatory drug 
OW 
once-weekly 
PCD 
primary completion date 
PG 
plasma glucose 
RAAS 
renin-angiotensin-aldosterone system 
RARI 
renal artery resistive index  
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SGLT-2 
sodium glucose cotransporter-2 
snRNAseq 
single nucleus RNA sequencing 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
SUSTAIN 
Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes 
TMM 
trial materials manual 
T2D 
type 2 diabetes 
WOCBP 
woman of child-bearing potential 
 
 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
83
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
84 of 89 
 
 
10.11 Appendix 11: Protocol amendment history 
The Protocol amendment summary of changes table for the current protocol version is located 
directly before the table of contents. 
Protocol version 2.0, including version 1: (29 January 2021), global 
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: 
To align minimum requirements for the kidney biopsy sites, kidney biopsy procedure and sponsor 
oversight. In addition, randomisation criterion no. 5 was added to ensure stable dose of RAAS 
blocking agent between screening and randomisation. Changes to the content of the protocol are 
presented in the table below. 
To increase consistency and clarity, semantic changes were introduced in Sections 1.2, 5.3.1, 6.1, 
6.3, 7.1, 8.2.1, 8.8, 8.8.1, and in Appendix 6. 
Section # and name 
Description of change 
Brief rationale 
Section 1.1 Synopsis 
Small changes to key inclusion and 
exclusion criteria, and minor editorial 
changes 
To align wording with eligibility criteria 
in section 5.1 and 5.2; and for clarity. 
Section 1.2 Flowchart 
Included X for concomitant medication at 
V1 
To align with text in Section 6.5 
Section 2.3.1 Risk 
assessment 
Addition of ‘angioedema’ to ‘Allergic 
reactions’ in Table 2-1 
The template text for the benefit-risk 
section for protocols has been updated 
with angioedema for trials with OW 
semaglutide 
Section 5.1 Inclusion 
criteria 
Definition of ‘screening UACR’ moved 
from Section 6.3 to this section, from 6.3 
To define screening UACR where it is 
most applicable. 
Section 5.2 Exclusion 
criteria 
1. Reference added to the additional 
exclusion criteria specific for the 
biopsy subpopulation 
2. Criteria 15 corrected 
3. Criteria 22 corrected 
1. To align minimum requirements for 
the biopsy subpopulation across 
sites 
2. To align with timing of the eye 
examination specified in the 
flowchart and in Section 8.2.3 
3. To align SGLT-2i requirements with 
Section 4.2 
Section 5.2.1 Biopsy 
subpopulation exclusion 
criteria 
Entire section 5.2.1 added. 
To align minimum safety requirements 
for subjects enrolled in the kidney biopsy 
subpopulation across all sites. 
Section 5.4 
Correction of which screening criteria can 
be re-screened. 
To align incorrect numbers with the 
correctly written text 
Section 5.5 Randomisation 
criteria 
Added criterion no 5 regarding stable dose 
of RAAS blocking agent 
To ensure subject is on stable treatment 
of RAAS blocking agent between 
screening and randomisation.  
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
84
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
85 of 89 
 
 
Section # and name 
Description of change 
Brief rationale 
Section 6.5 Concomitant 
medication 
Section restructured and split into sub-
sections. The following text was added: 
1. Clarify that RAAS blocking agent 
must be kept stable between 
‘screening and randomisation’ 
2. Correct the number of days subjects can 
be treated with systemic anti-
inflammatory drugs 
3. Recommendations on dose reductions 
of sulphonylurea and insulin when 
initiating treatment with trial product. 
For clarity 
1. To align with the new randomisation 
criterion no 5. 
2. To align with section 7.1 
3. To reduce the risk of hypoglycaemia 
is subjects treated with 
sulphonylurea or insulin. 
Section 8.1.1 Magnetic 
resonance imaging 
1. Text on where to find information on 
MRI setup, conduct, analysis and 
archiving updated 
2. Details added on plasma glucose 
measurement before MRI 
3. Update to description of subjects 
discontinuing during week 3. 
4. Explanation on medical reading of 
MRI updated 
5. Text about informed consent form for 
MRI test person removed 
1. To clarify that information on 
imaging processes and analysis can 
be found in more than 2 documents 
2. To clarify where to document the 
glucose measurement, and to 
describe dietary requirements 
3. To improve clarity 
4. To ensure medical reading of MRI 
and reporting of potential SAEs 
5. To correct a mistake (not all MRI 
sites will have this informed consent 
form) 
Section 8.1.2 Kidney 
biopsy 
New section (including 3 sub-sections) 
added to describe: 
• minimum requirements for the kidney 
biopsy operator 
• minimum biochemical, imaging and 
clinical requirements that subjects must 
fulfil in advance of the biopsy 
• minimum requirements for the post-
biopsy regimen and information to be 
provided to subjects 
Text regarding requirements for kidney 
biopsy operator moved to new section 
8.1.2.1.1. In addition, minor editorial 
changes to text. 
To align minimum safety requirements 
for the kidney biopsy across all sites, and 
to improve readability of document 
Section 8.1.4 Urine 
collection 
Text added to ensure subject is instructed 
to keep 24-hour urine samples refrigerated 
at home and cooled during transit to site 
To increase reliability of pH assessment 
of urine samples 
Appendix 1 Regulatory, 
ethical and trial oversight 
Section 10.1.12 
Responsibilities 
Text added to clarify investigator’s 
responsibilities with regards to confidential 
information on shared IT equipment 
To reduce the risk of unauthorised access 
to subject’s confidential information.  
Appendix 2 Clinical 
laboratory tests 
Table 10-1 Protocol-
required efficacy 
laboratory assessments 
Update of visit numbers for assessments of 
UACR, sodium and fractional sodium 
excretion. 
Correction, to align with planned 
assessments. According to the flowchart, 
first morning void (for UACR 
assessment) was to be collected at V4, 
but this was not correctly listed in 
Appendix 2. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
85
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
86 of 89 
 
 
Section # and name 
Description of change 
Brief rationale 
Appendix 7 Severe 
hypoglycaemic episodes 
Text added on reporting of severe 
hypoglycaemic episodes 
To clarify reporting requirements 
Appendix 8 Mitigations to 
ensure subject safety and 
data integrity in the case of 
a local or country-wide 
COVID-19 lockdown 
Appendix added. The content of this 
memo was previously included in a memo, 
finalised in September 2020. 
To ensure transparent and consistent 
handling of mitigations for COVID-19 
pandemic 
Appendix 9 Country-
specific requirements 
Removed requirements for Denmark 
 
No sites from Denmark are planned to be 
included in REMODEL. 
 
Appendix 10 
Abbreviations 
New abbreviations included 
Maintain readability of the document 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
86
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
87 of 89 
 
 
 
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. 
Novo Nordisk A/S. Ozempic®(semaglutide), US prescribing Information (PI). January 
2020. 
3. 
Novo Nordisk A/S. Ozempic® (semaglutide), EU Summary of Product Characteristics 
(SmPC). 2018. 
4. 
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 
2016;375(19):1834-44. 
5. 
Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, et al. Kidney 
disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24(2):302-
8. 
6. 
National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 
2012 Update. Am J Kidney Dis. 2012;60(5):850-86. 
7. 
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. 
Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 
2019. 
8. 
Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and 
Possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-45. 
9. 
Tuttle K, Lakshmanan M, Rayner B, Busch R, Zimmermann A, Woodward D, et al. 
Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe 
chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet 
Diabetes Endocrinol. 2018;6(8):605-17. 
10. 
Mann JF, Buse J, Idorn T, Leiter LA, Pratley RE, Rasmussen S, et al. Renoprotection with 
Semaglutide and Liraglutide: Direct or Indirect  Effects? [Abstract]. J Am Soc Nephrol; 
2019. p. 102. 
11. 
Rodbard HW, Rosenstock J, Canani LH, Deerochanawong C, Gumprecht J, Lindberg S, et 
al. Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled 
on Metformin: The PIONEER 2 Trial. Diabetes Care. 2019;42(12):2272-81. 
12. 
Rakipovski G, Rolin B, Nøhr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 
Analogs Liraglutide and Semaglutide Reduce Atherosclerosis in ApoE−/− and LDLr−/− 
Mice by a Mechanism That Includes Inflammatory Pathways. JACC Basic Transl Sci. 
2018;3(6):844-57. 
13. 
Skov J, Pedersen M, Holst JJ, Madsen B, Goetze JP, Rittig S, et al. Short-term effects of 
liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized 
clinical trial. Diabetes Obes Metab. 2016;18(6):581-9. 
14. 
Skov J, Dejgaard A, Frøkiær J, Holst JJ, Jonassen T, Rittig S, et al. Glucagon-like peptide-1 
(GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in 
healthy men. J Clin Endocrinol Metab. 2013;98(4):E664-71. 
15. 
Asmar A, Simonsen L, Asmar M, Madsbad S, Holst JJ, Frandsen E, et al. Renal extraction 
and acute effects of glucagon-like peptide-1 on central and renal hemodynamics in healthy 
men. Am J Physiol Endocrinol Metab. 2015;308(8):E641-9. 
16. 
Muskiet MH, Tonneijck L, Smits MM, Kramer MH, Diamant M, Joles JA, et al. Acute renal 
haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy 
overweight men. Diabetes Obes Metab. 2016;18(2):178-85. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
87
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
88 of 89 
 
 
 
17. 
von Scholten BJ, Persson F, Rosenlund S, Hovind P, Faber J, Hansen TW, et al. The effect 
of liraglutide on renal function: A randomized clinical trial. Diabetes Obes Metab. 
2017;19(2):239-47. 
18. 
Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, et al. 
GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev 
Nephrol. 2017;13(10):605-28. 
19. 
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 
2016;375(19):1834-44. 
20. 
Pichler R, Afkarian M, Dieter BP, Tuttle KR. Immunity and inflammation in diabetic kidney 
disease: translating mechanisms to biomarkers and treatment targets. Am J Physiol Renal 
Physiol. 2017;312(4):F716-F31. 
21. 
Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, et al. The 
Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical 
Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics. Am J 
Nephrol. 2017;46(6):462-72. 
22. 
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. 
Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 
2016;375(4):323-34. 
23. 
Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, et al. 
Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 
diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-
REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 
2017;5(8):610-21. 
24. 
Pruijm M, Hofmann L, Maillard M, Tremblay S, Glatz N, Wuerzner G, et al. Effect of 
sodium loading/depletion on renal oxygenation in young normotensive and hypertensive 
men. Hypertension. 2010;55(5):1116-22. 
25. 
Pruijm M, Hofmann L, Charollais-Thoenig J, Forni V, Maillard M, Coristine A, et al. Effect 
of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy 
volunteers. Clin Nephrol. 2013;80(3):211-7. 
26. 
Pruijm M, Hofmann L, Piskunowicz M, Muller ME, Zweiacker C, Bassi I, et al. 
Determinants of renal tissue oxygenation as measured with BOLD-MRI in chronic kidney 
disease and hypertension in humans. PLoS One. 2014;9(4):e95895. 
27. 
Pruijm M, Milani B, Pivin E, Podhajska A, Vogt B, Stuber M, et al. Reduced cortical 
oxygenation predicts a progressive decline of renal function in patients with chronic kidney 
disease. Kidney Int. 2018;93(4):932-40. 
28. 
Cox EF, Buchanan CE, Bradley CR, Prestwich B, Mahmoud H, Taal M, et al. 
Multiparametric Renal Magnetic Resonance Imaging: Validation, Interventions, and 
Alterations in Chronic Kidney Disease. Front Physiol. 2017;8:696. 
29. 
European Medicines Agency. Guideline on adjustment for baseline covariates in 
clinical  trials ( EMA/CHMP/295050/2013). 26 Feb 2015. 
30. 
World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects. Last amended by the 64th WMA General Assembly, 
Fortaleza, Brazil. October 2013. 
31. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
32. 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial 
registration: a statement from the International Committee of Medical Journal Editors. N 
Engl J Med. 2004;351(12):1250-1. 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
88
 .
-
 |
1
 |
CONFIDENTIAL

Protocol 
CONFIDENTIAL 
Date: 
21 April 2022 Novo Nordisk 
Trial ID: NN9535-4662 
Version: 
3.0 
     
Status: 
Final 
     
Page: 
89 of 89 
 
 
 
33. 
U.S. Department of Health and Human Services, Food and Drug Administration. Food and 
Drug Administration Amendments Act of 2007 as amended by the Final Rule "Clinical 
Trials Registration and Results Information Submission". 21 September 2016. 
34. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
726/2004 of the European Parliament and of the Council of 31 March 2004 laying down 
Community procedures for the authorisation and supervision of medicinal products for 
human and veterinary use and establishing a European Medicines Agency, article 57. 30 
April 2004. 
35. 
The European Parliament and the Council of the European Council. Regulation (EC) No 
1901/2006 of the European Parliament and of the Council of 12 December 2006 on 
medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, 
Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004, article 41. 
Official Journal of the European Communities. 27 Dec 2006. 
36. 
International Committee of Medical Journal Editors. Recommendations for the Conduct, 
Reporting, Editing and Publication of Scholarly Work in Medical Journals; current version 
available at www.icmje.org. 
37. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia 
and diabetes: a report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95. 
38. 
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. 
Kidney Int Suppl. 2013;3(1):1-150. 
39. 
Clinical Trial Facilitation Group (CTFG), Heads of Medicines Agencies. Recommendations 
related to contraception and pregnancy testing in clinical trials. 15 Sep 2014. 
 
 Protocol  v3.0
NN9535-4662
NN9535
0
 |
VV-TMF-5179642
89
 of
89
 .
-
 |
1
 |
CONFIDENTIAL