Clinical trial NCT03819153
Conditions: Diabetes Mellitus, Type 2
Sponsor: Novo Nordisk A/S
Start date: 2019-06-17; Completion date: 2024-01-09
Enrollment: 3533 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The researchers are doing this study to see if semaglutide can slow down the growth and worsening of chronic kidney disease in people with type 2 diabetes. Participants will get semaglutide (active medicine) or placebo ('dummy medicine'). This is known as participants' study medicine - which treatment participants get is decided by chance. Semaglutide is a medicine, doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine in a skin fold once a week. The study will close when there is enough information collected to show clear result of the study. The total time participants will be in this study is about 3 to 5 years, but it could be longer.

Detailed description:

Arms: arm 1: Participants are to receive semglutide for up to 5 years or more (event driven). The trial is event driven with a pre-defined minimum number of renal endpoint events for the primary endpoint. arm 2: Participants are to receive placebo (semglutide) for up to 5 years or more (event driven). The trial is event driven with a pre-defined minimum number of renal endpoint events for the primary endpoint.
Interventions: intervention 1: Semaglutide intervention 2: Placebo (semaglutide)
Intervention descriptions: intervention 1: Participants are to inject semaglutide with a needle in the stomach, thigh or upper arm. Participants will use a pen to inject semaglutide under their skin. Participants will inject semaglutide 1 time a week on the same day of the week. Participants' dose of semaglutide will be changed over time. Participants start by taking a smaller amount (0.25 mg). After 4 weeks the dose will be increased to 0.5 mg. It will be increased more (to 1 mg) at 8 weeks. Participants will then stay on the same dose for the rest of the study. intervention 2: Participants are to inject placebo (semaglutide) with a needle in the stomach, thigh or upper arm. Participants will use a pen to inject placebo (semaglutide) under their skin. Participants will inject placebo (semaglutide) 1 time a week on the same day of the week. Participants' dose of placebo (semaglutide) will be changed over time. Participants start by taking a smaller amount (0.25 mg). After 4 weeks the dose will be increased to 0.5 mg. It will be increased more (to 1 mg) at 8 weeks. Participants will then stay on the same dose for the rest of the study.

Protocol documents:
Prot_000.pdf: 
Cover Page for Protocol 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03819153 
Sponsor trial ID: 
NN9535-4321 
Official title of study: 
FLOW – Effect of Semaglutide versus Placebo on the 
Progression of Renal Impairment in Subjects with Type 2 
Diabetes and Chronic Kidney Disease 
Document date: 
25 January 2021 
*Document date refers to the date on which the document was most recently updated.
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Protocol
Including: 
amendment 1 (Argentina), 2 (Germany) and 3 (India), dated 11 November 2020, protocol version 
4.0 
amendment 4 (all countries), dated 03 November 2020, protocol version 3.0 
amendment 5 (China), dated 25 January 2021, protocol version 5.0 
Protocol title: FLOW - Effect of semaglutide versus placebo on the 
progression of renal impairment in subjects with type 2 diabetes and 
chronic kidney disease
Substance name: Semaglutide 
Universal Trial Number: U1111-1217-6259 
EUdraCT Number: 2018-002878-50 
Trial phase: 3b 
In the following, Novo Nordisk A/S and its affiliates will be stated as “Novo Nordisk”. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
CONFIDENTIAL
This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.
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Protocol amendment summary of changes table  
DOCUMENT HISTORY 
Document 
Date 
Version 
Updated protocol including 
amendment 5 (China) 
25 January 2021 
5.0 
Updated protocol including 
amendment 1 (Argentina), 2 
(Germany), 3 (India)  
11 November 2020 
4.0 (includes all amendments from 
1-4) 
Updated protocol including 
amendment 4 (all countries) 
03 November 2020 
3.0 
Original protocol 
07 December 2018 
2.0 (version 1.0 was never part of a 
CTA submission) 
Protocol amendment no. 5 (dated 25 January 2021, included in version 5.0) 
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  
Co-participation in COVID-19 trials is not allowed in China due to local requirements, and not 
allowing co-participation in COVID-19 trials does not affect patient safety. 
Section # and name 
Description of change 
Rationale 
Appendix 8                            
Country-specific requirements for 
China, amendment 5 
The following change is not 
applicable for China: Section 6.2, 
exclusion criteria #4: *Simultaneous 
participation in a trial with the 
primary objective of evaluating an 
approved or non-approved 
investigational medicinal product for 
prevention or treatment of COVID-19 
disease or postinfectious conditions is 
allowed if the last dose of the 
investigational medicinal product has 
been received more than 30 days 
before screening 
Co-participation in COVID-19 
trials is not allowed in China due 
to local requirements 
Appendix 8                            
Country-specific requirements for 
China, amendment 5 
The following change is not 
applicable for China: Section 8.1, 
discontinuation/withdrawal criteria: 
*Simultaneous participation in a trial 
with the primary objective of 
evaluating an approved or non-
approved investigational medicinal 
product for prevention or treatment of 
COVID-19 disease or postinfectious 
conditions is allowed at the 
investigator discretion without 
discontinuing trial product 
Co-participation in COVID-19 
trials is not allowed in China due 
to local requirements 
Appendix 10                            
Protocol amendment history, 
amendment 5 
Previous protocol amendments 
relocate in Appendix 10 
To align with internal SOP 
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Table of Contents     
Protocol amendment summary of changes table ........................................................................................... 2 
1 
Synopsis ...................................................................................................................................................... 6 
2 
Flowchart ................................................................................................................................................... 8 
2.1 
Flowchart explanatory descriptions ............................................................................................. 11 
3 
Introduction ............................................................................................................................................. 12 
3.1 
Trial rationale ............................................................................................................................... 12 
3.2 
Background .................................................................................................................................. 12 
3.3 
Benefit-risk assessment ................................................................................................................ 13 
3.3.1 
Benefits related to semaglutide .................................................................................. 13 
3.3.2 
Risks related to semaglutide ...................................................................................... 13 
3.3.3 
Risk-benefit conclusion ............................................................................................. 15 
4 
Objectives and endpoints ........................................................................................................................ 16 
4.1 
Primary, secondary and exploratory objectives ........................................................................... 16 
4.2 
Primary, secondary and exploratory endpoints ............................................................................ 16 
4.2.1 
Primary endpoint ........................................................................................................ 16 
4.2.2 
Secondary endpoints .................................................................................................. 16 
4.2.2.1 
Confirmatory secondary endpoints ..................................................... 16 
4.2.2.2 
Supportive secondary endpoints .......................................................... 17 
4.2.3 
Exploratory endpoints ................................................................................................ 17 
5 
Trial design .............................................................................................................................................. 19 
5.1 
Overall design .............................................................................................................................. 19 
5.2 
Subject and trial completion ........................................................................................................ 19 
5.3 
End of trial definition ................................................................................................................... 20 
5.4 
Scientific rationale for trial design ............................................................................................... 20 
5.5 
Justification for dose .................................................................................................................... 21 
6 
Trial population ....................................................................................................................................... 22 
6.1 
Inclusion criteria .......................................................................................................................... 22 
6.2 
Exclusion criteria ......................................................................................................................... 22 
6.3 
Lifestyle restrictions .................................................................................................................... 23 
6.4 
Screen failures .............................................................................................................................. 23 
6.5 
Randomisation criteria ................................................................................................................. 24 
7 
Treatments ............................................................................................................................................... 25 
7.1 
Treatments administered .............................................................................................................. 25 
7.1.1 
Medical devices ......................................................................................................... 25 
7.2 
Dose modification ........................................................................................................................ 25 
7.2.1 
Missed doses .............................................................................................................. 26 
7.3 
Method of treatment assignment .................................................................................................. 26 
7.4 
Blinding ....................................................................................................................................... 26 
7.5 
Preparation/Handling/Storage/Accountability ............................................................................. 27 
7.6 
Treatment compliance .................................................................................................................. 28 
7.7 
Concomitant medication .............................................................................................................. 28 
7.8 
Treatment after the end of the trial .............................................................................................. 29 
8 
Discontinuation/Withdrawal criteria .................................................................................................... 30 
8.1 
Discontinuation of trial treatment ................................................................................................ 30 
8.1.1 
Temporary discontinuation of trial treatment ............................................................ 31 
8.2 
Withdrawal from the trial............................................................................................................. 31 
8.2.1 
Replacement of subjects ............................................................................................ 31 
8.3 
Lost to follow-up ......................................................................................................................... 31 
9 
Trial assessments and procedures ......................................................................................................... 33 
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9.1 
Optional pre-screening ................................................................................................................. 33 
9.2 
Efficacy assessments .................................................................................................................... 34 
9.2.1 
Self-measured plasma glucose ................................................................................... 34 
9.2.2 
Clinical efficacy laboratory assessments ................................................................... 34 
9.2.3 
Patient reported outcomes .......................................................................................... 35 
9.3 
Adverse events ............................................................................................................................. 35 
9.3.1 
Time period and frequency for collecting AE and SAE information ........................ 35 
9.3.1.1 
Events for adjudication ........................................................................ 38 
9.3.2 
Method of detecting AEs and SAEs .......................................................................... 39 
9.3.3 
Follow-up on AEs and SAEs ..................................................................................... 39 
9.3.4 
Regulatory reporting requirements for SAEs............................................................. 39 
9.3.5 
Cardiovascular and death events ................................................................................ 40 
9.3.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE 
or SAE........................................................................................................................ 40 
9.3.7 
Pregnancies and associated adverse events ................................................................ 40 
9.3.8 
Medical device incidents (including malfunctions) ................................................... 41 
9.3.9 
Technical complaints ................................................................................................. 41 
9.4 
Treatment of overdose ................................................................................................................. 42 
9.5 
Safety assessments ....................................................................................................................... 42 
9.5.1 
Physical examinations ................................................................................................ 43 
9.5.2 
Vital signs .................................................................................................................. 43 
9.5.3 
Eye examination ........................................................................................................ 44 
9.5.4 
Clinical safety laboratory assessments ....................................................................... 44 
9.6 
Pharmacokinetics ......................................................................................................................... 44 
9.7 
Pharmacodynamics ...................................................................................................................... 44 
9.8 
Genetics ....................................................................................................................................... 45 
9.9 
Biomarkers ................................................................................................................................... 45 
10 Statistical considerations ........................................................................................................................ 46 
10.1 
Sample size determination ........................................................................................................... 46 
10.2 
Definition of analysis sets ............................................................................................................ 47 
10.3 
Statistical analyses ....................................................................................................................... 47 
10.3.1 
Primary endpoint ........................................................................................................ 48 
10.3.2 
Secondary endpoints .................................................................................................. 49 
10.3.2.1 
Confirmatory secondary endpoints ..................................................... 49 
10.3.2.2 
Supportive secondary endpoints .......................................................... 50 
10.3.3 
Exploratory endpoints ................................................................................................ 51 
10.3.4 
Interim testing for efficacy......................................................................................... 51 
10.3.5 
Sequential safety analysis and safety monitoring ...................................................... 51 
10.4 
Pharmacokinetic and/or pharmacodynamic modelling ................................................................ 51 
11 References ................................................................................................................................................ 52 
12 Appendices ............................................................................................................................................... 54 
Appendix 1 
Abbreviations and Trademarks.............................................................................. 55 
Appendix 2 
Clinical laboratory tests .......................................................................................... 57 
Appendix 3 
Trial governance considerations ............................................................................. 59 
Appendix 4 
Adverse events: definitions and procedures for recording, evaluation, 
follow-up, and reporting ......................................................................................... 68 
Appendix 5 
Contraceptive guidance and collection of pregnancy information ...................... 72 
Appendix 6 
Technical complaints: Definition and procedures for recording, evaluation, 
follow-up and reporting .......................................................................................... 75 
Appendix 7 
Retention of human biosamples .............................................................................. 77 
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Appendix 8 
Country-specific requirements ............................................................................... 78 
Appendix 9 
Mitigations to ensure subject safety and data integrity during 
epidemics/pandemics (e.g. COVID-19) .................................................................. 83 
Appendix 10 
Protocol amendment history ................................................................................... 84 
 
Attachment I Global list of key staff and relevant departments and suppliers 
Attachment II Country list of key staff and relevant departments 
 
 
 
 
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1 
Synopsis  
Rationale 
Chronic kidney disease (CKD) and diabetes often co-exist and for the majority of cases, the kidney 
damage and/or reduced kidney function is caused directly by longstanding and poorly controlled 
diabetes. Improved glycaemic control has been suggested to reduce the progression of CKD in type 
2 diabetes (T2D) and both glycaemic and blood pressure control are key recommendations in 
international treatment guidelines for CKD in T2D. Yet there remains a major unmet medical need 
to improve the treatment of CKD in patients with T2D. The purpose of this trial is to demonstrate 
that semaglutide subcutaneously (s.c.) delays the progression of renal impairment and lowers the 
risk of renal and cardiovascular (CV) mortality in subjects with T2D and CKD. 
Objectives and endpoints 
The primary objective is to demonstrate that semaglutide delays the progression of renal 
impairment and lowers the risk of renal and cardiovascular mortality compared to placebo, both 
added to standard-of-care, in subjects with type 2 diabetes and chronic kidney disease. 
The key secondary objectives are to compare the effect of treatment with semaglutide versus 
placebo, both added to standard-of-care in subjects with type 2 diabetes and chronic kidney disease 
with regards to cardiovascular morbidity, peripheral artery disease, glycaemic control, body weight, 
blood pressure and safety. 
The primary endpoint is time to first occurrence of a composite endpoint consisting of: Onset of 
persistent ≥ 50% reduction in estimated glomerular filtration rate (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, or cardiovascular death. 
The key secondary endpoints are annual rate of change in eGFR (CKD-EPI) (total eGFR slope), 
time to first occurrence of a composite major adverse cardiovascular event (MACE) endpoint 
(consisting of: non-fatal myocardial infarction, non-fatal stroke, CV death) and all-cause death. 
The estimand for all objectives is based on the intention-to-treat principle evaluating the effect of 
the randomised treatment intervention irrespective of adherence to this and changes to background 
medication. 
Overall design 
This is a multi-centre, international, randomised, double-blind, parallel-group, placebo-controlled 
trial comparing semaglutide 1.0 mg versus placebo both administered s.c. once weekly and added to 
standard-of-care in subjects with T2D and pre-existing CKD. Subjects will be randomised 1:1 to 
receive either semaglutide or placebo. Randomisation will be stratified by use of sodium glucose 
cotransporter-2 (SGLT-2) inhibitors (yes versus no) at baseline. The number of subjects with 
inclusion eGFR ≥ 60 mL/min/1.73 m2 will be capped at 20%.  
Key inclusion criteria 
• Male or female, age ≥ 18 years at the time of signing informed consent. Japan: For country 
specific requirements, please see Appendix 8.  
• Diagnosed with type 2 diabetes mellitus 
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•
HbA1c ≤ 10% (≤ 86 mmol/mol)
•
Renal impairment defined either by:
a) serum creatinine-based eGFR ≥ 50 and ≤ 75 mL/min/1.73 m2 (CKD-EPI) and UACR > 300
and < 5000 mg/g
or 
b) serum creatinine-based eGFR ≥ 25 and < 50 mL/min/1.73 m2 (CKD-EPI) and UACR > 100
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 an
angiotensin II receptor blocker (ARB), unless such treatment is contraindicated or not tolerated.
Treatment dose must be stable for at least 4 weeks prior to the date of the laboratory
assessments used for determination of the inclusion criteria for renal impairment and kept stable
until screening.
Key exclusion criteria 
•
Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune
kidney diseases including glomerulonephritis or congenital urinary tract malformations
•
Use of any glucagon-like peptide-1 (GLP-1) receptor agonist within 30 days prior to screening
•
Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic
attack within 60 days prior to the day of screening
•
Presently classified as being in New York Heart Association (NYHA) Class IV heart failure
•
Planned coronary, carotid or peripheral artery revascularisation
•
Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal dialysis
•
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 randomisation. Pharmacological pupil-dilation is a requirement unless using a
digital fundus photography camera specified for non-dilated examination
Number of subjects 
Approximately 5,400 subjects will be screened to achieve 3,508 subjects randomly assigned to trial 
product.  
Treatment groups and duration 
The trial is event driven and includes a pre-defined minimum number of renal endpoint events; 
therefore, end of trial will be scheduled according to projected trial closure. Trial duration from the 
first subject visit is expected to be 61 months or more following randomisation of the first subject. 
Trial duration for each subject is expected to be approximately 3 to 5 years.  
The trial products are: 
•
Active trial product: Semaglutide 1.34 mg/mL, solution for injection.
•
Semaglutide placebo, solution for injection.
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h Only at year 2 and 3 (week 104 and 156) 
i Only at year 3 (week 156) 
j Only applicable for women of childbearing potential; urine HCG. 
kThe yearly visits should take place approximately 13 weeks after the previous visit 
2.1 
Flowchart explanatory descriptions 
As individual follow up time will differ depending on enrolment date, visits in the treatment maintenance period will be added or removed depending on 
time of randomisation and trial closure timing. 
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3 
Introduction 
In this document, the term investigator refers to the individual responsible for the overall conduct of 
the clinical trial at a trial site. 
3.1 
Trial rationale 
Chronic kidney disease (CKD) and diabetes often co-exist and for the majority of cases the kidney 
damage and/or reduced kidney function is caused directly by longstanding and poorly controlled 
diabetes. Up to 40% of patients with type 2 diabetes (T2D) have some degree of CKD, and diabetes 
is the single leading cause of end-stage renal disease (ESRD) requiring chronic dialysis treatment or 
kidney transplantation.2 Improved glycaemic control has been suggested to reduce the development 
and progression of CKD in T2D3, 4 and both glycaemic and blood pressure control are key 
recommendations in international treatment guidelines for CKD in T2D.5 Blocking the renin-
angiotensin-aldosterone system (RAAS) with angiotensin-converting-enzyme inhibitors (ACE 
inhibitors) or angiotensin II receptor blockers (ARBs) for the treatment of CKD in patients with 
T2D and increased levels of albuminuria is recommended as first-line therapy and some of the 
RAAS blocking agents (irbesartan6, losartan7 and captopril8) have a labelled indication for the 
treatment of CKD in diabetes.5 However, up to 70% of the patients with T2D and CKD experience 
continued deterioration of the kidney function despite RAAS blocker treatment.9-11 Hence, there is a 
major unmet medical need to improve the treatment of CKD in patients with T2D, thereby reducing 
the risk of developing ESRD. The aim of the current trial is to demonstrate that treatment with once 
weekly semaglutide subcutaneously (s.c.) delays the progression of renal impairment and lowers the 
risk of renal and cardiovascular mortality in subjects with T2D and CKD. 
3.2 
Background 
Recently conducted clinical trials with the glucagon-like peptide-1 (GLP-1) receptor agonists 
semaglutide, liraglutide, dulaglutide, and exenatide have suggested a possible renoprotective effect 
in patients with T2D, CKD and high cardiovascular (CV) risk.12-16 A similar beneficial effect on 
new or worsening nephropathy in patients with T2D and established or high risk for CV disease has 
also been suggested17-19 in another class of glucose lowering drugs; the sodium glucose 
cotransporter-2 (SGLT-2) inhibitors, and dedicated renal outcomes trials are currently running or 
have been announced for empagliflozin20 and dapagliflozin (ClinicalTrials.gov Identifier: 
NCT03036150). In addition, the CREDENCE renal outcomes trial with canagliflozin 
(ClinicalTrials.gov Identifier: NCT02065791) was stopped early based on the achievement of pre-
specified efficacy criteria at a pre-planned interim analysis. 
The current trial will include subjects with T2D and established CKD defined by increased urinary 
albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR). These 
enrichment criteria are selected as reduced eGFR and increased UACR have been shown to be 
independent risk factors for progression of renal impairment and development of ESRD.21 Thus, a 
population of subjects with T2D and primarily moderate CKD and increased UACR is considered 
an appropriate target population for a risk reduction intervention and will ensure that the primary 
objective of the trial can be met within a reasonable timeframe and sample size. The number of 
subjects with inclusion eGFR values in the high end of the eGFR range, i.e. eGFR ≥ 60 
mL/min/1.73 m2, will be capped at 20% to ensure a sufficient event rate for the primary endpoint, as 
the event rate is expected to be lower in these subjects.  
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The inclusion and exclusion criteria in this study have been selected to capture a study population 
with an increased risk for progression of renal impairment and therefore most patients should have 
severely increased albuminuria at enrolment. Communications to sites may be used over the course 
of the recruitment period to focus recruitment efforts on patients with high risk for CKD 
progression without restricting the enrolment of any eligible subgroups.  
Detailed information for semaglutide s.c. is available in the current edition and any updates of the 
Investigator’s Brochure. 
3.3 
Benefit-risk assessment 
3.3.1 
Benefits related to semaglutide 
In clinical trials semaglutide has provided superior long-term glycaemic control in T2D patients 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.13 
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 
receptor agonists 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. 
3.3.2 
Risks related to semaglutide 
Identified risks 
Based on the clinical development programme a causal relationship with semaglutide was suggested 
for the following risks: 
Gastrointestinal disorders: For semaglutide as for other GLP-1 receptor agonists, the most 
frequently reported adverse reactions in clinical trials were gastrointestinal (GI) disorders, including 
nausea, diarrhoea and vomiting. In general, these reactions were mild or moderate in severity and of 
short duration. A dose dependency has been observed for most of the GI disorders. Clinical trials 
have shown that a low starting dose and gradual dose escalation mitigates the risk of GI adverse 
events (AEs).  
In patients treated with GLP-1 receptor agonists, nausea, vomiting and diarrhoea may lead to 
significant dehydration. This should be considered when treating patients with impaired renal 
function as it may lead to further deterioration of renal function. Subjects with GI AEs are 
recommended to drink plenty of fluids, unless medically contraindicated, to avoid volume 
depletion. 
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Hypoglycaemia: Patients treated with semaglutide in combination with a sulfonylurea or insulin 
may have an increased risk of hypoglycaemia compared to patients treated with semaglutide as 
monotherapy or in combination with other anti-hyperglycaemic medications. The risk of 
hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating 
treatment with semaglutide. 
Diabetic retinopathy complications: Adjudicated events of diabetic retinopathy complications 
occurred in more patients treated with semaglutide (3.0%) when compared to placebo (1.8%) in a 2-
year clinical trial involving 3,297 subjects with T2D and high CV risk, long duration of diabetes 
and poor glycaemic control. Diabetic retinopathy complications were a composite of: need for 
retinal photocoagulation, need for treatment with intravitreal agents, vitreous haemorrhage and 
onset of diabetes-related blindness. The absolute risk increase for diabetic retinopathy 
complications was greatest among patients with a history of diabetic retinopathy at baseline. In 
patients who did not have a documented history of diabetic retinopathy, the number of events was 
similar for semaglutide and placebo.  
In other clinical trials of up to 1 year duration involving 4,807 subjects with T2D, AEs related to 
diabetic retinopathy were distributed similarly between subjects treated with semaglutide (1.7%) 
and comparators (2.0%). 
Rapid improvement in glycaemic control, for example with insulin, has been associated with a 
temporary worsening of diabetic retinopathy. Long-term sufficient glycaemic control decreases the 
risk of diabetic retinopathy. Subjects with a history of diabetic retinopathy should be monitored for 
worsening and treated according to clinical guidelines. 
Other risks: Patients treated with semaglutide may also experience cholelithiasis, decreased 
appetite, dizziness, dysgeusia, fatigue, increased heart rate, increased lipase and amylase, injection 
site reactions and weight decrease. 
Potential risks 
A possible association with semaglutide has been suspected for the following risks, although the 
relationship has not yet been confirmed: 
Allergic reactions: As in the case with all protein-based pharmaceuticals, treatment with 
semaglutide may evoke allergic reactions, including serious allergic reactions such as anaphylactic 
reactions. 
Acute pancreatitis: Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. 
Patients 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. 
Malignant neoplasms: Based on available data, there is no indication of a causal relationship 
between semaglutide and malignant neoplasms. However, it is not possible to draw any firm 
conclusions due to very low numbers. 
Pancreatic cancer: Patients with T2D have an increased risk of certain types of cancer such as 
pancreatic cancer. In the development programme, rates of pancreatic cancer were low and do 
not support a causal association with semaglutide. Furthermore, no safety concerns related to 
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the pancreas were identified in the nonclinical programme with semaglutide. Pancreatic cancer 
has however, been classified as a potential class risk for all marketed GLP-1 receptor agonists 
by regulatory agencies.  
Medullary thyroid cancer: Thyroid C-cell tumours were seen in mice 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 of exposure up to 27-
fold above the clinical plasma exposure at 1.0 mg/week. The GLP-1 receptor is not expressed in 
the normal human thyroid and the risk of GLP-1 receptor-mediated C-cell changes in humans is 
considered to be low. 
Other safety considerations 
Drug interactions: Semaglutide delays gastric emptying and has the potential to impact the rate of 
absorption of concomitantly administered oral medicinal products. The potential effect of 
semaglutide on the absorption of co-administered oral medications was studied in trials at 
semaglutide 1 mg/week steady state exposure. No clinically relevant drug-drug interactions with 
semaglutide were observed based on the evaluated medications.  
Semaglutide did not change the overall pharmacodynamics of warfarin as measured by the 
international normalised ratio (INR). However, upon initiation of semaglutide treatment in patients 
on warfarin and/or coumarin derivatives, frequent monitoring of INR is recommended. 
Pregnancy, lactation and fertility: Studies in animals have shown reproductive toxicity. There are 
limited data from the use of semaglutide in pregnant women. Therefore, semaglutide should not be 
used during pregnancy. If a subject wishes to become pregnant, or pregnancy occurs, semaglutide 
should be discontinued, see Appendix 5 for details. In lactating rats, semaglutide was excreted in 
milk. As a risk to a breast-fed child cannot be excluded, semaglutide should not be used during 
breast-feeding. 
The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male 
fertility in rats. In female rats, an increase in oestrous length and a small reduction in number of 
ovulations were observed at doses associated with maternal body weight loss. 
3.3.3 
Risk-benefit conclusion 
Data from the 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 reasonably 
expected AEs of semaglutide may be found in the Investigator’s Brochure. 
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a End-of-trial: a period expected to be up to 61 months or more for the individual subject. Abbreviations: CKD-EPI, 
chronic kidney disease - epidemiology collaboration; CV, cardiovascular; eGFR, estimated glomerular filtration rate; 
EQ-5D-5L, five-level version of the EuroQol five-dimensional questionnaire; MACE, major adverse cardiovascular 
event; UACR, urinary albumin-to-creatinine ratio.  
Definition of terms 
When classifying chronic renal replacement therapy or kidney transplantation, the date of event 
should be the date of initiation of the therapy or surgery, respectively. The baseline for eGFR is 
defined as the mean of the two assessments from the screening visit (V1) and the randomisation 
visit (V2).  
eGFR will be calculated using the chronic kidney disease – epidemiology collaboration (CKD-EPI) 
formula.24 Sustained kidney failure is defined as persistent eGFR < 15 mL/min/1.73 m2 or initiation 
of chronic renal replacement therapy. For the eGFR components of the primary endpoint, a 
persistent outcome in eGFR is defined as having two consecutive central laboratory assessments at 
least 4 weeks apart meeting the criteria. When classifying the events based on consecutive 
laboratory assessments, the date of the event should be the date of the first sample meeting the 
definition. 
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5 
Trial design 
5.1 
Overall design 
This is a multi-centre, international, randomised, double-blind, parallel-group, placebo-controlled 
trial comparing semaglutide 1.0 mg versus placebo both administered s.c. once weekly 
(subsequently referred to as semaglutide and placebo) and added to standard-of-care in subjects 
with T2D and pre-existing CKD. Subjects will be randomised 1:1 to receive either semaglutide or 
placebo. Randomisation will be stratified by SGLT-2 inhibitor use at baseline (yes versus no). The 
number of subjects with inclusion eGFR ≥ 60 mL/min/1.73 m2 will be capped at 20%. 
The trial is event driven with a pre-defined minimum number of renal endpoint events (all 
components of the primary composite endpoint except CV death) for the primary endpoint. The trial 
will employ a group sequential design and interim testing for efficacy will be performed by an 
independent external Data Monitoring Committee (DMC). The DMC will provide recommendation 
on trial continuation, modification or termination. The observed number and type of confirmed 
primary endpoint events will be monitored throughout the trial. If the trial is not stopped for 
efficacy at a planned interim testing the trial will be terminated when both of the following criteria 
are fulfilled: 
•
A minimum of 854 primary endpoint events
•
A minimum of 515 primary renal endpoint events
The follow-up period after end of treatment is 5 weeks for all subjects. 
A schematic overview of the trial design is shown in Figure 5-1. 
Figure 5-1 
Trial design diagram  
5.2 
Subject and trial completion 
Approximately 5,400 subjects will be screened to achieve 3,508 subjects randomly assigned to trial 
product. For a description of screen failures see Section 6.4. The recruitment period is expected to 
be 21 months. Subjects will be followed for the complete duration of the trial and extensive efforts 
will be made to collect data for all randomised subjects.  
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Trial period completion for a subject 
Trial period completion is defined as: 
•
when the randomised subject has completed the final scheduled visit (follow-up visit according
to the flowchart).
or 
•
when the randomised subject has died during trial.
Treatment period completion for a subject 
Treatment period completion is defined as when the randomised subject has received the required 
treatment and attended the end of treatment visit, according to the flowchart.  
The trial is event driven; therefore, end of treatment and follow-up visit will be scheduled according 
to projected trial closure. When the trial is approaching the end investigators will be notified and 
instructed by Novo Nordisk regarding the visit schedules for their subjects. 
When the trial comes to an end, the investigator must make every effort to ascertain efficacy and 
safety endpoint data for all subjects. This should be done by direct contact with the subject 
whenever possible. If a subject proves difficult to reach for the follow-up visit, all attempts to re-
establish direct contact must be made (see section 8.3). In case several attempts are required to 
establish direct contact to a subject, exceeding the visit window of the follow-up visit may be 
needed. In order for the data set to be as complete as possible, end of trial follow-up information 
can be collected until the randomisation codes are broken. If allowed by local regulations, 
publically available data sources may also be searched for withdrawn subjects in order to determine 
their vital status.  
5.3 
End of trial definition  
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
5.4 
Scientific rationale for trial design 
To ensure robust evaluation the trial is randomised, double-blinded and placebo-controlled. Blinded 
treatment with semaglutide or placebo offers a robust method for assessment of the effects of 
semaglutide. A broad spectrum of concomitant anti-hyperglycaemic medication, as well as 
treatments for comorbidities, CKD and CV risk factors can be introduced or adjusted throughout the 
trial based on individual requirements and at investigator’s discretion. This is in accordance with a 
pragmatic approach to compare two treatments: one where semaglutide is available and another 
where it is not.  
To support the subject during the dose escalation period, site visits will occur more frequently 
during the first months of the trial. To maximise retention and compliance and to optimise treatment 
and safety the subject is in contact with the investigator every 13th week throughout the trial. A 
multinational design has been chosen to ensure a sufficient screening pool of subjects and to reflect 
the anticipated global target population and ensure generalisability. The long half-life of 
semaglutide supports once weekly administration and the 5-week follow-up is considered 
appropriate to the time that semaglutide remains in circulation. 
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5.5 
Justification for dose 
In order to lower the risk of gastrointestinal AEs, a dose-escalation regimen is included. The dose of 
1.0 mg per week has been tested for glycaemic control in patients with T2D in a comprehensive 
phase 3a programme and shown to have a positive benefit risk profile. Further, the benefit risk 
profile for the 1.0 mg dose was evaluated to be favourable over the 0.5 mg dose with lower 
proportions of subjects having a renal event in SUSTAIN 6. For information regarding dose 
modifications, see Section 7.2. 
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6 
Trial population 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.  
6.1 
Inclusion criteria  
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any
procedures that are carried out as part of the trial, including activities to determine suitability for
the trial, except for protocol described pre-screening activities which require a separate
informed consent.
2. Male or female, age above or equal to 18 years at the time of signing informed consent. Japan:
For country specific requirements, please see Appendix 8.
3. Diagnosed with type 2 diabetes mellitus.
4. HbA1c ≤ 10% (≤ 86 mmol/mol)*.
5. Renal impairment defined either by:
a.
serum creatinine-based eGFR ≥ 50 and ≤ 75 mL/min/1.73 m2 (CKD-EPI)*, ** and
UACR > 300 and < 5000 mg/g.*
or 
b. serum creatinine-based eGFR ≥ 25 and < 50 mL/min/1.73 m2(CKD-EPI)* and
UACR > 100 and < 5000 mg/g.*
6. Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone system
(RAAS) blocking agent including an angiotensin converting enzyme (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 4 weeks prior to the date of the laboratory
assessments used for determination of inclusion criterion 5 and kept stable until screening.
* Laboratory results for inclusion can be based on:
•
measurements no more than 90 days old at screening, documented in medical records or
•
measurements from the optional pre-screening visit (see Section 9.1), documented in medical
records or
•
central laboratory measurement obtained at the screening visit
The subject must have been/be in usual health condition at the time of sample collection used for 
inclusion as evaluated by the investigator and treated with a RAAS blocking agent, according to 
inclusion criterion 6. See Appendix 2 for all requirements regarding clinical laboratory tests. 
** The number of subjects with inclusion eGFR ≥ 60 mL/min/1.73 m2 will be capped at 20% of 
randomised subjects. 
6.2 
Exclusion criteria  
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.
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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 5).
4. Participation in any clinical trial of an approved or non-approved investigational medicinal
product within 30 days before screening*. Brazil: For country specific requirements, please see
Appendix 8.
5. Any disorder, which in the investigator’s opinion might jeopardise subject’s safety or
compliance with the protocol.
6. Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune
kidney diseases including glomerulonephritis or congenital urinary tract malformations.
7. Use of any GLP-1 receptor agonist within 30 days prior to screening.
8. Personal or first degree relative(s) history of multiple endocrine neoplasia type 2 (MEN2) or
medullary thyroid carcinoma (MTC).
9. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic
attack within 60 days prior to the day of screening.
10. Presently classified as being in New York Heart Association (NYHA) Class IV heart failure.
11. Planned coronary, carotid or peripheral artery revascularisation.
12. Current (or within 90 days) chronic or intermittent haemodialysis or peritoneal dialysis.
13. 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 randomisation. Pharmacological pupil-dilation is a requirement unless using a
digital fundus photography camera specified for non-dilated examination.
14. Presence or history of malignant neoplasm within 5 years prior to the day of screening. Basal
and squamous cell skin cancer and any carcinoma in-situ are allowed.
15. A prior solid organ transplant or awaiting solid organ transplant.
16. Combination use of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin II
receptor blocker (ARB).
*Simultaneous participation in a trial with the primary objective of evaluating an approved or non-
approved investigational medicinal product for prevention or treatment of COVID-19 disease or
postinfectious conditions is allowed if the last dose of the investigational medicinal product has
been received more than 30 days before screening.
6.3 
Lifestyle restrictions 
Not applicable for this trial. 
6.4 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical trial, but are not 
eligible for participation according to in/exclusion criteria. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet 
requirements from regulatory authorities. Minimal information includes demography, screen failure 
details, and eligibility criteria. A screen failure session must be made in the IWRS for subjects who 
are not randomised.  
Re-screening of previous screen failures is allowed twice in case the investigator assesses that 
potential changeable or fluctuating in- or exclusion criteria may have changed (e.g. biochemical 
parameters (eGFR, UACR and HbA1c) or change in concomitant medication). Previously 
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randomised subjects cannot be re-screened. In case of re-screening a new subject number must be 
assigned in the IWRS. 
6.5 
Randomisation criteria 
Not applicable for this trial. 
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notified immediately after breaking the blind. The date when and reason why the blind was broken 
must be recorded in the source documentation. Whenever the blind is broken, the person breaking 
the blind must print the "code break confirmation" notification generated by the IWRS, record the 
reason and sign and date the document. Treatment with trial product can be resumed if there are no 
safety concerns at the discretion of the investigator. 
When the blind is broken, the treatment allocation will be accessible to the investigator and the 
Novo Nordisk Global Safety department. If IWRS is not accessible at the time of blind break, the 
IWRS helpdesk should be contacted. Contact details are listed in Attachment I.  
7.5 
Preparation/Handling/Storage/Accountability 
Only subjects enrolled in the trial may receive trial product and only authorised site staff may 
supply or administer trial product. Each trial site will be supplied with sufficient trial products for 
the trial on an on-going basis controlled by the IWRS. Trial product will be distributed to the trial 
sites according to screening and randomisation. 
The investigator must confirm that appropriate temperature conditions have been maintained during 
transit for all trial products received and any discrepancies are reported and resolved before use of 
the trial products. 
All trial products must be stored in a secure, controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator and 
authorised site staff. For the storage and in-use conditions see the trial materials manual (TMM) and 
the labels of trial product. The investigator must inform Novo Nordisk immediately if any trial 
product has been stored outside specified conditions. Additional details regarding handling of 
temperature deviations can be found in the TMM. Trial product that has been stored improperly 
must not be dispensed to any subject before it has been evaluated and approved for further use by 
Novo Nordisk. 
Subjects must return all used, partly used and unused trial products as instructed by the investigator. 
The investigator 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 as used/partly used, unused or as lost. 
Destruction of trial products can be performed on an ongoing basis and will be done according to 
local procedures after accountability is finalised by the site and reconciled by the monitor. 
Destruction of trial products must be documented in the IWRS. 
All returned, expired or damaged trial products (for technical complaint samples see Appendix 6) 
must be stored separately from non-allocated trial products. No temperature monitoring is required. 
Non-allocated trial products including expired or damaged products must be accounted as unused, 
at the latest at closure of the trial site. 
In case local restrictions due to epidemic/pandemic lead to lockdown of a site, alternative ways of 
dispensing may be used if permitted by local regulations (see Appendix 9 for further details). 
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7.6 
Treatment compliance 
Throughout the trial, the investigator will remind the subjects to follow the trial procedures and 
requirements to ensure subject compliance. If a subject is found to be non-compliant the 
investigator will remind the subject of the importance of following the instructions including taking 
the trial products as prescribed. Additionally, reporting of changes in the dose taken and monitoring 
of drug accountability will support documentation of treatment compliance. 
7.7 
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. 
Initiating GLP-1 receptor agonists is not allowed during the entire trial. Additional CV and anti-
hyperglycaemic medications, excluding GLP-1 receptor agonists, may be added or changed during 
the trial in both treatment groups at the discretion of the investigator and in accordance with local 
treatment guidelines. Investigators will be encouraged to optimise standard-of-care treatment for 
T2D, CKD, and CV risk management according to local treatment practice. Recommendations for 
this will be provided in guidance documents during trial conduct.   
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. If the subject is not treated with a RAAS blocking agent, previous treatment 
attempt must be documented in medical records and that this has led to intolerance or unacceptable 
side effects. If intolerance for an ACE-inhibitor is documented, due to cough, a treatment attempt 
with an ARB must have been made. If a subject is treated with the maximum tolerated dose but not 
the maximum labelled dose of the RAAS blocking agent a previous dose escalation attempt is not a 
requirement, but the reason why the subject is not expected to tolerate a higher dose must be 
documented in the medical records. 
Anti-hyperglycaemic and CKD standard-of-care treatment is considered background treatment and 
will not be provided by Novo Nordisk A/S. 
For randomised subjects the following medication(s) other than the trial product that the subject is 
receiving at the time of screening (V1) or receives during the trial must be recorded in the electronic 
case report form (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 9.3
•
medication administered in relation to a clinical trial for COVID-19 prevention or treatment
•
an approved COVID-19 vaccine
The medication must be recorded in the eCRF along with start date and stop date or continuation 
and related AE number when applicable. For anti-hyperglycaemic medication and for RAAS 
blocking agents (ACE inhibitors and ARBs), the total daily dose needs to be included in the eCRF. 
Stable dose changes (2 weeks or more) should be captured as a new concomitant medication with 
the new dose and relevant start and stop date. 
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Changes in concomitant medication must be recorded at each visit. If a change is due to an AE or 
serious adverse event (SAE), then this must be reported according to Section 9.3.  
7.8 
Treatment after the end of the 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 receptor agonists and interference with safety 
data collection, initiating GLP-1 receptor agonists should be avoided between the end of treatment 
visit and the follow-up visit. All other medications are allowed. 
Brazil: For country specific requirements, please see Appendix 8. 
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8 
Discontinuation/Withdrawal criteria  
8.1 
Discontinuation of trial treatment  
The subject may be discontinued at any time during the trial at the discretion of the investigator for 
safety, behavioural, compliance or administrative reasons.  
The subject must be discontinued from trial product, if the following applies: 
1. Pregnancy 
2. Intention of becoming pregnant 
3. Simultaneous participation in another clinical trial of an approved or non-approved 
investigational medicinal product* 
4. If acute pancreatitis is suspected, trial product must be discontinued; and if confirmed, trial 
product must not be restarted 
5. Treatment with another GLP-1 receptor agonist 
6. Other safety concerns 
*Simultaneous participation in a trial with the primary objective of evaluating an approved or non-
approved investigational medicinal product for prevention or treatment of COVID-19 disease or 
postinfectious conditions is allowed at the investigator discretion without discontinuing trial 
product.   
Ad 3: With the exception of an approved or non-approved investigational product for prevention or 
treatment of COVID-19, subjects must not receive an investigational product from another clinical 
trial. If done, treatment with trial product must be discontinued. If the use of investigational medical 
product in the other trial is discontinued, treatment with trial product can be resumed if there are no 
safety concerns at the discretion of the investigator. 
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 8.1.1). For some events, when the circumstances have 
changed and/or there are no longer safety concerns, treatment with trial product may be continued 
or resumed at the discretion of the investigator and in agreement with the Novo Nordisk medical 
expert. If a subject becomes pregnant during the trial, the trial product must be discontinued 
immediately and must not be re-initiated until breast feeding, if performed, has stopped. If a subject 
intends to become pregnant, the trial product must be discontinued at least 5 weeks  prior to the 
planned intention (Appendix 5). 
If a trial product is discontinued, the subject should continue to follow the trial schedule without 
being withdrawn from the trial and encouraged to attend the site for at least the end of treatment and 
follow-up visits in order to collect the required data for the analysis of the primary (and 
confirmatory secondary) endpoints. Subjects must be educated about the continued scientific 
importance of their data, even if they discontinue trial product. The primary reason for 
discontinuation of trial product must be specified in the eCRF, and final drug accountability must be 
performed. 
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The long half-life of semaglutide (approximately one week) should be considered when initiating 
new anti-hyperglycaemic treatment after discontinuation of the trial product. 
8.1.1 
Temporary discontinuation of trial treatment  
Temporary treatment discontinuation and dose adjustment is allowed at the discretion of the 
investigator. Treatment with trial product should be resumed if the circumstances later allow. Start 
and stop dates and dose should be recorded in the eCRF. A treatment status session must be made in 
the IWRS when a subject is on treatment pause and when resuming treatment. 
8.2 
Withdrawal from the trial  
A subject may withdraw consent at any time at his/her own request. Only subjects who withdraw 
consent will be considered as withdrawn from the trial.  
If a randomised subject is considering withdrawing from the trial, the investigator may offer the 
subject flexible participation in the trial. This could be attending fewer visits (i.e. reduced visit 
schedule), converting site visits to phone contacts, treatment pause, or only being followed-up for 
AEs, especially those related to the primary objective. It must be explained to the subject that this 
must include information on their AEs, especially those related to the primary objective that 
occurred since last contact to the subject. This is important to ensure that the information gained is 
complete and accurate, and that the correct conclusions are drawn. Only if the subject declines all 
alternatives, should the subject be recorded as withdrawn. 
Although a subject is not obliged to give his/her reason(s) for withdrawing, the investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. Where 
the reasons are obtained, the primary reason for withdrawal must be specified in the end of trial 
form in the eCRF. 
Final drug accountability must be performed even if the subject is not able to come to the trial site.  
If a subject withdraws from the trial, he/she may request destruction of any samples taken and not 
tested, and the investigator must document this in the medical record. If the subject withdraws 
consent, Novo Nordisk may retain and continue to use any data collected before such a withdrawal 
of consent. 
Mexico: For country specific requirements, please see Appendix 8. 
8.2.1 
Replacement of subjects  
Subjects who discontinue trial product or withdraw from trial will not be replaced. 
8.3 
Lost to follow-up  
A subject will be considered potentially lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the trial site. The following actions must be taken 
if a subject fails to return to the trial site for a required visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as possible 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain whether or not the subject wishes to and/or should continue in the trial. 
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• Before a subject is deemed lost to follow-up, the investigator must make every effort to contact 
the subject, see Section 5.2. The following contact attempts will be made and documented in the 
subject’s source documents where as a minimum, renal impairment status related to primary 
objective, the AE status and/or vital status (dead or alive) should be determined: 
• 
To subjects: three phone calls and one written contact (e.g. certified letter) 
• 
To the primary physician and/or other health care professionals: phone calls until 
contact is established 
• 
If direct contact to the subject is not possible, relatives or other person(s) will be 
contacted: three phone calls and one written contact 
• 
Search/contact to public registries of deceased persons, if available and allowed by 
local regulation 
Should the subject continue to be unreachable at the end of the trial, he/she will be considered to 
have withdrawn from the trial with a primary reason of lost to follow-up. A subject cannot be 
declared lost to follow-up before the trial has come to an end. 
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9 
Trial assessments and procedures  
• Trial procedures and their timing are summarised in the flowchart (Section 1). 
• Informed consent must be obtained before any trial related activity, see Appendix 3. 
• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. 
• The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reason for screen failure, as applicable. 
• At screening, subjects will be provided with a card stating that they are participating in a trial 
and giving contact details of relevant trial site staff.  
• Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
• The investigator should inform the subjects’ primary physician, if applicable, about the subjects’ 
participation in the trial if the subject agrees to the primary physician being informed. 
• Each subject should be asked to provide contact information for persons (preferably at least 3), 
e.g. relatives, primary care provider or other, to whom the investigator can contact in case of 
issues when trying to contact the subject during the trial. 
• The investigator must ensure to keep regular contact with each subject throughout the entire 
trial, and at all times have updated contact information for the subject. Even if a visit (or phone 
contact) is missed and it is not possible to re-schedule, the investigator must take every effort to 
have all subjects followed for primary endpoint events (see Section 4.2.1).  
• All of the assessments and procedures at a given trial visit do not need to be performed on the 
same day, provided that they are completed within the visit window. 
• Review of completed PROs, laboratory reports, etc. must be documented either on the 
documents or in the subject's source documents. The review must be performed by an 
investigator. 
• Repeat samples may be taken for technical issues and unscheduled samples or assessments may 
be taken for safety reasons or to confirm the primary endpoint (see Section 9.2.2). Please refer 
to Appendix 2 for further details on laboratory samples. 
• There are no fasting visits. 
• In case local restrictions due to epidemic/pandemic lead to lockdown of a site, site visits can be 
performed as home nursing (see Appendix 9) 
9.1 
Optional pre-screening  
The investigator may, after obtaining separate informed consent, perform pre-screening of potential 
trial candidates. It is not necessary to obtain full informed consent for the remaining trial period 
before pre-screening. Pre-screening assessments include obtaining blood and urine samples for 
eGFR and/or UACR and/or HbA1c. The subject must have been/be in usual health condition at the 
time of sample collection used for inclusion as evaluated by the investigator and treated with a 
RAAS blocking agent, according to inclusion criterion 6 (see Section 6.1). The pre-screening 
samples must be analysed locally with standardised assays as described in Appendix 2. The 
parameters that fulfil inclusion criteria can be used to determine eligibility for the trial, if 
measurements were taken no more than 90 days prior to screening and are documented in the 
medical records. Those subjects determined eligible for the trial based on these results will follow 
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the flowchart schedule for all screening assessments including eGFR, UACR and HbA1c (see 
Section 1) to determine the baseline values (see Section 10.3). 
Results of pre-screening assessments will not be collected in the trial database and will not be 
monitored unless used to fulfil inclusion criteria (see Section 6.1). Concerns related to any pre-
screening assessment must not be reported as an AE. 
Pre-screening assessments performed after signature of the separate informed consent can be 
reimbursed by Novo Nordisk A/S. 
China: For country specific requirements, please see Appendix 8. 
Germany: For country specific requirements, please see Appendix 8. 
9.2 
Efficacy assessments  
Planned time points for all efficacy assessments are provided in the flowchart (Section 1). 
9.2.1 
Self-measured plasma glucose  
Subjects have the option to be provided with a BG meter including auxiliaries as well as 
instructions for use, or to continue to use their own BG meter. Those subjects who choose to use the 
BG meter provided by Novo Nordisk 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 and how to note the values and dates. The measurements 
are supportive for the investigator’s treatment decisions when optimising glycaemic control. 
The BG meters provided by Novo Nordisk, use test strips calibrated to plasma values. Therefore, all 
measurements performed with capillary blood are automatically calibrated to plasma equivalent 
glucose values, which will be shown on the display. 
9.2.2 
Clinical efficacy laboratory assessments  
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the flowchart and the laboratory manual. 
Collection of creatinine values from medical records  
Throughout the trial period the investigator should report (in the eCRF) any creatinine values 
measured at a local laboratory and documented in medical records if they are considered to reflect 
the usual kidney function. Values that are considered to be due to reversible cause (e.g. acute 
hospitalisation, volume depletion or nephrotoxic medication) should not be reported. 
If a subject initiates chronic dialysis or receives a renal transplant, further collection of creatinine 
values from medical records is not needed.  
Central laboratory confirmatory eGFR samples 
When an eGFR result from the central laboratory indicates that one of the thresholds has been 
reached (see Section 4.2.1),  
• ≥ 50% reduction in eGFR from baseline or 
• eGFR < 15 mL/min/1.73 m2 
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a confirmatory sample of this endpoint must be obtained and sent to the central laboratory as soon 
as possible, but at least 4 weeks after the date of the first eGFR assessment meeting the threshold 
was obtained. The subject should be called for an unscheduled visit in order to obtain the 
confirmatory test, unless a scheduled visit is planned. 
If medical records indicates that one of the thresholds has been reached the subject should be called 
in for a central laboratory eGFR assessment as described above as soon as possible. If this central 
laboratory value has reached one of the thresholds, a confirmatory sample from the central 
laboratory must be obtained at least 4 weeks after the date of the first central laboratory 
measurement. 
Confirmatory tests should not be collected after the end of treatment visit. 
9.2.3 
Patient reported outcomes  
The EQ-5D-5L questionnaire is a patient reported outcome (PRO) tool. The PRO will be used to 
estimate the impact on subjects’ health-related quality of life and provides a description of subjects’ 
problems by dimensions (descriptive system), a score for overall self-rated health (visual analogue 
scale [VAS] as well as an index score [EQ-5D-5L index]). If clarification of the test is needed, care 
must be taken not to bias the subject. Data from completed questionnaires must be transcribed to the 
eCRF by delegated site staff. 
9.3 
Adverse events  
The definitions of AEs and SAEs can be found in Appendix 4. 
Japan: For country specific requirements, please see Appendix 8.  
The investigator is responsible for detecting, documenting, recording and following up on: 
• All SAEs  
• AEs leading to discontinuation of trial product 
• AEs related to COVID-19, irrespective of seriousness. 
Note: Suspected COVID-19 should be reported if the clinical presentation is suggestive of 
COVID-19, even in the absence of a positive COVID-19 test. In the absence of clinical 
symptoms, a positive COVID-19 test (antigen or antibody) should be reported, if available.  
• Selected types of AEs (SAEs and non-SAEs) requiring additional data collection (on specific 
event forms) and events for adjudication (see Table 9-1). 
9.3.1 
Time period and frequency for collecting AE and SAE information  
All events meeting the definition of an SAE (see Appendix 4) and events listed in Section 9.3 and 
Table 9-1 must be collected and reported. This includes events from the day of randomisation until 
the follow-up visit/end of trial visit, at the time points specified in the flowchart (Section 1). All 
SAEs will be recorded and reported to Novo Nordisk or designee within 24 hours, as indicated in 
Appendix 4. The investigator must submit any updated SAE data to Novo Nordisk within 24 hours 
of it being available. 
Investigators are not obligated to actively seek for AE or SAE in former trial subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject has been 
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discontinued from/completed the trial, and the investigator considers the event to be 
possibly/probably related to the investigational trial product or trial participation, the investigator 
must promptly notify Novo Nordisk. 
The method of recording, evaluating and assessing causality of AE and SAE and the procedures for 
completing and transmitting SAE reports are provided in Appendix 4. Timelines for reporting of 
AEs, including events for adjudication, Section 9.3.1.1, are listed in Figure 9-1. 
Some AEs require additional data collection via a specific event form. The relevant specific events 
are listed in Table 9-1 and the reporting timelines in.  
Figure 9-1 
Decision tree for determining the event type and the respective forms to 
complete with associated timelines  
 
 
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9.3.1.1 
Events for adjudication  
The list of events for adjudication can be found in Table 9-1and the reporting timelines in 
Figure 9-1.  
Event adjudication will be performed for events in randomised subjects. These events are reviewed 
by an independent external event adjudication committee (EAC) in a blinded manner; refer to 
Appendix 3 for further details. 
There are four ways to identify events relevant for adjudication as described below:  
1. Investigator-reported events for adjudication: When reporting AEs, the investigator must select 
the appropriate AE category based on pre-defined criteria (see Table 9-1).If the selected AE 
category is in scope for adjudication, an event specific adjudication form must be completed. 
Relevant predefined source documents must, if obtainable, be collected and uploaded to the 
Event Adjudication System (EAS). 
2. Deaths (AEs reported with fatal outcome): When an AE is reported with fatal outcome, a death 
adjudication form will appear in the eCRF. This form must be completed and all source 
documents associated with the subjects’ death must, if obtainable, be collected and uploaded to 
the EAS. 
3. AE search (standardised screening): All AEs not directly reported by the investigator as 
requiring adjudication, will undergo screening to identify potential events for adjudication. If 
the AE is deemed relevant for adjudication, an event specific adjudication form will be 
1. abdominal pain consistent with acute pancreatitis (acute 
onset of a persistent, severe, epigastric pain often radiating 
to the back) 
2. serum lipase activity (and/or amylase activity) at least 
three times greater than the upper limit of normal  
3. characteristic findings of acute pancreatitis on imaging 
 
Diabetic retinopathy 
New onset or worsening of diabetic retinopathy 
Not applicable 
Specific event form 
Malignant neoplasm 
Malignant neoplasm confirmed by histopathology or other 
substantial clinical evidence. 
Not applicable 
Specific event form 
Medication error 
Medication errors related to trial product. For details regarding 
medication errors, see Appendix 4, Table 12-4.  
Not applicable 
Specific event form 
Severe hypoglycaemic episode 
Hypoglycaemia associated with severe cognitive impairment 
requiring external assistance for recovery.22, 23 
Not applicable 
 
Specific event form 
 
If the episode fulfils the 
criteria of an SAE, an 
AE form and a safety 
information form must 
also be completed 
Japan: For country 
specific requirements, 
refer to Appendix 8. 
 
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generated in the eCRF. This form must be completed, and all predefined source documents 
must, if obtainable, be collected and uploaded to the EAS. 
4. EAC-identified events: During review of source documents provided for another event for 
adjudication, the EAC may identify additional events in scope for adjudication that were not 
initially reported by the investigator. In these instances, the investigator will be notified of the 
newly identified event and has the option to report the EAC-identified event. Regardless of 
whether the investigator decides to report the event, it will undergo adjudication. Occasionally, 
EAC-identified events may require the investigator to collect additional source documents and 
upload these, if obtainable, to the EAS. 
The specific adjudication form for the event in question should be completed in the eCRF within 7 
calendar days of the investigator's first knowledge of the event. 
Copies of source documents should be labelled with trial ID, subject number, AE number (if 
applicable), redacted (anonymised of personal identifiers) and uploaded to the EAS as soon as 
possible and preferably within 4 weeks. If no or insufficient source documents are provided to the 
adjudication supplier, the investigator can be asked to complete a clinical narrative to be uploaded 
to the EAS. 
If new information becomes available for an event sent for adjudication, it is the responsibility of 
the investigator to ensure the new information is uploaded to the EAS. 
An Event Adjudication site manual will be provided to each site detailing which source documents 
are relevant and how these should be provided to the adjudication supplier. The anonymization and 
labelling requirements are also described in the site manual. 
The assessments made by both the event adjudication committee and the investigator will be 
evaluated and included in the clinical trial report (CTR). 
9.3.2 
Method of detecting AEs and SAEs  
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the subject is the preferred method to inquire about events. 
9.3.3 
Follow-up on AEs and SAEs  
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All events will be followed until resolution, stabilization, or if the event 
is otherwise explained (e.g. chronic condition) or the subject is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4. 
9.3.4 
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 
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will comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, institutional review board/independent ethics committee (IRB/IEC), and 
investigators. 
To avoid introducing bias and to maintain the integrity of the primary analysis, Novo Nordisk will 
exempt SAEs that are part of the primary objective evaluation from unblinding and reporting during 
trial conduct, even if the cases fulfil the definition of suspected unexpected serious adverse 
reactions (SUSARs). The DMC (Appendix 3) receives unblinded data and makes recommendations 
to the Novo Nordisk safety committee on an ongoing basis. This ensures adequate monitoring of 
safety while maintaining SAE reports related to the primary endpoint blinded for Novo Nordisk. 
At the end of the trial, when treatment is revealed, all exempted cases which meet the criteria for 
expedited reporting SUSARs will be submitted to the regulatory authorities. Because multiple cases 
will be identified simultaneously, Novo Nordisk will not be able to fulfil the 7 days requirement for 
fatal or life-threatening events, but will within 60 days after code break have all SUSARs submitted 
to the regulatory authorities. 
In case a regulatory authority requires the blinded report on an expedited basis, Novo Nordisk will 
submit individual blinded case reports related to investigational product to the relevant regulatory 
authorities on an expedited basis. 
Investigator safety reports must be prepared for SUSARs according to local regulatory requirements 
and Novo Nordisk policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing 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. 
9.3.5 
Cardiovascular and death events  
Specified in Table 9-1 
9.3.6 
Disease-related events and/or disease-related outcomes not qualifying as an AE or 
SAE  
Not applicable for this trial. 
9.3.7 
Pregnancies and associated adverse events  
Details of pregnancies in female subjects will be collected after the first trial-related activity after 
obtaining informed consent and until pregnancy outcome. 
If a pregnancy is reported in female subjects, the investigator should inform Novo Nordisk within 
14 calendar days of learning of the pregnancy and should follow the procedures outlined in 
Figure 9-2 and Appendix 5.  
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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. 
Figure 9-2 
Decision tree for determining the forms to complete with associated timelines 
for pregnancy  
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 2.
Prior to 
birth or 
pregnancy 
termination 
For female subjects
 
9.3.8 
Medical device incidents (including malfunctions)  
Not applicable for this trial. Refer to technical complaints in Section 9.3.9. 
9.3.9 
Technical complaints  
The investigator must assess whether a technical complaint is related to an AE. 
The definitions and reporting process for technical complaints can be found in Appendix 6. 
Timelines for reporting technical complaints are listed in Figure 9-3. 
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The following concomitant illness/medical history should be reported in the eCRF: 
• T2D including date of diagnosis 
• Diabetes complications, including hypoglycaemia unawareness and neuropathy 
• History of kidney disease including data on previous eGFR and UACR measurements  
• History of CV disease including peripheral artery disease 
• History of eye diseases 
• History of pancreatitis 
• History of gallbladder diseases 
• History of malignant neoplasms 
• Other relevant concomitant illness/medical history including COVID-19  
In case of an abnormal and clinically significant finding, the investigator must record the finding on 
the Medical History/Concomitant Illness form if it is present at randomisation. Any new finding 
fulfilling the SAE definition (see Appendix 4) or included in Section 9.3 or Table 9-1 during the 
trial and any clinically significant worsening from baseline (visit 2) must be reported as an AE (see 
Section 9.3). 
9.5.1 
Physical examinations  
A physical examination will include assessments of the: 
• General appearance 
• Thyroid gland 
• Respiratory system 
• Cardiovascular system 
• Abdomen 
• Extremities 
• Skin 
• Central and peripheral nervous system  
Relevant findings present at or prior to randomisation should be recorded on the Medical 
History/Concomitant Illness form in the eCRF in accordance with Section 9.5. Findings not present 
at randomisation should be reported as AEs according to Section 9.3.  
Body measurements (height and weight) will also be measured and recorded as specified in the 
flowchart (Section 1). Height should be assessed without shoes. Body weight should be assessed in 
light clothes without shoes.  
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
9.5.2 
Vital signs  
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
subject in a sitting position and a quiet setting without distractions (e.g. television, cell phones). 
• Blood pressure will consist of 3 diastolic and systolic blood pressure measurements with 
intervals of at least 1 minute in between. All three readings must be entered in the eCRF and the 
average of the 3 blood pressure readings will be calculated in the eCRF. 
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• Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available. 
• The measured values should be recorded without rounding.  
9.5.3 
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 
randomisation 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 precorneal 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 randomisation 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 randomisation an eye examination performed according to the above must be performed as 
per the flowchart within visit window (see Section 1) or within 8 weeks before the applicable visit. 
The investigator should indicate the outcome of each examination. Relevant findings prior to 
randomisation must be recorded as concomitant illness/medical history, while relevant findings 
occurring after randomisation should be reported as an AE, if applicable according to Section 9.3. 
The subject must be informed that pharmacologically pupil-dilated fundus examination may make 
the eyes more sensitive to light and cause blurry vision, and that driving should not take place if the 
vision is impaired. 
India: For country specific requirements, please see Appendix 8. 
9.5.4 
Clinical safety laboratory assessments  
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the laboratory manual and the flowchart in Section 1. 
9.6 
Pharmacokinetics  
Not applicable for this trial. 
9.7 
Pharmacodynamics  
Not applicable for this trial. 
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9.8 
Genetics  
Not applicable for this trial. 
9.9 
Biomarkers  
Collection of blood and urine samples for future research 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 analysis. 
The samples are collected for the purpose of allowing future analyses of circulating 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 circulating biomarkers may include analysis of hormones, metabolites or other non-
genetic plasma or serum parameters with the purpose of understanding and predicting response to 
semaglutide as well as to increase understanding nephrologic and cardiometabolic diseases. 
These 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 a central 
laboratory (see Appendix 7). 
Brazil, China, Israel, South Africa and Turkey: For country specific requirements, please see 
Appendix 8. 
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10 Statistical considerations  
10.1 
Sample size determination  
The trial is designed with 90% power to confirm superiority for the primary endpoint, i.e., reject the 
null-hypothesis H0: HR >=1.0 against the one-sided alternative Ha: HR <1.0, where HR represents 
the hazard ratio comparing semaglutide to placebo. For the group sequential design, an alpha 
spending function will be used that approximates O'Brian Fleming stopping boundaries for the 
overall Type I error probability of 2.5% (one-sided). Based on a randomisation ratio of 1:1 and a 
true HR of 0.8, a total of 854 primary endpoint events are required for 90% power. 
The assumptions for all the power calculations below are based on analysis of data from the 
subpopulation, approximately 5%, from the liraglutide CV outcome trial EX2211-3748 (LEADER), 
which fulfilled inclusion criteria 2-6 described in Section 6.1. All assumptions are further supported 
by data from the similar subpopulation in the smaller and shorter semaglutide CV outcome trial 
NN9535-3744 (SUSTAIN 6).  
For the calculation of number of randomised subjects it is assumed that: 
• annual primary endpoint rate in the placebo group is 7.5% 
• uniform recruitment occurs in 21 months 
• annual lost to follow-up rate in both treatment groups is of 1% 
• trial duration is five years and five weeks (from first subject randomised to last subject last visit 
(LSLV)) 
Under these assumptions a total of 3,508 subjects are needed for randomisation. 
Compared to when LEADER was conducted, the use of SGLT-2 inhibitors is anticipated to become 
more widespread at the time of conduct of this trial. The event rate observed in LEADER for this 
nephropathy composite outcome was 9.4% in the placebo group. Recently conducted trials with 
SGLT-2 inhibitors have suggested a beneficial effect on new or worsening nephropathy.17, 18 Taking 
this into account, a primary endpoint event rate of 7.5% in the placebo group and hazard ratio of 0.8 
is assumed.  
The annual loss rate of 2% (considered a worst case scenario) is based on lost to follow-up rates 
seen in the SUSTAIN 6 and LEADER trials, while also taking into account missing data for eGFR 
due to e.g. missing blood samples among subjects being followed.  
Confirmatory secondary endpoints 
If superiority is confirmed for the primary endpoint the below confirmatory secondary endpoints 
will be controlled for multiplicity through a hierarchical testing strategy. The marginal powers 
below are calculated under the assumptions that the trial continues to the final analysis and that 
testing is done at a 2.5% level (one-sided).     
The confirmatory secondary endpoint, annual rate of change in eGFR, is analysed using a linear 
random regression model. Under the assumption of a difference in slope of 1mL/min/1.73 m2 for 
semaglutide compared to placebo, a between subject variance for the slope of 20 and a residual 
variance of 45, the marginal power is >99%.  
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Assuming a hazard ratio of 0.8, an annual loss rate of 1% and an annual event rate of 7% in the 
placebo group for the confirmatory secondary MACE endpoint, the marginal power for confirming 
superiority is 89%. With similar assumptions for hazard ratio and loss rate and assuming an event 
rate of 5% in the placebo group, the marginal power for the third confirmatory secondary endpoint, 
time to all-cause death, is 78%.  
10.2 
Definition of analysis sets  
The full analysis set (FAS) is defined as all randomised subjects and grouped in analyses according 
to the treatment assigned at randomisation. 
Subjects continue in the trial and are part of FAS regardless of discontinuation of randomised 
treatment and any other intercurrent event. A subject is considered lost to follow-up if the subject 
does not complete the trial and does not withdraw consent. Trial completers are defined as subjects 
that either attend the follow-up visit or who die during the in-trial period. 
The in-trial observation period for a subject is defined as the period from date of randomisation to 
the first of (both inclusive): 
• date of follow-up visit 
• date when subject withdrew consent 
• date of last contact with subject (for subject lost to follow-up)  
• date of death 
In line with the estimand for this trial, all endpoints will be evaluated in terms of the in-trial 
observation period only. 
10.3 
Statistical analyses  
A comprehensive statistical analysis plan (SAP) will be available before first subject first visit, 
including details of interim testing.  
Novo Nordisk will perform the statistical analyses except the interim testing, see Section 10.3.4. A 
statistician independent of trial conduct, DMC analyses, interim testing, and external to Novo 
Nordisk will repeat the statistical analyses of the primary endpoint and secondary confirmatory 
endpoints. 
General considerations 
For confirmatory endpoints controlled for multiplicity, estimated treatment effects will be presented 
together with two-sided 95% confidence intervals (CIs) and one-sided p-values for tests of the 
hypotheses of superiority. For reporting of results, the estimated treatment effect and the 95% 
confidence interval will be accompanied by the two-sided p-value.  
For non-confirmatory endpoints, the estimated treatment effects will be presented together with 
two-sided 95% confidence intervals and two-sided p-values corresponding to testing the exploratory 
hypotheses of no difference. 
Unless otherwise mentioned, baseline assessment is defined as the latest available measurement 
from the randomisation visit (V2) or the screening visit (V1). Thus, if a V2 assessment is missing 
then the assessment from V1 will be used as the baseline assessment, if available. For eGFR, the 
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baseline assessment is defined as the mean of the two assessments from the randomisation visit 
(V2) and the screening visit (V1). If only one of the assessments is available, this will be used as the 
baseline assessment. For UACR, the baseline assessment is defined as the mean of the two 
assessments from the randomisation visit (V2). If only one of the assessments is available, this will 
be used as the baseline assessment. 
Missing data are defined as data that are planned and can be observed but are not present in the 
database. This implies that data that are structurally missing due to death or administrative 
censoring are not considered missing. 
If adjudicated, time-to-event endpoints are defined based on outcomes of the EAC evaluations. If a 
subject experience the event of interest during the in-trial observation period, the endpoint is the 
time from randomisation to the date of event. While vital status is ascertained systematically 
throughout the trial, non-fatal events cannot be systematically collected after withdrawal of consent, 
lost-to-follow-up, or after end-of-trial follow-up visit. For this reason, any event occurring after the 
in-trial observation period is not included in analyses, unless otherwise stated. 
Time-to-event endpoints are censored at the end of the in-trial period if the event of interest did not 
happen during this period and the subject is alive at the end of the period. Censoring due to lost to 
follow-up and withdrawal of consent assume independent censoring. Additional anticipated 
intercurrent events and handling of these in context of the estimand for the primary and 
confirmatory secondary time-to-event endpoints are described in Table 10-1. 
10.3.1 
Primary endpoint  
The hazard ratio for comparing semaglutide versus placebo will be estimated from a stratified Cox 
proportional hazards model with treatment (semaglutide, placebo) as fixed factor together with the 
2-sided 95% confidence interval and one-sided p-value for hypothesis testing. Stratification is by 
use of SGLT-2 inhibitors (yes/no) at baseline. The score test from the Cox model will be used for 
testing. The following superiority hypothesis will be tested: 
H0: HR ≥ 1.0 against Ha: HR < 1.0. 
Superiority of semaglutide versus placebo will be considered confirmed if the associated H0 is 
rejected based on nominal significance level derived from the pre-specified alpha spending based 
on the actual observed number of events available for the analysis. Final inference on termination is 
adjusted for the group sequential design by using the likelihood ratio ordering for the p-value and 
95% CI and HR.  
In the primary analysis missing data for scheduled central laboratory eGFR values due to e.g. 
missing blood samples while subjects are still being followed are not imputed, implicitly assuming 
no eGFR component events observed during the in-trial observation period with missing eGFR 
values. 
Sensitivity analysis 
If superiority is established for the primary endpoint, the following sensitivity analysis is 
performed. The primary analysis assumes independent censoring for subjects who are lost to 
follow-up or who withdrawn consent. To investigate the impact of this assumption on the 
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superiority conclusion of the primary analysis, a tipping point analysis will be made. In this 
analysis, subjects in the semaglutide treatment group will have their event times imputed with an 
increasing penalty in the sense that their risk of a primary endpoint event is increased (the penalty) 
following censoring compared to while under observation. The placebo subjects will be imputed 
with no penalty, i.e. assuming same event rate before and after censoring. Multiple imputed data 
sets will be analysed with separate stratified Cox regressions as for the primary analysis and results 
will be combined using Rubin’s rule. The tipping point is then defined as the penalty needed to turn 
around the superiority conclusion. 
10.3.2 
Secondary endpoints  
Secondary endpoints are categorised as being confirmatory when they are analysed under 
multiplicity control. 
10.3.2.1 
Confirmatory secondary endpoints  
If superiority is established for the primary endpoint, the superiority hypothesis stated in Section 
10.3.1 is tested for the three confirmatory secondary endpoints under multiplicity control via a 
hierarchical testing scheme using the following order: 
1. Annual rate of change in eGFR (total eGFR slope) 
2. Time to first occurrence of MACE 
3. Time to occurrence of all-cause death 
The testing procedure is stopped the first time an analysis fails to confirm superiority of the 
endpoint in question. The statistical significance levels of the confirmatory secondary endpoint 
analyses are specified in the SAP.  
The annual rate (slope) of decline in eGFR will be compared between treatment groups based on a 
linear random regression model on eGFR values with treatment, use of SGLT-2 inhibitors (yes/no) 
at baseline,  time (as a continuous variable) and treatment time interaction as fixed effects, and 
including subject effect as a random intercept and time as a random slope. The random intercept 
and slope is assumed to be bivariate normal distributed with mean zero and an unstructured 
covariance matrix. The independent error term is assumed to be identical univariate normal 
distributed with mean zero. To estimate the slope the model will be fitted to scheduled central 
laboratory baseline and post-baseline data. The parameter of interest is the coefficient for the 
treatment and time interaction term, which measures the slope difference between semaglutide and 
placebo. The two confirmatory secondary time-to-event endpoints will be analysed using the 
stratified Cox proportional hazards model as described for the primary endpoint. 
The following Table 10-1 describes in how anticipated intercurrent events during the trial are 
handled for confirmatory endpoints. 
 
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In addition, all-cause death is analysed using FAS and an extended in-trial observation period 
including the follow-up for vital status for subjects who withdraw consent or are lost to follow-up. 
The stratified Cox proportional hazards model as described for the primary endpoint will be used. 
10.3.3 
Exploratory endpoints  
The exploratory endpoints will be analysed the same way as the supportive secondary continuous 
endpoints.  
10.3.4 
Interim testing for efficacy  
Interim testing evaluating the primary endpoint for superiority will be performed based on a locked 
snapshot of the study database at the time-point of an interim testing. Subjects without a primary 
endpoint event prior to the analysis cut-off date will be censored with the censoring date defined as 
the first of in-trial end-date and analysis cut-off date.  
Interim testing will be performed by a statistician independent of trial conduct and external to Novo 
Nordisk. The DMC evaluates the unblinded interim testing using the group sequential stopping 
boundaries as guidance, as defined in the SAP. Stopping the trial for superiority is allowed if a 
stopping boundary is crossed and the DMC makes the decision to recommend early trial 
termination. 
If the trial is terminated early for superiority following an interim testing, definitive evaluation of 
superiority for the primary endpoint will be performed based on updated nominal significance 
levels. All events from the in-trial observation period including events collected after interim cut-off 
date will be included in this confirmatory evaluation. 
10.3.5 
Sequential safety analysis and safety monitoring  
Blinded and unblinded data analyses during trial conduct will be performed by the DMC, as 
described in the DMC charter. Trial integrity will be ensured by using a statistician independent of 
trial conduct and external to Novo Nordisk to prepare data for the DMC. The sequential analyses 
performed by the DMC will be based on accumulated efficacy (see Section 10.3.4) and safety data 
and will be performed to make recommendations regarding the ongoing conduct of the trial to 
ensure acceptable benefit/risk ratio for subjects in the trial. 
10.4 
Pharmacokinetic and/or pharmacodynamic modelling  
Not applicable for this trial. 
 
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11 References  
1. 
The European Parliament and the Council of the European Council. Directive 2001/20/EC 
of the European Parliament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the member states relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use. 2001. 
2. 
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. 
3. 
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with 
sulphonylureas or insulin compared with conventional treatment and risk of complications 
in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-53, Erratum 
1999; 354: 602. 
4. 
Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose 
control in development of renal end points in type 2 diabetes mellitus: systematic review and 
meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med. 
2012;172(10):761-9. 
5. 
National Kidney Foundation. KDOQI Clinical Practice Guideline for Diabetes and CKD: 
2012 Update. Am J Kidney Dis. 2012;60(5):850-86. 
6. 
Sanofi-Aventis.  AVAPRO (irbesartan),   US Prescribing Information (PI). February 2016. 
7. 
Merch and CO. COZAAR (losartan), US Prescribing Information (PI). Mar 2013. 
8. 
Par Phrmaceutical. CAPOTEN (captopril), US Prescribing Information (PI). Dec 2014. 
9. 
Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective 
effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to 
type 2 diabetes. N Engl J Med. 2001;345(12):851-60. 
10. 
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of 
losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and 
nephropathy. N Engl J Med. 2001;345(12):861-9. 
11. 
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme 
inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 
1993;329(20):1456-62. 
12. 
Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. 
Liraglutide and Renal Outcomes in Type 2 Diabetes. N Engl J Med. 2017;377(9):839-48. 
13. 
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;375:1834-
44. 
14. 
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. 
15. 
Bethel M, Mentz R, Merrill P, Buse J, Chan J, Goodman S, et al. Renal Outcomes in the 
EXenatide Study of Cardiovascular Event Lowering (EXSCEL). Diabetes. 2018;67(Suppl. 
1). 
16. 
Tuttle KR, Lakshmanan MC, Rayner B, Busch RS, Zimmermann AG, Woodward DB, 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. 
17. 
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin 
and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-
57. 
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18. 
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. 
19. 
Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, et al. Diabetic 
kidney disease: a report from an ADA Consensus Conference. Diabetes Care. 
2014;37(10):2864-83. 
20. 
Lilly. Boehringer Ingelheim and Lilly announce an academic collaboration with University 
of Oxford to investigate the effects of Jardiance in adults with chronic kidney disease 2018 
[cited 2018 31-May-2018]. 
21. 
Gansevoort RT, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, et al. 
Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. 
A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int. 
2011;80(1):93-104. 
22. 
Group IHS. Glucose Concentrations of Less Than 3.0 mmol/L (54 mg/dL) Should Be 
Reported in Clinical Trials: A Joint Position Statement of the American Diabetes 
Association and the European Association for the Study of Diabetes. Diabetes Care. 
2017;40(1):155-7. 
23. 
American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in 
Diabetes-2018. Diabetes Care. 2018;41(Suppl 1):S55-S64. 
24. 
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. 
25. 
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. 
26. 
ICH Harmonised Tripartite Guideline. Guideline for Good Clinical Practice E6(R2), Step 4 
version. 09 Nov 2016. 
27. 
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. 
28. 
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. 
29. 
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. 
30. 
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, article 11. Official Journal of the European Communities. 01 May 
2001. 
31. 
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. 
 
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12 Appendices  
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Appendix 1 
Abbreviations and Trademarks  
ACE 
angiotensin converting enzyme  
AE 
adverse event 
ARB 
angiotensin II receptor blocker 
BG 
blood glucose 
CKD 
chronic kidney disease  
CKD-EPI  
chronic kidney disease - epidemiology collaboration 
COVID-19 
Coronavirus disease 2019 
CTR 
clinical trial report 
CV 
cardiovascular 
DMC 
data monitoring committee 
DUN 
dispensing unit number 
EAC 
event adjudication committee 
EAS 
event adjudication system 
eCRF 
electronic case report form  
eGFR 
estimated glomerular filtration rate 
ESRD 
end-stage renal disease  
FAS 
full analysis set 
FSH 
follicle-stimulating hormone  
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GLP-1 
glucagon-like peptide-1 
HbA1c 
glycated haemoglobin 
HRT 
hormonal replacement therapy 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalised ratio  
IRB 
institutional review board 
IUD 
intrauterine device 
IWRS 
interactive web response system 
LSLV 
last subject last visit 
MACE 
major adverse cardiovascular event  
MALE 
major adverse limb event  
PCD 
primary completion date 
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PRO 
patient reported outcome 
RAAS 
renin-angiotensin-aldosterone system 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneously 
SGLT-2 
sodium glucose cotransporter-2  
SUSAR 
suspected unexpected serious adverse reaction 
T2D 
type 2 diabetes 
TMM 
trial materials manual 
UACR 
urinary albumin-to-creatinine ratio  
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 
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Appendix 3 
Trial governance considerations  
1) Regulatory and ethical considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki25 and applicable ICH Good Clinical Practice (GCP) 
Guideline26. 
• 
Applicable laws and regulations 
• The protocol, informed consent form, investigator’s brochure (as applicable) and other relevant 
documents (e.g. advertisements), must be submitted to an IRB/IEC and reviewed and approved 
by the IRB/IEC before the trial is initiated. 
• Regulatory authorities will receive the clinical trial application, protocol amendments, reports 
on SAEs, and the CTR according to national requirements. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate safety 
hazard to trial subjects. 
• Before a trial site is allowed to start screening subjects, written notification from Novo Nordisk 
must be received. 
• The investigator will be responsible for: 
• 
providing written summaries of the status of the trial annually or more frequently in 
accordance with the requirements, policies, and procedures established by the 
IRB/IEC and/or regulatory authorities 
• 
notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• 
providing oversight of the conduct of the trial at the site and adherence to 
requirements of ICH guidelines, the IRB/IEC, and all other applicable local 
regulations 
• 
ensuring submission of the CTR synopsis to the IRB/IEC. 
Japan, Mexico and Russia: For country specific requirements, please see Appendix 8. 
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 trial sites: verification under disclosures per Code of Federal Regulations (CFR) of 
Financial Conflict of Interest. 
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. This includes the use of an impartial witness where 
required according to local requirements. 
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• The investigator must ensure the subject ample time to come to a decision whether or not to 
participate in the trial. 
• Subjects must be informed that their participation is voluntary. 
• Subjects will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, ICH guidelines26, Declaration of Helsinki25 and the IRB/IEC 
or trial site. 
• The medical record must include a statement that written informed consent was obtained before 
any trial related activity and the date when the written consent was obtained. The authorised 
person obtaining the informed consent must also sign and date the informed consent form before 
any trial related activity. 
• The responsibility of seeking informed consent must remain with the investigator, but the 
investigator may delegate the task of informing to a medically qualified person, in accordance 
with local requirements. 
• Subjects must be re-consented to the most current version of the informed consent form(s) 
during their participation in the trial. 
• The informed consent form will contain a separate form that addresses long-term storage of 
human samples and the use of samples for optional exploratory research. The investigator must 
explain to each subject the objectives of the exploratory research. Subjects must be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. 
• A separate informed consent form for optional pre-screening is available. This must be signed 
before any optional pre-screening activities are performed, but it is not necessary to obtain full 
informed consent for the remaining trial period before pre-screening, see Section 9.1. 
• A copy of the informed consent form(s) must be provided to the subject. Brazil: For country 
specific requirements, please see Appendix 8. 
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. 
5) Data protection 
• Subjects will be assigned a 6-digit unique identifier, a subject number. Any subject records or 
datasets that are transferred to Novo Nordisk will contain the identifier only; subject names or 
any information which would make the subject identifiable will not be transferred. 
• The subject and any biological material obtained from the subject will be identified by subject 
number, visit number and trial ID. Appropriate measures such as encryption or leaving out 
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certain identifiers will be enforced to protect the identity of subjects as required by local, 
regional and national requirements.  
• The subject must be informed that his/her personal trial related data will be used by Novo 
Nordisk in accordance with local data protection law. The disclosure of the data must also be 
explained to the subject.  
• The subject must be informed that his/her medical records may be examined by auditors or 
other authorised personnel appointed by Novo Nordisk, by appropriate IRB/IEC members, and 
by inspectors from regulatory authorities. United Kingdom: For country specific requirements, 
please see Appendix 8. 
6) Committee structure 
Novo Nordisk safety committee 
Novo Nordisk will constitute an internal safety committee to evaluate the ongoing safety of 
semaglutide. The safety committee may recommend unblinding of any data for further analysis, and 
in this case an independent ad hoc group will be established in order to maintain the blinding of the 
trial personnel. 
Data monitoring committee (DMC) 
The DMC is an independent, external committee composed of members whose expertise cover 
relevant specialties including statistics. The DMC is established to review and evaluate accumulated 
data from the trial at predefined time points as well as ad hoc. This is done in order to protect the 
safety of the subjects and to evaluate the benefit-risk balance. The DMC will have access to 
unblinded data, and will provide recommendations on trial continuation, modification or 
termination. 
Information regarding responsibilities, procedures and workflow to be used by the DMC are 
specified in the DMC charter. 
Event adjudication committee 
An independent external event adjudication committee (EAC) is established to perform ongoing 
blinded adjudication of selected AEs and deaths, see Table 9-1.The EAC will evaluate events sent 
for adjudication using pre-defined definitions and guidelines in accordance with the EAC Charter. 
The evaluation is based on review of pre-defined clinical data collected by the investigational sites. 
The EAC is composed of permanent members covering all required medical specialties. EAC 
members must disclose any potential conflicts of interest and must be independent of Novo 
Nordisk. The EAC will have no authorisations to impact on trial conduct, trial protocol or 
amendments. The assessment made by both the EAC and the investigator will be presented in the 
CTR. 
The purpose of the adjudication is to confirm events in a consistent manner according to 
standardized criteria using independent external medical experts. 
The AEs for adjudication are listed in Section 9.3. 
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Steering committee 
A steering committee will provide scientific and operational leadership for the trial. The committee 
will consist of experts from outside Novo Nordisk, and designated Novo Nordisk employees. The 
committee will operate under a charter agreed with Novo Nordisk. 
Global expert panel 
Global expert panel(s) (GEP) consisting of selected investigators and study coordinators, referred to 
as National Leaders (NL) and National Study Coordinators (NSC), respectively, will be formed. 
The panel members will discuss and provide global as well as local, guidance and advice on 
operational aspects of the trial, including e.g. subject recruitment and retention topics, as well as 
supporting peer-to-peer communication within the trial. 
7) Publication policy 
The information obtained during the conduct of this trial is considered confidential, and may be 
used by or on behalf of Novo Nordisk for regulatory purposes as well as for the general 
development of the trial product. All information supplied by Novo Nordisk in connection with this 
trial shall remain the sole property of Novo Nordisk and is to be considered confidential 
information. 
No confidential information shall be disclosed to others without prior written consent from Novo 
Nordisk. Such information shall not be used except in the performance of this trial. 
The information obtained during this trial may be made available to other investigators who are 
conducting other clinical trials with the trial product, if deemed necessary by Novo Nordisk. 
Provided that certain conditions are fulfilled, Novo Nordisk may grant access to information 
obtained during this trial to researchers who require access for research projects studying the same 
disease and/or trial product studied in this trial. 
Novo Nordisk may publish on its clinical trials website a redacted CTR for this trial. 
One investigator will be appointed by Novo Nordisk to review and sign the CTR (signatory 
investigator) on behalf of all participating investigators. 
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 testing, because the release of such information may 
influence the results of the entire trial. 
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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. 
China: For country specific requirements, please see Appendix 8. 
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.27 
All authors will be provided with the relevant statistical tables, figures, and reports needed to 
evaluate the planned publication.  
Where required by the journal, the investigator from each trial site will be named in an 
acknowledgement or in the supplementary material, as specified by the journal.  
Site-specific publication(s) by investigator(s) 
For a multicentre clinical trial, analyses based on single-site data usually have significant statistical 
limitations and frequently do not provide meaningful information for healthcare professionals or 
subjects, and therefore may not be supported by Novo Nordisk. Thus, Novo Nordisk may deny a 
request or ask for deferment of the publication of individual site results until the primary manuscript 
is accepted for publication. In line with Good Publication Practice, such individual reports should 
not precede the primary manuscript and should always reference the primary manuscript of the trial. 
Investigator access to data and review of results 
As owner of the trial database, Novo Nordisk has the discretion to determine who will have access 
to the database. Individual investigators will have their own research subjects' data, and will be 
provided with the randomisation code after results are available. 
8) Dissemination of clinical trial data 
Information of the trial will be disclosed at clinicaltrials.gov and novonordisk-trials.com. It will also 
be disclosed according to other applicable requirements such as those of the International 
Committee of Medical Journal Editors (ICMJE)28, the Food and Drug Administration Amendment 
Act (FDAAA)29, European Commission Requirements30, 31 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 
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result of increasing requirements for transparency, some countries require public disclosure of 
investigator names and their affiliations. 
The Primary Completion Date (PCD) is the last assessment of the primary endpoint, and is for this 
trial Last Subject Last Visit (LSLV). The trial will therefore be registered with an estimated PCD 
corresponding to the estimated LSLV, which is first subject randomised plus 61 months. The PCD 
determines the deadline for results disclosure at clinicaltrials.gov according to FDAAA. 
9) Data quality assurance 
Case Report Forms (CRFs) 
• 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:  
• 
Pregnancy forms 
• 
Other CRFs 
• The following will be provided as paper CRFs to be used when access to the CRF is revoked or 
the CRF is temporarily unavailable:  
• 
AE forms  
• 
Safety information forms  
• 
Technical complaint forms (also to be used to report complaints that are not subject 
related, e.g. discovered at trial site before allocation)  
• Corrections to the CRF data may be made by the investigator or the investigator’s delegated 
staff. An audit trail will be maintained in the CRF application containing as a minimum: the old 
and the new data, identification of the person entering the data, date and time of the entry and 
reason for the correction. If corrections are made by the investigator’s delegated staff after the 
date when the investigator signed the CRF, the CRF must be signed and dated again by the 
investigator. 
• The investigator must ensure that data is recorded in the CRF as soon as possible, preferably 
within 5 working days after the visit. Once data has been entered, it will be available to Novo 
Nordisk for data verification and validation purposes.  
Monitoring 
• The investigator must permit trial-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents (original documents, 
data and records). Direct access includes permission to examine, analyse, verify and reproduce 
any record(s) and report(s) that are important to the evaluation of the trial. If the electronic 
medical record does not have a visible audit trail, the investigator must provide the monitor with 
signed and dated printouts. In addition the relevant trial site staff should be available for 
discussions at monitoring visits and between monitoring visits (e.g. by telephone).  
• Trial monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete and verifiable from source 
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documents; that the safety and rights of subjects are being protected, to monitor drug 
accountability and collect completed paper CRF pages, if applicable, and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 
• Monitoring will be conducted using a risk based approach including risk assessment, monitoring 
plans, centralised monitoring (remote assessment of data by Novo Nordisk) and visits to trial 
sites.  
• Monitors will review the subject’s medical records and other source data to ensure consistency 
and/or identify omissions compared to the CRF.  
Protocol compliance 
Deviations from the protocol should be avoided. If deviations do occur, the investigator must 
inform the monitor and the implications of the deviation must be reviewed and discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the CRF or via listings from the trial database.  
10) Source documents 
• All data entered in the CRF must be verifiable in source documentation other than the CRF. 
• The original of the completed PROs must not be removed from the trial site, unless they form 
part of the CRF and a copy is kept at the site.  
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the trial site. 
• Data reported on the paper CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records. 
Also, current medical records must be available.  
• It must be possible to verify subject’s medical history in source documents such as subject’s 
medical record 
• The investigator must document any attempt to obtain external medical information by noting 
the date(s) when information was requested and who was contacted. 
• Definition of what constitutes source data can be found in a source document agreement at each 
trial site. There will only be one source document defined at any time for any data element. 
11) Retention of clinical trial documentation 
• Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the investigator for 15 years after end of trial unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novo Nordisk. No records 
may be transferred to another location or party without written notification to Novo Nordisk. 
Spain: For country specific requirements, please see Appendix 8. 
• The investigator must be able to access his/her trial documents without involving Novo Nordisk 
in any way. If applicable, electronic CRF and other subject data will be provided in an 
electronic readable format to the investigator before access is revoked to the systems supplied 
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by Novo Nordisk. Site-specific CRFs and other subject data (in an electronic readable format or 
as paper copies or prints) must be retained by the trial site. If the provided electronic data (e.g. 
the CD-ROM) is not readable during the entire storage period, the investigator can request a 
new copy. A copy of all data will be stored by Novo Nordisk. 
• Subject’s medical records must be kept for the maximum period permitted by the hospital, 
institution or private practice 
12) Trial and site closure 
Novo Nordisk reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of Novo Nordisk. If the trial is suspended or terminated, the 
investigator must inform the subjects promptly and ensure appropriate therapy and follow-up. The 
investigator and/or Novo Nordisk must also promptly inform the regulatory authorities and 
IRBs/IECs and provide a detailed written explanation. 
Trial sites will be closed upon trial completion. A trial site is considered closed when all required 
documents and trial supplies have been collected and a trial site closure visit has been performed. 
The investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by Novo Nordisk or investigator may include but are not 
limited to: 
• failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or local 
health authorities, Novo Nordisk procedures or GCP guidelines 
• inadequate recruitment of subjects by the investigator 
• discontinuation of further trial product development 
Pre-planned interim testing may allow for premature termination of the trial. 
13) Responsibilities 
The investigator is accountable for the conduct of the trial at his/her site and must ensure adequate 
supervision of the conduct of the trial at the trial site. If any tasks are delegated, the investigator 
must maintain a log of appropriately qualified persons to whom he/she has delegated specified trial-
related duties. The investigator must ensure that there is adequate and documented training for all 
staff participating in the conduct of the trial. It is the investigator’s responsibility to supervise the 
conduct of the trial and to protect the rights, safety, and well-being of the subjects. 
A qualified physician, who is an investigator or a 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. 
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The investigator will take all necessary technical and organisational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The investigator will prevent any 
unauthorised access to data or any other processing of data against applicable law. The investigator 
must be able to provide the necessary information or otherwise demonstrate to Novo Nordisk that 
such technical and organisational safety measures have been taken. 
During any period of unavailability, the investigator must delegate responsibility for medical care of 
subjects to a specific qualified physician who will be readily available to subjects during that time. 
If the investigator is no longer able to fulfil the role as investigator (e.g. if he/she moves or retires) a 
new investigator will be appointed in consultation with Novo Nordisk.  
The investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 
14) Indemnity statement  
Novo Nordisk carries product liability for its products, and liability as assumed under the special 
laws, acts and/or guidelines for conducting clinical trials in any country, unless others have shown 
negligence. 
Novo Nordisk assumes no liability in the event of negligence or any other liability of the sites or 
investigators conducting the trial or by persons for whom the said site or investigator are 
responsible.  
Belgium, France and Mexico: For country specific indemnity statements, please refer to Appendix 
8. 
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Appendix 5 
Contraceptive guidance and collection of pregnancy 
information  
It must be recorded in the CRF whether female subjects are of childbearing potential.  
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile.  
Women in the following categories are not considered WOCBP 
1. Premenarcheal 
2. Premenopausal female with one of the following: 
• 
Documented hysterectomy 
• 
Documented bilateral salpingectomy 
• 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of subject’s medical records, 
medical examination or medical history interview. 
3. Postmenopausal female 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high Follicle Stimulating Hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or Hormonal Replacement Therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
• 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the trial. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before trial enrolment. 
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(s) below: 
 
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Table 12-5 
Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependent a and b  
Failure rate of <1% per year when used consistently and correctly.  
Combined (oestrogen and progestogen containing) oral, intravaginal or transdermal hormonal contraception associated 
with inhibition of ovulation  
Progestogen only oral or injectable hormonal contraception associated with inhibition of ovulation 
Highly effective methods that are user independentb  
• Implantable progesteron only hormonal contraception associated with inhibition of ovulation 
• Intrauterine Device (IUD) 
• Intrauterine hormone-releasing System (IUS) 
• Bilateral tubal occlusion 
Vasectomised partner  
A vasectomised partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
Sexual abstinenceb 
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 product. 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:  
aTypical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical trials.  
bContraception should be utilised during the treatment period and for at least 5 weeks 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 above or where 
the use of any listed highly effective contraceptive measures are contraindicated in the 
individual subjects, and/ or 
• if the risk of initiating treatment with a specific highly effective method outweigh the predicted 
benefits of trial participation for the female subject. 
Justification for accepting double barrier method should be at the discretion of the investigator. The 
justification must be stated in the medical records.   
Argentina, Belgium, Germany, Italy, Spain and United Kingdom: For country specific 
requirements, please see Appendix 8. 
Pregnancy testing 
• WOCBP should only be included after a negative highly sensitive urine pregnancy test. 
• Additional urine pregnancy testing should be performed at monthly intervals during the 
treatment period, if required locally (Appendix 8). 
• Pregnancy testing should be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
• A urine pregnancy test must also be completed for WOCBP at the end of treatment and follow-
up visits. 
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Collection of pregnancy information  
Female subjects who become pregnant  
• Investigator will collect pregnancy information on any female subject, who becomes pregnant 
while participating in this trial. 
• Information will be recorded on the appropriate form and submitted to Novo Nordisk via secure 
fax line, encrypted e-mail or courier within 14 calendar days of learning of a subject's 
pregnancy. 
• Subject will be followed to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on subject and neonate, which will be forwarded to Novo 
Nordisk. Generally, follow-up will not be required for longer than 1 month beyond the delivery 
date. 
• Any termination of pregnancy will be reported, regardless of foetal status (presence or absence 
of anomalies) or indication for procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE.  
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-trial pregnancy which is considered possibly/probably 
related to the trial product by the investigator will be reported to Novo Nordisk as described in 
Appendix 4. While the investigator is not obligated to actively seek this information in former 
subjects, he or she may learn of an SAE through spontaneous reporting.  
Any female subject who becomes pregnant while participating in the trial will discontinue trial 
product.  
 
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Appendix 7 
Retention of human biosamples  
In countries where allowed, the trial will involve collection of human biosamples to be stored in a 
central archive for future use as noted in Section 9.9. The following samples will be stored: 
• EDTA plasma (for future analyses of circulating biomarkers) 
• Urine (for future analyses of urinary biomarkers)  
The samples will be stored at a secure central bio-repository 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. 
Subjects may withdraw from the biobank component of the trial at any time, independent of 
participation in the trial. The subject can chose 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 stored biosamples 
obtained from their own body will be destroyed. 
Confidentiality and personal data protection will be ensured during storage after the end of trial. 
In the event that the collected biosamples will be used in the future, care will be taken to target 
analyses within the scope defined in Section 9.9. 
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Appendix 8 
Country-specific requirements  
Argentina: 
• Appendix 5: Use of barrier contraceptive method with spermicide in combination with another 
highly effective method as described in Table 12-5 is required for WOCBP. 
• Appendix 5: Monthly testing with highly sensitive urine pregnancy tests is required for 
WOCBP. 
• Novo Nordisk will reimburse costs of standard of care treatment for CKD (angiotensin 
converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB)), pregnancy tests 
and contraceptive methods 
Belgium: 
• Appendix 3, section 14: Even if without fault, the sponsor is liable for the damage which the 
subject and/or his rightful claimants sustain and which shows either a direct or an indirect 
connection with the trial (according to law concerning experiments on the human person of 07 
May 2004 - Article 29: §1). 
• Appendix 5: Contraceptive measures considered adequate include highly effective contraceptive 
methods in accordance with the CTFG (Clinical Trial Facilitation Group) “Recommendations 
related to contraception and pregnancy testing in clinical trials”, as listed in Table 12-5. This 
means that the use of double barrier methods is not applicable for Belgium.  
Brazil: 
• Section 6.2, exclusion criterion #4: Participation in other trials within one year prior to 
screening visit (Visit 1), unless there is a direct benefit to the research subject at the 
investigator's discretion (according to Resolution 251/97, item III.2.j). 
• Section 7.8: At the end of the trial, all participant subjects should be assured the access to the 
best proved prophylactic, diagnostic and therapeutic methods identified during the study 
(according to resolution CNS 466/12). 
• Section 9.9: No subjects from Brazil will take part in the optional biobank part of the trial and 
no genetic testing will be performed. 
• Appendix 2: All laboratory results will be communicated to the investigators. 
• Appendix 3, section 3: Two original informed consent forms will be signed and dated and one 
original will be given to the subject (according to resolution CNS 466/12). 
• Novo Nordisk will reimburse costs of standard-of-care treatment for CKD. 
Bulgaria: 
• Collection of age is needed for the calculation of eGFR (CKD-EPI).24 
China: 
• Section 6.2, exclusion criteria #4: ‘Simultaneous participation in a trial with the primary 
objective of evaluating an approved or non-approved investigational medicinal product for 
prevention or treatment of COVID-19 disease or postinfectious conditions is allowed if the last 
dose of the investigational medicinal product has been received more than 30 days before 
screening.’ is not applicable for China. 
• Section 8.1, discontinuation/withdrawal criteria: ‘Simultaneous participation in a trial with the 
primary objective of evaluating an approved or non-approved investigational medicinal product 
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for prevention or treatment of COVID-19 disease or postinfectious conditions is allowed at the 
investigator discretion without discontinuing trial product.’ is not applicable for China. 
• Section 9.1: Optional pre-screening is not allowed in China. 
• Section 9.9: No subjects from China will participate in the optional biobank part of the trial and 
no genetic testing will be performed. 
• Appendix 2: Laboratory samples for Chinese subjects will be destroyed according to local 
regulatory requirements, both for samples tested inside and outside China. No sample will be 
stored after the latest date of local regulatory approval. 
• Appendix 3, section 7: Information of the trial will be disclosed at clinicaltrials.gov, china, 
drugtrials.org.cn and novonordisk-trials.com, as China HA has requested to disclose trial 
information (phase 1-3) at chinadrugtrials.org.cn since 2013.  
France 
• Appendix 3, section 14: 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 of 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 (according to 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). 
• Collection of age is needed for the calculation of eGFR (CKD-EPI).24 
Germany: 
• Section 9.1: Optional pre-screening is not allowed in Germany 
• Appendix 5: Contraceptive measures considered adequate include highly effective contraceptive 
methods in accordance with the CTFG (Clinical Trial Facilitation Group) “Recommendations 
related to contraception and pregnancy testing in clinical trials”, as listed in Table 12-5. This 
means that the use of double barrier methods is not applicable for Germany. 
• Subject's full date of birth is not allowed to be collected and must be shortened to year of birth. 
Collection of age is needed for the calculation of eGFR (CKD-EPI).24 
Hungary: 
• Collection of age is needed for the calculation of eGFR (CKD-EPI).24 
India: 
• Section 9.5.3: (additional clarifications in italics) 
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. A subject with uncontrolled 
and potentially unstable retinopathy or maculopathy would be a subject that is not well-controlled 
in the sense that appropriate treatment and follow-up has not been received. 
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 
randomisation to assess eligibility. The eye examination should be performed as a fundus 
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photography (e.g. 2-field 60 degree or better, colour or red-free) or by slit-lamp biomicroscopy 
examination (e.g. using a precorneal 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 randomisation 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.  
Each eye should be evaluated separately, and presence of the following should be assessed and 
documented 
• Diabetic retinopathy – using the below staging: 
o Mild non-proliferative diabetic retinopathy (only microaneurysms) 
o Moderate-severe non-proliferative diabetic retinopathy  
o Proliferative diabetic retinopathy 
• Diabetic macular oedema 
• Impaired visual acuity (best corrected) – state Snellen grading if assessed 
Israel: 
• Section 9.9: No subjects from Israel will take part in the optional biobank part of the trial and no 
genetic testing will be performed. 
Italy: 
• Appendix 5: Contraceptive measures considered adequate include highly effective contraceptive 
methods in accordance with the CTFG (Clinical Trial Facilitation Group) “Recommendations 
related to contraception and pregnancy testing in clinical trials”, as listed in Table 12-5. This 
means that the use of double barrier methods is not applicable for Italy. 
Japan: 
• Section 6.1, inclusion criterion #2: Male or female, age above or equal to 20 years at the time of 
signing informed consent. 
• Section 7.5: The head of the study site or the trial product storage manager assigned by the head 
of the study site (a pharmacist in principle) is responsible for control and accountability of the 
trial products.  
• Section 9.3, Table 9-1: For Japan all AEs, irrespective of seriousness, should be collected from 
the day of randomisation and until the follow-up visit, at the time points specified in the 
flowchart. A non-severe non-serious hypoglycaemic episode should be reported as an AE. A 
severe non-serious hypoglycaemic episode should be reported as an AE and in addition a 
specific event form (severe hypoglycaemic episode) should be filled out. 
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• Appendix 3, section 1: A name and seal is accepted as a signature. 
Mexico: 
• Section 8.2: Should the subject, his/her family members parents, or legal representative decide 
to withdraw the consent for participation in the trial, the subject will be entitled to receive 
appropriate, free of charge medical care and/or trial drug during the follow up period of the 
protocol when it will be established with certainty that no untoward medical consequences of 
the subject´s participation in the research occurred. 
• Appendix 3, section 1: The following responsibilities for the head of the Institution/Health Care 
Establishment, Ethics, Research and, when applicable, Biosafety Committees and sponsor 
within their scope of responsibility: 
• 
Investigation follow-up. 
• 
Damages to health arising from the investigation development; as well as those 
arising from interruption or advanced suspension of treatment due to non-attributable 
reasons to the subject. 
• 
Timely compliance of the terms in which the authorization of a research for health in 
human beings had been issued. 
• 
To present in a timely manner the information required by the Health Authority. 
• Appendix 3, section 14: 
• 
Novo Nordisk carries product liability for its products assumed under the special 
laws, acts/and/or guidelines for conducting trials in any country, including those 
applicable provisions on the Mexican United States. If the subject feels that 
something goes wrong during the course of this trial, the subject should contact the 
trial staff in the first instance. 
• 
If during their participation in the trial the subject experiences a disease or injury 
that, according to the trial doctor and the sponsor, is directly caused by the trial 
medication and/or a trial procedure that otherwise would not have been part of 
his/her regular care, the subject will receive from the institution or medical care 
establishment and free of charge, the appropriate medical treatment as required. In 
this case, the costs resulting from such treatment as well as the costs of any 
indemnification established by law will be covered by the trial sponsor in accordance 
with the terms provided by all applicable regulations; even if the subject discontinues 
his/her participation in the trial by his own will or by a decision from the 
investigator. 
• 
By signing the informed consent, the subject will not renounce to any compensation 
or indemnification he/she may be entitled to by law, nor will he/she will incur any 
additional expense as a result of his/her participation in the trial; any additional 
expense resulting from the subject’s participation in the trial will be covered by the 
trial sponsor. 
Russia: 
• Appendix 3, section 1: The trial should be conducted in compliance with the protocol, Ministry 
of Healthcare of Russian Federation’ order #200н from April, 01, 2016 ”Approval of rules of 
good clinical practice” and legal requirements of the Russian Federation regulating circulation 
of medicines. 
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South Africa: 
• Section 9.9: No subjects from South Africa will participate in the optional biobank part of the 
trial and no genetic testing will be performed. 
Spain: 
• Appendix 3, section 11: Records and documents, including signed informed consent forms, 
pertaining to the conduct of this trial must be retained by the investigator for 25 years after end 
of trial.  
• Appendix 5: Contraceptive measures considered adequate include highly effective contraceptive 
methods in accordance with the CTFG (Clinical Trial Facilitation Group) “Recommendations 
related to contraception and pregnancy testing in clinical trials”, as listed in Table 12-5. This 
means that the use of double barrier methods is not applicable for Spain. 
Turkey: 
• Section 9.9: No subjects from Turkey will participate in the optional biobank part of the trial 
and no genetic testing will be performed. 
United Kingdom: 
• Appendix 3, section 5: In the United Kingdom the IRB/IEC does not have access to the patients’ 
medical records. 
• Appendix 5: Contraceptive measures considered adequate include highly effective contraceptive 
methods in accordance with the CTFG (Clinical Trial Facilitation Group) “Recommendations 
related to contraception and pregnancy testing in clinical trials”, as listed in Table 12-5. This 
means that the use of double barrier methods is not applicable for United Kingdom. 
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Appendix 9 
Mitigations to ensure subject safety and data integrity 
during epidemics/pandemics (e.g. COVID-19)  
In case local restrictions due to an epidemic/pandemic leads to lockdown of a site, the site must 
contact the Sponsor (Novo Nordisk) to allow for implementation of the mitigations mentioned in 
this appendix based on mutual agreement. Implementation of specific mitigations should be based 
on assessment of feasibility at the individual site. 
If local regulations, requirements and/or guidelines have been issued, these must be complied with. 
Assessments 
In case local restrictions due to an epidemic/pandemic lead to the lockdown of a site, site visits can 
be performed as home nursing. On-site visits are always preferred, but trial assessments can be 
performed by site staff visiting the subject´s home (or at alternative location) if needed. As a pre-
requisite it must be ensured that trial site staff is covered by workers’ compensation insurance to 
protect workers. For all assessments done at the subject´s home site specific equipment has to be 
used and procedures in the lab manual have to be followed. It must be documented in the medical 
records that the subject has consented to this process, and if any local requirements for informed 
consent applies, these must be followed. Home nursing may also be performed by a third-party 
nursing agency, if permissible by local regulation. 
Trial product alternative dispensing methods 
Alternative dispensing methods of study intervention may be implemented and details will be 
communicated and documented. The dispensing options will be based on options and requirements 
at country level and if permitted by local regulations and Novo Nordisk A/S. The trial product 
should be returned to the trial site or pharmacy when site is open and fully functioning again. 
 
 
 
 
 
 
 
 
 
 
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Appendix 10 Protocol amendment history  
Protocol amendment no. 1 (dated 24 January 2019, included in version 4.0) 
This amendment is considered to be substantial for Argentina 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 
Argentina Local Team noticed post protocol approval that the wording stating what type of standard 
of care treatment costs will be reimbursed by Novo Nordisk was included by default in Appendix 8, 
however this wording is not fully applicable due to the trial specific set-up: Novo Nordisk will 
reimburse standard of care for CKD (treatment with an angiotensin converting enzyme (ACE) 
inhibitor or an angiotensin II receptor blocker (ARB) in accordance with inclusion criteria # 6 ) and 
not for T2D in this trial. 
Section # and name 
Description of change 
Rationale 
Appendix 8                            
Country-specific requirements for 
Argentina, amendment 1 
Update of requirement: Novo Nordisk 
will reimburse costs of standard of 
care treatment for CKD (angiotensin 
converting enzyme (ACE) inhibitors 
or angiotensin II receptor blockers 
(ARB)), pregnancy tests and 
contraceptive methods 
See overall rationale 
Protocol amendment no. 2 (dated 03 June 2019, included in version 4.0) 
This amendment is considered to be substantial for Germany 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 
Changes are introduced to fulfil local requirements in Germany due to request of local HA 
Section # and name 
Description of change 
Rationale 
Appendix 8                            
Country-specific requirements for 
Germany, amendment 2 
Update of requirement: Section 9.1: 
Optional pre-screening is not allowed 
in Germany 
See overall rationale 
Protocol amendment no. 3 (dated 01 August 2019, included in version 4.0) 
This amendment is considered to be substantial for India 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 
Additional clarification on the eye examination have been added for India only to reflect 
clarification of the fundus criteria for uncontrolled and potentially unstable retinopathy or 
maculopathy as required by Central Drug Standard Control Organisation (CDSCO), Office of 
Drugs Controller General (India). 
Section # and name 
Description of change 
Rationale 
Appendix 8                            
Country-specific requirements for 
India, amendment 3 
Additions to section 9.5.3 
See overall rationale 
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Protocol amendment no. 4 (03-November-2020) 
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 
Due to the COVID-19 pandemic the exclusion and discontinuation criteria have been amended to 
allow for simultaneous participation in trials with the primary objective of evaluating an approved 
or non-approved investigational medicinal product for prevention or treatment of COVID-19 
disease or COVID-19 postinfectious conditions. In addition, the AE collection have been expanded 
to reflect these changes. 
The sample size has been increased with 348 subjects. 
This amendment also addresses changes to the statistical testing strategy, as well as clarifications 
and administrative changes. 
Section # and name 
Description of change 
Rationale 
Section 2 Flowchart 
Insertion of subject contact 
information check 
To ensure that the subject contact 
information is valid 
Section 2 Flowchart 
Footnote “g” revised 
To clarify when the collection of 
urine samples take place 
Section 2 Flowchart 
Footnote “k” added 
To clarify that yearly visits should 
take place approximately 13 weeks 
after the previous visit  
Section 3.2 Background 
Background section has been 
elaborated  
 
Background information expanded 
to provide expected population 
information captured by 
inclusion/exclusion criteria and to 
introduce communication options 
that may be used to motivate 
focused recruitment. 
Section 3.3.2 Risks related to 
semaglutide 
Removed sentence regarding that 
semaglutide should be discontinued 2 
months before a planned pregnancy. 
Inserted reference to Appendix 5 in 
pregnancy, lactation and fertility 
section. 
To align across protocol, appendix 
and SI-IC form and to specify that 
semaglutide should be 
discontinued at least 5 weeks 
before a planned pregnancy. 
Section 4.2 Exploratory endpoints 
Statement deleted that eGFR samples 
meeting a threshold and followed by 
a non-eGFR component of the 
primary endpoint before confirmation 
will have the date of the eGFR 
sample as event date. 
Description corrected because un-
confirmed eGFR samples followed 
by a non-eGFR component of the 
primary endpoint will not have the 
eGFR sample as primary endpoint 
event date. Details on derivation of 
eGFR components in the presence 
of intercurrent events are given in 
the SA 
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Section 6.2 Exclusion criteria 
Addition to exclusion criterion 4 
*Simultaneous participation in a trial 
with the primary objective of 
evaluating an approved or non-
approved investigational medicinal 
product for prevention or treatment of 
COVID-19 disease or COVID-19 
postinfectious conditions is allowed if 
the last dose of the investigational 
medicinal product has been received 
more than 30 days before screening    
To allow for co-participation in 
COVID-19 trials 
Section 7.2 Dose modification 
Specification of visit periods in Table 
7.2 
For clarification 
Section 7.7 Concomitant medication 
Text revised 
To specify that if a subject is 
treated with the maximum 
tolerated dose but not the 
maximum labelled dose of the 
RAAS blocking agent a previous 
dose escalation attempt is not a 
requirement, but the reason why 
the subject is not expected to 
tolerate a higher dose must be 
documented in the medical 
records. Further to specify that in 
case of intolerance to and ACE-
inhibitor due to cough an ARB 
must have been tried 
Section 7.7 Concomitant medication 
Text included for collection of 
COVID-19 concomitant medication 
To specify that medication(s)in 
relation to a clinical trial for 
COVID-19 prevention or treatment 
as well as approved COVID-19 
vaccine must be recorded. 
Section 8.1 
Discontinuation/Withdrawal criteria 
Text added to discontinuation 
criterion 3 
*Simultaneous participation in a trial 
with the primary objective of 
evaluating an approved or non-
approved investigational medicinal 
product for prevention or treatment of 
COVID-19 disease or COVID-19 
postinfectious conditions is allowed 
at the investigator discretion without 
discontinuing trial product.   
To allow for co-participation in a 
COVID-19 trial 
Section 8.1 
Discontinuation/Withdrawal criteria 
Text revised 
To clarify that subjects who 
participate in other trials can 
resume trial product if the 
investigational medicinal product 
of the other trial has been 
discontinued, if deemed safe by the 
investigator and the Novo Nordisk 
medical expert. 
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Section 8.1 
Discontinuation/Withdrawal criteria 
Text regarding pregnancy updated 
To specify that contraception 
should be utilised for at least 5 
weeks after the last dose of trial 
product. 
Section 9 Trial assessments and 
procedures 
Text regarding review of PROs 
updated 
To specify that the review must be 
performed by an investigator. 
Section 9.2.1 Self-measured plasma 
glucose 
Text revised 
To specify that subjects can use 
either their own BG meter or one 
provided by Novo Nordisk and to 
note that it is not necessary to file 
the measurements at the site.  
Section 9.2.2 Clinical efficacy 
laboratory assessments 
Text regarding collection of 
creatinine values from medical 
records revised. 
For clarification 
Section 9.3 Adverse events 
Text regarding COVID-19 AEs 
included. 
‘including all fatal events’, 
pregnancies and technical complaints 
deleted on the list  
To describe the procedure for 
collection of COVID-19 AEs 
Fatal events are per default SAEs, 
as they fulfil the first seriousness 
criteria. Hence there is no need to 
mention this here where it clearly 
states that all SAEs are collected. 
Pregnancies and technical 
complaints are not AEs and the 
collection and reporting of them is 
covered elsewhere in the protocol 
(section 9.3.7 and section 9.3.9, 
and Appendix 5 and 6). 
Section 9.3.1 Adverse events,   
Figure 2 
Text regarding COVID-19 AEs 
included 
To describe the procedure for 
collection of COVID-19 AEs 
Section 9.5 Safety assessments 
Addition of COVID-19 in text  
To include COVID-19 to the 
concomitant illness/medical history 
that should be reported in the 
eCRF 
Section 9.5.3 Eye examination 
Window for eye examination changed 
from 5 weeks to 8 weeks 
To allow more time for performing 
eye examinations. 
Section 10.1 Sample size 
determination 
The event rate for the nephropathy 
composite outcome in LEADER 
adjusted to 9.4% 
To align with the population 
fulfilling the inclusion criteria, 
including UACR<5000mg/g 
Section 10.1 Sample size 
determination 
Lowering of expected event rate and 
dropout and consequently an increase 
in expected recruitment time and 
sample size as well as updated power 
calculations for confirmatory 
secondary endpoints. 
To account for potentially lower 
event rate than initially expected. 
Section 10.1 Sample size 
determination, confirmatory 
secondary endpoints 
Text updated to reflect analysis on 
raw eGFR values  
Log transformation is not 
considered necessary in order to 
achieve the appropriate 
distributional properties. 
Section 10.3.1 Primary endpoint 
Description of handling of missing 
eGFR data updated 
Imputation of missing eGFR 
values is not considered necessary 
for the primary analysis. 
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Section 10.3.2.1 Confirmatory 
secondary endpoints  
Updated text for the statistical testing 
strategy for the confirmatory 
secondary endpoints. 
To preserve control of the type 1 
error for confirmatory endpoints. 
Section 10.3.2.1 Confirmatory 
secondary endpoints  
Log-transformation prior to analysis 
of annual change in eGFR removed 
and baseline included as response 
variable. 
Analysis will be done on raw 
eGFR value as it is not believed 
that log transformation is required 
in order to achieve the appropriate 
distributional properties. 
Section 10.3.2.2 Supportive 
secondary endpoints 
Text revised 
Specification of imputation model 
since reference to primary analysis 
no longer appropriate after update. 
Section 10.3.4 Interim testing for 
efficacy 
The requirement that 60% of the total 
primary endpoint events are renal 
events is removed 
Requirement not considered 
necessary for valid interim results 
Appendix 2 
Text revised 
To specify that urine hCG 
pregnancy testing will be 
performed locally unless serum 
testing is required by local 
regulation or IRB/IEC. 
Appendix 2 
hsCRP, Cholesterol, High density 
lipoprotein (HDL) cholesterol, Low 
density lipoprotein (LDL) cholesterol 
and Triglycerides moved to efficacy 
assessments 
For correctness 
Appendix 5 
Changes to formatting  
For clarification 
Appendix 5 
Text revised 
To specify that contraception 
should be utilised for at least 5 
weeks after the last dose of trial 
product. 
Appendix 9                       
Mitigations to ensure subject safety 
and data integrity during 
epidemics/pandemics (e.g. COVID-
19) 
Implementation of mitigations (home 
nursing and alternative ways of 
dispensing) in case sites are locked 
down due to epidemics/pandemics 
(e.g. COVID-19) 
To ensure subject safety and data 
integrity in case of restrictions due 
to epidemics/pandemics (e.g. 
COVID-19) 
 
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SAP_001.pdf: 
Cover Page for SAP 
 
Sponsor name: 
Novo Nordisk A/S 
NCT number 
NCT03819153 
Sponsor trial ID: 
NN9535-4321 
Official title of study: 
FLOW – Effect of Semaglutide versus Placebo on the 
Progression of Renal Impairment in Subjects with Type 2 
Diabetes and Chronic Kidney Disease 
Document date* 
09 February 2023 
*Document date refers to the date on which the document was most recently updated. 
 


Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
3.0 
UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
Page: 
1 of 34 
 
Trial ID: NN9535-4321 
FLOW – Effect of semaglutide versus placebo on the 
progression of renal impairment in subjects with type 2 
diabetes and chronic kidney disease 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
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This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be 
disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant 
parties.


Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
3.0 
UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
Page: 
2 of 34 
 
Table of contents 
Page 
Table of contents ............................................................................................................................................... 2
List of abbreviations ......................................................................................................................................... 3
1 
Introduction ............................................................................................................................................... 4
1.1
Trial information ............................................................................................................................ 4
1.1.1
Rationale ...................................................................................................................... 4
1.1.2
Objectives, endpoints and estimand ............................................................................. 4
1.1.3
Overall design .............................................................................................................. 4
1.2
Scope of the statistical analysis plan .............................................................................................. 5
2 
Statistical considerations .......................................................................................................................... 6
2.1
Sample size determination ............................................................................................................. 6
2.2
General considerations ................................................................................................................... 8
2.2.1
Definition of analysis sets ............................................................................................ 8
2.2.2
Definition of observation periods ................................................................................ 8
2.2.3
Estimands ..................................................................................................................... 9
2.2.4
Time-to-event endpoints, censoring and competing risks ......................................... 10
2.3
Primary endpoint .......................................................................................................................... 11
2.3.1
Primary analysis ......................................................................................................... 12
2.3.2
Sensitivity analyses .................................................................................................... 12
2.3.3
Supplementary analyses ............................................................................................. 15
2.3.4
Subgroup analyses ..................................................................................................... 15
2.3.5
Supplementary analyses evaluating impact of the COVID-19 pandemic .................. 16
2.3.6
Supplementary analyses evaluating impact of co-participation in COVID-19 
treatment or prevention trials ..................................................................................... 16
2.3.7
Supplementary analysis using CKD-EPI equation not including race ....................... 17
2.4
Secondary endpoints .................................................................................................................... 17
2.4.1
Confirmatory secondary endpoints ............................................................................ 17
2.4.2
Supportive secondary endpoints ................................................................................ 19
2.5
Exploratory endpoints .................................................................................................................. 20
2.6
Other assessments ........................................................................................................................ 20
3 
Interim testing ......................................................................................................................................... 21
3.1
Role of DMC ............................................................................................................................... 21
3.2
Stopping boundary for superiority at interim ............................................................................... 21
3.3
Analysis on termination ............................................................................................................... 21
4 
Changes to the statistical analyses plan ................................................................................................. 23
5 
Appendix .................................................................................................................................................. 26
6 
References ................................................................................................................................................ 34
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
3.0 
UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
Page: 
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List of abbreviations 
ANCOVA 
analysis of covariance 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-EPI 
chronic kidney disease - epidemiology collaboration 
CV 
cardiovascular 
DBL 
data base lock 
DMC 
data monitoring committee 
EAC 
event adjudication committee 
eGFR 
estimated glomerular filtration rate 
ESRD 
end-stage renal disease 
EQ-5D-5L 
five-level version of the EuroQol five-dimensional questionnaire 
FAS 
full analysis set 
HbA1c 
glycosylated haemoglobin 
HR 
hazard ratio 
LTFU 
lost to follow-up 
MACE 
major adverse cardiovascular event 
MALE 
major adverse limb event 
MI 
myocardial infarction 
MImp 
multiple imputation 
SAP 
statistical analysis plan 
s.c.
subcutaneously 
TTE
time-to-event 
UACR
urinary albumin-to-creatinine ratio 
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
3.0 
UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
Page: 
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1 
Introduction 
1.1 
Trial information 
1.1.1 
Rationale 
Chronic kidney disease (CKD) and diabetes often co-exist and for most of cases, the kidney damage 
and/or reduced kidney function is caused directly by longstanding and poorly controlled diabetes. 
Improved glycaemic control has been suggested to reduce the progression of CKD in type 2 
diabetes (T2D) and both glycaemic and blood pressure control are key recommendations in 
international treatment guidelines for CKD in T2D. Yet there remains a major unmet medical need 
to improve the treatment of CKD in subjects with T2D. The purpose of this trial is to demonstrate 
that semaglutide s.c. delays the progression of renal impairment and lowers the risk of renal and 
cardiovascular (CV) mortality in subjects with T2D and CKD. 
1.1.2 
Objectives, endpoints and estimand 
The primary objective is to demonstrate that semaglutide delays the progression of renal 
impairment and lowers the risk of renal and cardiovascular mortality compared to placebo, both 
added to standard-of-care, in subjects with type 2 diabetes and chronic kidney disease. 
The key secondary objectives are to compare the effect of treatment with semaglutide versus 
placebo, both added to standard-of-care in subjects with type 2 diabetes and chronic kidney disease 
with regards to cardiovascular morbidity, peripheral artery disease, glycaemic control, body weight, 
blood pressure and safety. 
The primary endpoint is time to first occurrence of a composite endpoint consisting of: Onset of 
persistent ≥ 50% reduction in estimated glomerular filtration rate (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, or cardiovascular death. 
The key secondary endpoints are annual rate of change in eGFR (CKD-EPI) (total eGFR slope), 
time to first occurrence of a composite major adverse cardiovascular event (MACE) endpoint 
(consisting of: non-fatal myocardial infarction, non-fatal stroke, or CV death) and all-cause death. 
The estimand for all objectives is based on the intention-to-treat principle evaluating the effect of 
the randomised treatment intervention irrespective of adherence to this and changes to background 
medication. 
1.1.3 
Overall design 
This is a multi-centre, international, randomised, double-blind, parallel-group, placebo-controlled 
trial comparing semaglutide 1.0 mg versus placebo both administered s.c. once weekly and added to 
standard-of-care in subjects with T2D and pre-existing CKD. Subjects are randomised 1:1 to 
receive either semaglutide or placebo. Randomisation is stratified by use of sodium glucose 
cotransporter-2 (SGLT-2) inhibitors (yes/no) at baseline. The number of subjects with inclusion 
eGFR ≥ 60 mL/min/1.73 m2 is capped at approximately 20%.  
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
3.0 
UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
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The trial is event driven; therefore, end of trial is scheduled according to accrual of events. The trial 
employs a group sequential design with one interim testing for superiority. Under the design 
assumptions, the trial duration is approximately 61 months following randomisation of the first 
subject and 3,508 subjects are planned to be randomly assigned to trial products.  
If the trial is not stopped for superiority at the planned interim testing the trial is terminated when 
both of the following criteria are fulfilled: 

A minimum of 854 primary endpoint events

A minimum of 515 primary renal endpoint events (components of the primary endpoint
except CV death)
A schematic overview of the trial design is shown in Figure 1. 
Figure 1 
Trial design 
1.2 
Scope of the statistical analysis plan 
The SAP includes elaborations on statistical analyses outlined in the protocol for the FLOW trial 
(NN9535-4321) as well as details on the interim testing for superiority. Any changes to the SAP 
after first subject first visit are documented in a change log. 
An external independent statistical service provider will conduct the interim analysis, see also 
section 3. Novo Nordisk is responsible for all other planned statistical analyses and in general 
reporting of data but will remain blinded to treatment allocations until data base lock (DBL). 
Additionally, another statistician independent of trial conduct, the DMC analyses, interim analysis, 
and external to Novo Nordisk will independently confirm the statistical analyses of the primary 
endpoint and secondary confirmatory endpoints. This statistician will also be blinded until DBL. 
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
3.0 
UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
Page: 
6 of 34 
 
2 
Statistical considerations 
2.1 
Sample size determination 
The trial is designed with 90% power to confirm superiority for the primary endpoint, i.e., reject the 
null-hypothesis of a hazard ratio (HR) ≥ 1.0 against the one-sided alternative of HR < 1.0, where 
HR is the hazard ratio of semaglutide versus placebo. 
The trial is designed with one interim testing for superiority of the primary endpoint when two 
thirds of the total planned number of primary endpoint events has been accrued. Testing for futility 
is not included. The Lan-DeMets alpha spending function, approximating the O'Brien-Fleming’s 
stopping boundaries, is used to test superiority at a study-wise one-sided type I error rate of 2.5%. 
The one-sided alpha spending function is given by 
𝑓(𝑡) = min(2 −2 ∙Φ(𝑧𝛼
2/ √𝑡), 𝛼)
where t is the proportion of information included in the interim analysis (accrued primary endpoint 
events relative to the total planned primary endpoint events), Φ denotes the standard normal 
cumulative distribution function, 𝛼 is the overall one-sided alpha of 2.5% and 𝑧𝛼/2 is the 98.75% 
quantile of the standard normal distribution. Based on a randomisation ratio of 1:1 and a design HR 
of 0.80 a total of 854 primary endpoint events are required.  
For calculating the number of randomised subjects, the following are assumed: 

annual primary endpoint rate in the placebo group of 7.5%

uniform recruitment in 21 months

annual lost to follow-up rate in both treatment groups of 1%

trial duration of five years and five weeks
Under these assumptions, a total of 3,508 subjects are needed for randomisation. 
A Cox model as described in section 2.3 is used for the interim testing using the fixed sample one-
sided lower p-value from the score test. Only a fixed sample p-value below the boundary specified 
by the error spending function will allow the DMC to recommend early trial termination for 
superiority. Table 1 provides the boundaries based on analyses performed after 570 (interim) and 
854 (scheduled termination) events, along with the approximate hazard ratio estimates that 
correspond to those boundaries if the analyses are timed exactly to that schedule. The actual 
stopping boundaries will be based on the exact number of events available for the interim analysis. 
Table 1 
Stopping boundary scales at interim and scheduled termination 
Stopping boundary scale 
Interim 
570 events 
Scheduled termination 
854 events 
Hazard ratio 
0.8103 
0.8725 
Nominal significance level 
0.00605 
0.02314 
Figure 2 below shows the probability of stopping the trial early at the interim (blue curve) and the 
overall power for confirming superiority for the primary endpoint (dashed red curve) as a function 
of alternative values for the true HR. The design HR of 0.80 is marked with a dashed vertical 
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Date: 
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reference line. The stopping probability at the interim and overall power for the design HR of 0.80 
can be seen to be 56% and 90%, respectively. 
Figure 2 
Stopping probability at interim and overall power as a function of true hazard 
ratio 
Confirmatory secondary endpoints 
If superiority is confirmed for the primary endpoint the below confirmatory secondary endpoints are 
controlled for multiplicity through a hierarchical testing strategy. The marginal powers below are 
calculated under the assumptions that the trial continues to the scheduled termination, a significance 
level of 2.5% (one-sided) and 3,508 randomised subjects. 
The confirmatory secondary endpoint, annual rate of change in eGFR, is analysed using a linear 
random regression model. Under the assumptions of a difference in annual slope of 1 mL/min/1.73 
m2 between treatment groups, a between subject variance for the slope of 20 and a residual variance 
of 45, the marginal power is >99%. For an annual rate of decline in the placebo group of 4 
mL/min/1.73 m2, a difference of 1 mL/min/1.73 m2 corresponds to a 25% reduction in the annual 
decline with semaglutide versus placebo. 
Assuming a hazard ratio of 0.8, an annual loss rate of 1% and an annual event rate of 7% in the 
placebo group for the confirmatory secondary MACE endpoint, the marginal power for confirming 
superiority is 89%. 
With similar assumptions for hazard ratio and loss rate and assuming an event rate of 5% in the 
placebo group, the marginal power for the third confirmatory secondary endpoint, time to all-cause 
death, is 78%.  
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Date: 
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UTN: U1111-1217-6259 
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2.2 
General considerations 
For confirmatory endpoints controlled for multiplicity (see section 2.4.1), estimated treatment 
effects are presented together with two-sided 95% confidence intervals (CIs) and one-sided p-values 
for tests of the hypothesis of superiority. For reporting of results, the hazard ratio and the 95% CI 
are accompanied by the two-sided p-value.  
For non-confirmatory endpoints, the estimated treatment effects are reported together with two-
sided 95% CIs and two-sided p-values. 
Unless otherwise specified, baseline value is defined as the eligible measurement associated with 
the randomisation visit (V2), if this measurement is taken before or at the date of first dose. If a 
randomisation assessment is missing or if it is taken after the date of first dose, then the assessment 
from the screening visit (V1) is used as the baseline assessment, if available. If more than one 
measurement is associated with the same visit, the earliest measurement is considered eligible. For 
eGFR, the baseline assessment is defined as the mean of the two assessments from the 
randomisation visit (V2) (if taken before or at the date of first dose) and the screening visit (V1). If 
only one of the assessments is available, this is used as the baseline assessment. For UACR, the 
baseline assessment is defined as the mean of the two assessments from the randomisation visit 
(V2) if these are taken before or at the date of first dose. If only one of the assessments is available, 
this is used as the baseline assessment. If no assessments are available from V2, then assessment 
from the screening visit (V1) will be used.  
Missing data are defined as data that are planned to be collected and could have been collected but 
are not present in the database. This implies that data that are structurally missing due to death or 
administrative censoring are not considered missing. Unless explicitly stated, unobserved data 
pertaining to subjects who are lost to follow-up or withdrawn and who would not have been 
administratively censored at the time point in question are considered missing, irrespectively of 
vital status as collected at end of trial.  
Assessments of UACR or eGFR taken after initiation of chronic renal replacement therapy will not 
be used for analyses or summary tables.  
2.2.1 
Definition of analysis sets 
The full analysis set (FAS) is defined as all unique randomised subjects and grouped according to 
the treatment assigned at randomisation.  
If a subject is randomised more than once, only the subject ID and treatment corresponding to the 
first randomisation will be included in FAS. The additional randomised subject IDs will be 
excluded from FAS. The list of subject ID’s to exclude will be part of the DBL minutes. 
2.2.2 
Definition of observation periods 
A trial completer is defined as a subject who either attends the follow-up visit or who dies while 
active in the trial. 
A subject is considered lost to follow-up (LTFU) if the subject does not complete the trial and does 
not withdraw consent. The date and status for LTFU are determined by investigator at trial 
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completion. Trial completion will be either following interim testing or after accrual of the total 
planned number of primary endpoint events. 
In-trial observation period 
The in-trial observation period for a subject is defined as the period from date of randomisation to 
the first of (both inclusive): 

date of follow-up visit

date when subject withdrew consent

date of last contact with subject for subjects who are LTFU

date of death
On-treatment observation period 
A time-point in the in-trial observation period is considered as on-treatment if any dose of trial 
product has been administered within the previous 5 weeks (35 days). The on-treatment observation 
period is defined as all times which are considered on-treatment and may consist of several time 
intervals with gaps between. 
First on-treatment observation period 
The first on-treatment observation period is defined as the on-treatment observation period until 
first time being off treatment for 5 consecutive weeks (35 days). Thus it is the first time interval in 
the on-treatment period.  
2.2.3 
Estimands 
Primary estimand(intention-to-treat) 
The estimand for all objectives is an intention-to-treat estimand, evaluating the effect of the 
randomised treatment intervention irrespective of adherence to treatment and changes to 
background medication. The estimand is addressed using FAS and the in-trial observation period. 
Secondary estimand (on-treatment) 
This estimand covers the primary and confirmatory secondary endpoints and is evaluating the effect 
of the randomised treatment intervention in all randomised subjects had they remained on their 
randomised treatment for the entire trial. The estimand is addressed using FAS and the first on-
treatment observation period. Intercurrent events 
Intercurrent events are events including but not limited to or associated with: 

randomised treatment adherence

change in background medication modifying cardio-renal risk e.g. change in dose of current
medication or initiation of additional medication

initiation of chronic renal replacement therapy

withdrawal

lost-to follow up

death (if not part of endpoint)
These are reported using descriptive statistics. 
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assumption. The population-level summary measure for TTE endpoints is the HR for semaglutide 
versus placebo. The assumption of proportional hazards is investigated by residuals. Tied event 
times are handled using the exact method and confidence intervals are based on the profile 
likelihood. 
Cumulative incidence functions for TTE endpoints are estimated by the Aalen-Johansen estimator 
which accounts for competing risks. 
Table 5 gives an overview of the TTE endpoints including any competing risk and whether the TTE 
endpoint is EAC-confirmed. 
2.3 
Primary endpoint 
Time to first occurrence of a composite endpoint consisting 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
For the eGFR components, a persistent outcome in eGFR is defined as having two consecutive 
central laboratory assessments at least 4 weeks apart meeting the criteria. When classifying the 
events based on consecutive laboratory assessments, the date of the event is the date of the first 
sample meeting the definition. 
When classifying chronic renal replacement therapy or kidney transplantation, the date of event is 
the EAC-confirmed date of initiation of the therapy or surgery, respectively. 
Deaths attributed to the category “undetermined cause of death” are presumed cardiovascular death. 
In the case that only a single eGFR value fulfils the criteria of ≥50% reduction in eGFR compared 
with baseline or eGFR <15 mL/min/1.73 m2 without any confirmatory sample Table 2 provides data 
handling rules for defining primary endpoint events. Any eGFR assessment made after initiation of 
chronic renal replacement therapy will not qualify as a confirmatory eGFR value. 
Table 2 
Data handling rules for eGFR components of the primary endpoint in the 
absence of a confirmatory test 
Rule 
number 
Event: 
One eGFR value fulfilling the criteria * 
with a subsequent event without any 
confirmatory eGFR value measured 
>=4 weeks after the first eGFR 
measurement being available. 
eGFR event 
Date of event 
1 
CV or renal death 
No 
Date of death 
2 
Non-CV and non-renal death 
No 
Not applicable 
3 
Initiation of chronic renal replacement 
therapy 
No 
Date of initiation 
4 
Lost-to-follow-up or withdrawal of 
consent 
No 
Not applicable 
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* ≥50% reduction in eGFR compared with baseline or eGFR <15 mL/min/1.73 m2
A persistent outcome in eGFR in the in-trial period is considered on-treatment if the first of the two 
consecutive measurements falls within the on-treatment period, irrespective of whether the 
confirmatory eGFR value falls within the on-treatment period or not. 
2.3.1 
Primary analysis 
The primary analysis will address the primary estimand (intention-to-treat). The HR for comparing 
semaglutide versus placebo is estimated from a stratified Cox proportional hazards model with 
treatment (semaglutide, placebo) as fixed factor together with the 2-sided 95% confidence interval 
and one-sided p-value for hypothesis testing. Stratification is use of SGLT-2 inhibitors (yes/no) at 
baseline.  
The score test from the Cox model is used for testing. The following superiority hypothesis is 
tested: 
H0: HR ≥ 1.0 against Ha: HR < 1.0. 
Superiority of semaglutide versus placebo is considered confirmed if the associated H0 is rejected. 
The nominal significance level is calculated using the alpha spending function and the actual 
observed number of events available for the analysis. Final inference on termination is adjusted for 
the group sequential design by using the likelihood ratio ordering. 
In the primary analysis missing data for scheduled central laboratory eGFR values due to e.g. 
missing blood samples while subjects are still being followed are not imputed, implicitly assuming 
no eGFR component events observed during the in-trial observation period with missing eGFR 
values. 
Competing risk from non-CV, non-renal death is handled as censorings in the Cox analysis as 
described in section 2.2.4.  
Please refer to Table 4 for handling of other intercurrent events. 
2.3.2 
Sensitivity analyses 
Tipping point 
If superiority is established for the primary endpoint, the following sensitivity analysis is 
performed. The primary analysis assumes independent censoring for subjects who have withdrawn 
consent or are lost to follow-up. To investigate the impact of this assumption on the primary 
analysis, a 2-way tipping point analysis based on the approach described in Zhao et al. (2014)1 is 
performed. In this analysis, subjects in the two treatment groups who have withdrawn or are lost to 
follow-up will have event times imputed from the conditional event distribution with a penalty in 
the sense that the risk (hazard) of primary endpoint events is changed following censoring 
compared to while under observation. Multiple imputed data sets are analysed with separate Cox 
regressions and results are combined using Rubin’s rule. The tipping points are then defined as the 
combination of penalties (in each of the treatment groups) needed to turn around the superiority 
conclusion. A range of plausible penalties will be specified based on blinded data and before DBL. 
5 
One eGFR value fulfilling the criteria* 
at the end of trial visit (V-FU) 
No 
Not applicable 
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Statistical Analysis Plan 
 
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Retrieved dropout 
To further investigate the potential impact of missing data for subjects who withdraw consent or are 
lost to follow-up, two additional sensitivity analyses will be performed by multiple imputing event 
times for these subjects using the retrieved dropout approach as described in He et al (2022)2. 
The first will be done by treatment arm using an estimated annual event rate from subjects who 
discontinue treatment permanently but remain in the trial. The event rate will be based on events 
and time while these subjects are permanently off-treatment. A time-point in the in-trial observation 
period is considered as belonging to the permanently off-treatment period if any dose of trial 
product has been administered more than 5 weeks (35 days) ago and the subject remains off-
treatment for the remainder of the trial. This analysis condition on the future in the sense that 
subjects are only known to be permanently off treatment by the end of the trial (or death). 
The second analysis avoids conditioning on the future by using an estimated annual event rate for 
subjects who discontinue treatment at any point in the trial. The imputations are done by treatment 
arm. The event rate will be based on events occurring from the first time subjects are off treatment 
corresponding to when their first on-treatment period ends and until end of the in-trial observation 
period. This may include time periods where the subjects actually went back on trial treatment.  
Technically, the first of the two sensitivity analyses will be performed in the following steps: 
For the purpose of estimating the off-treatment event rates, a set of retrieved dropouts are selected. 
The selection criteria are that the subject shall, have their date of last dose during the trial reported 
as a treatment discontinuation, have ended the on-treatment observation period before the end of the 
in-trial observation period, and not having had an event before the end of the on-treatment 
observation period. For each selected subject, the off-treatment event time is calculated from a start 
date set to the day after the end of the on-treatment observation period. The event time is considered 
censored at the end of the in-trial observation period.  
The off-treatment event time data are fitted within treatment arms to a piecewise exponential model 
using Bayesian analysis and accounting for censoring. The event rate is modelled to be constant 
within 3 intervals that are chosen such that the intervals contain roughly the same number of events.  
A noninformative improper prior distribution is used for the rate parameters in each treatment arm. 
500 replicates of the off-treatment event rates are then randomly sampled from the posterior 
distribution.  
To prepare the imputation, 500 copies of the original data set are created and linked to the 
corresponding replicate of the off-treatment event rates. For each subject who is censored due to 
withdrawal or being lost to follow up, the off-treatment event time is imputed by sampling from the 
corresponding piecewise exponential model conditional on being event-free from treatment 
discontinuation until the original censoring date. The imputed off-treatment event time is rounded 
up to whole days and added to the end of the on-treatment observation period. If it lies beyond the 
planned date of end of trial for the subject, it is considered censored at this date. There will now be 
500 complete data sets.  
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Statistical Analysis Plan 
 
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Each complete data set is analysed using the same stratified Cox regression as in the primary 
analysis. The analysis gives the estimated log hazard ratio and associated standard error.  
The log hazard ratios and standard errors from the 500 data sets are pooled using Rubin’s rule to 
obtain a single point estimate, confidence interval and p-value.  
The procedure for the second sensitivity analysis is identical to the first analysis except for the 
selection of retrieved dropouts and the observation period during which the subjects are considered 
to be on treatment. The selection criteria for a retrieved dropout are instead that the subject shall 
have their date of last dose during the first on-treatment observation period reported as a treatment 
discontinuation, have ended the first on-treatment observation period before the end of the in-trial 
observation period and not having had an event during the first on-treatment observation period. 
The off-treatment event time is calculated from a start date set to the day after the end of the first 
on-treatment observation period.   
Imputation of missing eGFR values 
In the primary analysis, missing data for scheduled central laboratory eGFR values are not imputed. 
The following sensitivity analysis using multiple imputation is planned. Prior to analysis, missing 
data are imputed using multiple imputation generating 500 data sets to account for the inherent 
uncertainty. The imputation is performed separately for each treatment group. In the first step, 
intermittent missing values are imputed using the Markov Chain Monte Carlo method based on an 
assumption of multivariate normality. In the second step, imputation of monotone missing values is 
done within subject groups defined by the treatment group and based on a sequential univariate 
regression approach. At each scheduled visit starting with the first post-baseline visit the imputation 
model includes use of SGLT-2 inhibitors (yes/no) at baseline as fixed factor and baseline value and 
the previous post-baseline scheduled values (observed and imputed) prior to the visit being imputed 
as covariates. For each eGFR component of the primary endpoint it is evaluated whether an eGFR 
event has occurred (yes/no) within the in-trial observation period. Intermittent imputed data are 
excluded from this evaluation. 
After imputation of missing eGFR data, the primary composite endpoint is derived, and the 500 
multiple-imputed data sets are analysed with the primary stratified Cox proportional hazards model 
described above. Subjects that do not experience a primary endpoint event during the in-trial 
observation period are censored at the in-trial observation period end date. The resulting estimates 
of the log(HR) are combined using the methods of Rubin and back transformed to HR scale to draw 
inference. 
Use of local laboratory serum creatinine values 
This sensitivity analysis of the primary analysis will use all collected data of eGFR values including 
conversion of local laboratory creatinine values and central laboratory data. Conversion of local 
laboratory creatinine values will be performed based on availability of demographic factors 
necessary for the conversion. If race is not available for a subject, e.g. due to country specific 
requirements, local laboratory creatinine values will not be included in the analysis. No imputation 
of missing data is done in this analysis. 
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Statistical Analysis Plan 
 
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Only eGFR from scheduled visits as potential event times 
For the primary analysis, subjects are supposed to have an eGFR measurement collected at an 
unscheduled visit in case a local laboratory creatinine value indicates a potential ≥50% reduction in 
eGFR or eGFR <15 mL/min/1.73 m2. In order to investigate the impact of potential differences in 
when and how often eGFR is measured in the two arms, this sensitivity analysis of the primary 
analysis will only consider eGFR values from central laboratory collected in connection with 
scheduled visits as potential eGFR events. Any central laboratory value can serve as confirmatory 
test to confirm persistency but only data from scheduled visit can serve as the first of the two 
consecutive measurements. 
2.3.3 
Supplementary analyses 
The following supplementary analyses are planned for the primary endpoint: 

Absolute risk difference: Estimation of the absolute risk difference (and 95% CI) at 2 and 3
years between semaglutide and placebo based on the Aalen-Johansen estimator for the
cumulative incidence function. The risk difference will be estimated using a generalized
linear regression model with identity link function on the pseudo-observations from the
Aalen-Johansen estimate at the specified time point, as described in Andersen & Perme
(2010)3. Treatment and use of SGLT-2 inhibitors (yes/no) at baseline will be included as
fixed factors in the regression model.

On-treatment: Analysis addressing the secondary estimand using a Cox proportional hazards
model, and the first on-treatment observation period.

Additionally, an analysis of non-CV, non-renal death using the same Cox model as for the
primary endpoint will be done to evaluate the influence of the competing risk non-CV, non-
renal death on the primary results.
2.3.4 
Subgroup analyses 
The consistency in the treatment effect for the primary endpoint is explored by subgroup analyses 
based on the below baseline information: 

Sex: Female, Male

Age < 65 years (yes/no)

Age: <65, 65≤ to <75, ≥75 years

Region: Europe, North America, Asia, Other. The regions are defined as
o
Europe: Belgium, Bulgaria, France, Germany, Greece, Hungary, Italy, Netherlands,
Poland, Slovakia, Spain, United Kingdom
o
North America: Canada, United States
o
Asia: Australia, China, India, Israel, Japan, Malaysia, Thailand, Turkey
o
Other: Argentina, Brazil, Mexico, Russia, South Africa, Ukraine

Race: White, Black or African-American, Asian, Other

Duration of T2D < 15 years (yes/no)

Ethnicity: Hispanic/Latino, Not Hispanic or Latino

HbA1c ≤ 8.0% (yes/no)

BMI ≤ 30 kg/m2 (yes/no)

Prior MI or stroke (yes/no)

Metformin use (yes/no)
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Statistical Analysis Plan 
 
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 Insulin use (yes/no) 
 SGLT-2i use (yes/no) 
 Chronic heart failure (yes/no) 
 eGFR (≤45, 45-60, ≥60 mL/min/1.73 m2 (CKD-EPI)) 
 eGFR: < 30, 30 ≤ to < 45, 45 ≤ to < 60, ≥ 60 mL/min/1.73m2 (CKD-EPI) 
 UACR <300 mg/g (yes/no)  
The subgroup analyses are based on stratified Cox proportional hazards models with an interaction 
between treatment group (semaglutide, placebo) and the specific subgroup as a factor and stratified 
for use of SGLT-2 inhibitors (yes/no) at baseline. 
2.3.5 
Supplementary analyses evaluating impact of the COVID-19 pandemic 
The following supplementary analyses will be made to assess the potential impact of the COVID-19 
pandemic on the primary endpoint:  
1. Time from randomisation to first primary endpoint event without concurrent COVID-19 
SAE. The definition of the primary endpoint is modified so any relevant event occurring 
concurrently with a COVID-19 SAE in a subject is not considered a primary endpoint event. 
The observation period and censoring are not changed. Any subsequent primary endpoint 
event can then qualify to be the first primary endpoint event for the subject. 
2. Time from randomisation to first primary endpoint event without concurrent COVID-19 AE. 
The definition of the primary endpoint is modified so any relevant event occurring 
concurrently with a COVID-19 AE in a subject is not considered a primary endpoint event. 
The observation period and censoring are not changed. Any subsequent primary endpoint 
event can then qualify to be the first primary endpoint event for the subject. 
3. Time from randomisation to first primary endpoint event or non-CV, non-renal death 
occurring concurrently with a COVID-19 SAE. The definition of the primary endpoint is 
modified to include all deaths potentially related to COVID-19. The observation period and 
censoring are not changed. 
The analyses will be done with the same stratified Cox regression model as for the primary analysis. 
An event is considered concurring with a COVID-19 (S)AE if the event occurs in the time period 
from the start day of the COVID-19 (S)AE and until 30 days after the last of the following two 
dates: the stop date of the COVID-19 (S)AE or the end of hospitalisation date for a hospitalisation 
reported together with the COVID-19 (S)AE.  
2.3.6 
Supplementary analyses evaluating impact of co-participation in COVID-19 
treatment or prevention trials 
To assess the potential impact on the primary analysis of subjects being allowed to co-participate in 
trials with primary objective of evaluating an approved or non-approved investigational medical 
product for treatment or prevention of COVID-19 disease, the following supplementary analysis 
will be done: An analysis of time to first primary endpoint event where all subjects co-participating 
in a COVID-19 treatment or prevention trial are censored at the day they receive the first trial 
treatment for preventing or treating COVID-19. This will reduce the observation time. The analysis 
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Statistical Analysis Plan 
 
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will be done using the same stratified Cox regression model as for the primary analysis. The 
analysis corresponds to the situation where subjects withdraw from the trial when they start co-
participation. If less than 10 subjects have co-participated in COVID-19 treatment or prevention 
trials then this analysis will not be performed. 
2.3.7 
Supplementary analysis using CKD-EPI equation not including race 
The equation used for estimating eGFR (CKD-EPI) for the primary endpoint incorporates age, sex 
and race. To fight racial bias in clinical trials a new equation where race is not incorporated has 
been introduced, as described in Inker et al. (2021)4. A supplementary analysis will be made using 
this new equation where race is not included to estimate eGFR using the same model as for the 
primary analysis described in section 2.3.1. 
2.4 
Secondary endpoints 
Confirmatory secondary endpoints are analysed under multiplicity control. 
2.4.1 
Confirmatory secondary endpoints 
If superiority is established for the primary endpoint, the superiority hypothesis stated in section 
2.3.1  is tested for each of the three confirmatory secondary endpoints under multiplicity control via 
a stagewise hierarchical testing scheme using the following order: 
1. Annual rate of change in eGFR (total eGFR slope) 
2. Time to first occurrence of MACE 
3. Time to occurrence of all-cause death 
For the type I error rate to be strongly controlled at a one-sided level of 2.5% (Glimm et al (2010)5) 
the same alpha-spending function and information proportion t as for the primary endpoint (section 
2.1) is used for the confirmatory secondary endpoints.  
No adjustments of the results for the confirmatory secondary endpoints due to the group sequential 
design will be done. 
Table 3 provides an example of the nominal significance levels at interim and scheduled 
termination in when the interim testing is conducted at exactly 2/3 of the planned number of 
primary endpoint events and where the number of events for the secondary endpoint at scheduled 
termination is 3/2 times the number of secondary endpoint events at the interim. 
The actual nominal significance level will be based on the exact number of events available at the 
interim analysis. 
Table 3 
Nominal significance level for confirmatory secondary endpoints at interim and 
scheduled termination – an example 
Stopping boundary scale 
Interim 
Scheduled termination 
Nominal significance level 
0.00605 
0.02314 
 
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Annual rate of change in eGFR (total eGFR slope) 
The annual rate (slope) of change in eGFR is compared between treatment groups based on a linear 
random regression model on eGFR values with treatment, use of SGLT-2 inhibitors (yes/no) at 
baseline, time (as a continuous variable) and treatment time interaction as fixed effects, and 
including subject effect as a random intercept and time as a random slope. The random intercept 
and slope is assumed to be bivariate normal distributed with mean zero and an unstructured 
covariance matrix. The independent error term is assumed to be identical univariate normal 
distributed with mean zero. The model is fitted to observed scheduled central laboratory data from 
baseline and post-baseline, excluding data from confirmatory testing. The parameter of interest is 
the regression coefficient for the treatment and time interaction term, which measures the slope 
difference between semaglutide and placebo. 
Two sensitivity analyses will also be done for the eGFR slope analysis. 
The first analysis will be done using a joint model (shared parameter model as described in Vonesh 
et al (2006)6) with two submodels: a longitudinal model and a time-to-event model with time to first 
occurrence of either all-cause death or chronic renal replacement therapy. The longitudinal 
submodel will be similar to the random slope model described above and the time-to-event 
submodel will be a (proportional hazard) Weibull model with treatment and use of SGLT-2 
inhibitors (yes/no) at baseline as covariates and with shared random effects added from the 
longitudinal model where each random intercept and random slope will be multiplied with a 
parameter respectively (random coefficients).  As above, the random intercept(s) and random 
slope(s) by subject is assumed to follow a bivariate normal distribution with mean zero and a 
unstructured covariance matrix. The mean slopes derived from the longitudinal submodel may be 
thought of as the mean eGFR slope where eGFR trajectories have been hypothesized to be 
measured beyond death or renal replacement therapy through the association between the two 
submodels. The parameter of interest is the regression coefficient for the treatment by time 
interaction term in the longitudinal submodel. Effectively, the model will account for subjects with 
missing eGFR values due to death or renal replacement therapy having a steeper eGFR decline 
compared to subjects who are still in the trial and contributing with eGFR values.  
In the second analysis, unobserved eGFR values due to initiation of renal replacement therapy or 
death will be multiple imputed with unfavourable eGFR values (<15mL/min/1.73 m2) and the 
resulting treatment estimates will be combined using Rubin’s rule. 
A supplementary analysis using the first on-treatment period as for the primary endpoint will also 
be done. 
To evaluate the impact of the COVID-19 pandemic and co-participation in COVID-19 treatment or 
prevention trials, the following supplementary analyses will be done: 
1. Exclusion of all eGFR values measured concurrently with a COVID-19 SAE. 
2. Exclusion of all eGFR values measured concurrently with a COVID-19 AE. 
3. Exclusion of all eGFR values measured after first trial treatment for preventing or treating 
COVID-19 in subjects co-participating in a COVID-19 treatment or prevention trial. If less 
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than 10 subjects have co-participated in COVID-19 treatment or prevention trials then this 
analysis will not be performed. 
An eGFR value is considered measured concurrently with a COVID-19 (S)AE if the measurement 
is taken in the time period from the start day of the COVID-19 (S)AE and until 30 days after the last 
of the following two dates: the stop date of the COVID-19 (S)AE or the end of hospitalisation date 
for a hospitalisation reported together with the COVID-19 (S)AE. 
MACE and all-cause death 
The confirmatory secondary time-to-event endpoints are analysed using the stratified Cox 
proportional hazards model as described for the primary endpoint. 
For time to first occurrence of MACE, fatal MI is defined as an EAC-confirmed MI occurring 
within (≤) 30 days of an EAC-confirmed CV death classified with cause of death being MI. All 
other MIs are defined as non-fatal. A similar definition is applied for fatal/non-fatal stroke. 
In addition, all-cause death is analysed using FAS and an extended in-trial observation period 
including the follow-up for vital status for subjects who withdraw consent or are lost to follow-up. 
The relative risk for the binary endpoint death/alive will be compared between the two treatment 
groups based on confidence intervals calculated using the Mantel-Haenszel method and a p-value  
calculated based on the Cochran-Mantel-Haenszel general association statistic stratified by use of 
SGLT-2 inhibitor (yes/no) at baseline. The model is chosen because it does not depend on the 
observation time which is only extended for subjects withdrawn or LTFU. 
For time to first MACE, a supplementary analysis will be done by replacing the CV death 
component with all-cause death. 
The retrieved dropout sensitivity analyses and the supplementary analyses described in section 2.3.2 
and 2.3.3 for the primary endpoint, will similarly be done for MACE and all-cause death, except the 
analysis assessing non-CV, non-renal death..  
Supplementary analyses described in section 2.3.5 with regards to the impact of the COVID-19 
pandemic for the primary endpoint will also be done for MACE. The analysis assessing the 
potential impact of co-participation in COVID-19 trials in section 2.3.6 will be done for both 
MACE and all-cause death. If less than 10 subjects have co-participated in COVID-19 treatment or 
prevention trials then this analysis will not be performed. 
2.4.2 
Supportive secondary endpoints 
Each of the supportive secondary time-to-event endpoints is analysed with a similar stratified Cox 
proportional hazards model as for the primary endpoint, see also Table 5. 
For the two time-to-event endpoints “Onset of persistent ≥50% reduction in eGFR” and “Onset of 
persistent eGFR <15 mL/min/1.73 m2” an event of initiation of chronic renal replacement therapy 
acts as competing risk. For these two endpoints subject will be censored in the Cox model at time of 
initiation of chronic renal replacement therapy. In case of one eGFR measurement fulfilling the 
criteria and no available confirmatory test, the data handling rules are as described for the primary 
endpoint (Table 2). 
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Statistical Analysis Plan 
 
Date: 
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Trial ID: NN9535-4321 
Version: 
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UTN: U1111-1217-6259 
Status: 
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For the endpoint “Onset of persistent ≥50% reduction in eGFR” only subjects with a valid baseline 
value will be included in the analysis.  
Annual rate of change in  eGFR (chronic slope) is analysed similarly to the total eGFR slope using 
only eGFR values from week 12 and onwards. 
The continuous supportive secondary endpoints (change from randomisation) are analysed using 
multiple imputation for missing values. An imputation model (linear regression) is estimated 
separately for each treatment group including baseline value and use of SGLT-2 inhibitors (yes/no) 
at baseline as covariates and fitted to subjects having an observed data point (irrespective of 
adherence to randomised treatment) at the endpoint-time (12 weeks or 3 years). Subjects without a 
baseline measurement will not be a part of the model. . If 10% or more of subjects from FAS have 
missed the year 3 visit due to trial termination earlier than planned (stopping after interim testing or 
event rates higher than expected) these secondary endpoints will be evaluated as change to 2 years. 
The fitted model is used to impute values for all subjects with missing data (see section 2.2) at the 
endpoint-time to create 500 complete data sets. The completed data sets are analysed by an analysis 
of covariance model with treatment group and use of SGLT-2 inhibitors (yes/no) at baseline as 
fixed factors and baseline value as covariate. Rubin’s rule is used to combine the results. Relative 
change in UACR is done on the logarithmic scale. 
Table 6 gives an overview of the continuous endpoints. 
Mean number of severe hypoglycaemic episodes is plotted as a function of study time and analysed 
using a marginal mean regression model for recurrent events accounting for competing risk of 
dying, as described in Ghosh & Linn (2000)7 Ghosh & Linn (2002)8. Treatment group and use of 
SGLT-2 inhibitors (yes/no) at baseline are used as fixed factors and treatment effect is reported as 
mean ratio and corresponding 95% robust CI to account for the dependency of within-subject of 
recurrent events. 
2.5 
Exploratory endpoints 
The exploratory endpoints are analysed like the continuous supportive secondary endpoints.  
2.6 
 Other assessments 
All systematically collected AEs, i.e. serious AEs and non-serious events requiring additional data 
collection as well as COVID-19 AEs are summarised as number of subjects with events, proportion 
of subjects with events, number of events and rate of events according to treatment group. 
Summaries of SAEs are categorised by severity, relation to treatment, and outcome. 
 
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Statistical Analysis Plan 
 
Date: 
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Trial ID: NN9535-4321 
Version: 
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3 
Interim testing 
The trial design includes one pre-planned interim testing for superiority of the primary endpoint. 
The planned timing is when 570 events (two thirds of the planned total events) of the primary 
endpoint have been accrued. The interim testing is performed based on a locked snapshot of the 
study database. The date of the snapshot defines the analysis cut-off date for the interim testing.  
Subjects without a primary endpoint event prior to the date of analysis cut-off are considered 
censored with the censoring date defined as the first of: 
 in-trial observation period end-date 
 analysis cut-off date 
The same stratified Cox model as described in section 2.3 is used for the interim testing addressing 
the primary estimand. Similarly, the data handling rules described in the same section applies. 
3.1 
Role of DMC 
Blinded and un-blinded data analyses during trial conduct are evaluated by the DMC, as described 
in the DMC charter. Trial integrity is ensured by using an external independent statistical service 
provider (independent of trial conduct and external to Novo Nordisk) to prepare these data and 
analyses for the DMC. 
The DMC will evaluate the interim result and make recommendation to terminate the trial early for 
superiority if appropriate. The DMC evaluates the un-blinded interim results using the above group 
sequential stopping boundary as guidance. Stopping the trial early for superiority is only allowed if 
the stopping boundary is crossed and the DMC makes the decision to recommend early trial 
termination based on this and other considerations as specified in the DMC charter. 
3.2 
Stopping boundary for superiority at interim 
The exact number of primary endpoint events used for the interim testing is only known at the time 
of analysis, and the exact boundary is re-calculated using the Lan-DeMets alpha spending function. 
Recommendations from the DMC back to Novo Nordisk and any other party will exclude any 
details of the interim results in order to maintaining trial integrity. 
3.3 
Analysis on termination 
If the trial is terminated early for superiority following the interim testing, definitive evaluation of 
superiority for the primary endpoint is performed based on all the available data at the end-of-trial, 
including overrun data. Overrun data include events happening between the cut-off date for the 
DMC interim testing and end-of-trial as well as additional confirmed events that were undergoing 
adjudication at the analysis cut-off time point. If the trial is not terminated early for superiority 
following the interim testing, the analysis at scheduled termination is performed when the planned 
number of 854 primary endpoint events and a minimum of 515 primary renal endpoint events have 
been accrued. If less than 515 out of 854 accrued primary endpoint events are renal events, the trial 
will continue until 515 renal events have been accrued. The exact number of primary endpoint 
events used for the analysis on termination is only known at the time of analysis, and nominal 
significance level is updated based on the exact number of total accrued events and the Lan-DeMets 
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
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UTN: U1111-1217-6259 
Status: 
Final 
EudraCT No.: 2018-002878-50 
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alpha spending function. Similarly, the significance levels for the confirmatory secondary endpoints 
are updated based on the exact number of events and all available data at end-of-trial are used for 
analyses of both secondary and exploratory endpoints.  
For reporting of results for the primary endpoint (p-value, HR and 95% CI), the analysis on 
termination (either early or at scheduled termination) are adjusted for the group sequential design 
using the likelihood ratio ordering. 
 
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
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UTN: U1111-1217-6259 
Status: 
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4 
Changes to the statistical analyses plan 
In general, this SAP describes in more details the statistical analyses planned in the protocol.  
 
SAP version 1.0 dated 07-APR-2019 
Changes and additions to protocol version 2.0 dated 07-Dec-2018: 
 Primary analysis for the primary endpoint changed to not include multiple imputation for 
missing eGFR data. Instead multiple imputation is applied in a sensitivity analysis. 
 Supplementary analyses for primary endpoint and confirmatory secondary endpoints: 
o Risk difference 
o Secondary estimand (on-treatment) 
 The confirmatory analysis of annual change in eGFR is updated to be done on raw eGFR 
values (not log-transformed)  
 Requirement of 60% renal events at interim analysis removed  
 Tipping point analysis expanded to a two way tipping point analysis 
 Supplementary analysis for MACE replacing CV death component with all-cause death 
 Supplementary analysis of all-cause death using an extended in-trial observation period 
 Supplementary analyses of MI and stroke using both fatal and non-fatal events 
 Additional exploratory analyses listed in Table 8. 
 Definition of eGFR components of primary endpoint in case of competing events added 
 
 
SAP version 2.0 dated 13-APR-2022 
Changes and additions to SAP version 1.0. 
 Author has been deleted from front page 
 It has been clarified that the independent statistician confirming the confirmatory analyses 
will also be blinded until DBL. 
 The planned sample size has been updated in accordance with protocol version 4.0 (section 
2.1) 
 The definition of baseline value has been clarified (section 2.2). 
 It has been clarified how missing data from subjects who are LTFU or withdrawn are 
handled (section 2.2). 
 It has been clarified that assessments of UACR or eGFR taken after initiation of chronic 
renal replacement therapy will not be used for analyses or summary tables (section 2.2).  
 It has been clarified how subjects randomised more than once will contribute to the FAS 
(section 2.2.1). 
 A definition of the first on-treatment period has been added (section 2.2.2). The use of it has 
been added to supplementary analyses regarding on treatment (section 2.2.3, 2.4.1).  
 It has been clarified that tied event times are handled using the exact method and risk limits 
are based on the profile likelihood (section 2.2.4). 
 The definition of eGFR components of primary endpoint in case of competing events 
(section 2.3) has been adjusted and a description of on-treatment for eGFR components has 
been added. 
 A sensitivity analysis for the primary endpoint using only scheduled eGFR measurements 
has been added (section 2.3.2). 
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Statistical Analysis Plan 
 
Date: 
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UTN: U1111-1217-6259 
Status: 
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 The absolute risk difference analysis has been further specified (section 2.3.3). 
 A supplementary analysis of non-CV, non-renal death has been added to evaluate the effect 
of competing risk on the primary endpoint (section 2.3.3). 
 In the specification of subgroup analyses EU has been changed to Europe and a description 
of which countries belong to each region has been added. The subgroup analysis for RAAS 
blocker use at baseline (Y/N) has been removed due to low number of subjects not using 
RAAS blockers at baseline. The subgroup Hispanic or Latino, Other has been updated to 
Hispanic or Latino, Not Hispanic or Latino (section 2.3.4).  
 Supplementary analyses evaluating the impact of the COVID-19 pandemic on the primary 
and confirmatory secondary endpoints have been added (section 2.3.5, 2.4.1). 
 Supplementary analyses evaluating the impact of co-participation in COVID-19 trials on the 
confirmatory endpoints have been added (section 2.3.6, 2.4.1).  
 A supplementary analysis using a new equation (CKD EPI) where race is not included to 
estimate eGFR has been added (section 2.3.7) 
 For confirmatory secondary endpoints the significance level used in the hierarchical testing 
procedure has been changed to follow a separate alpha spending function (section 2.4.1 and 
3.3) 
 The analysis for all-cause death using the extended in-trial period (section 2.4.1) has been 
further specified. 
 The requirement for when year 2 will be used instead of year 3 has been clarified (section 
2.4.2) and the requirement has been added for the additional exploratory analyses in Table 8.  
 The imputation model for the ANCOVA for continuous endpoints has been clarified 
(section 2.4.2). 
 Section 2.6 has been added 
 The part describing that Novo Nordisk will replicate the interim analysis has been removed 
(section 3.3). 
 It has been clarified in the appendix that UACR, urea, bicarbonate, lipids and hsCRP are 
log-transformed prior to analysis. 
 It has been specified in the appendix that change in insulin dose is analysed in subjects who 
are using insulin at baseline and that both absolute and relative change will be analysed.  
 Various smaller editorial changes and corrections to ease reading or add clarification and 
ensure alignment with SAPs for trials EX9924-4473 (SOUL) and NN9536-4388 (SELECT) 
have been made. 
SAP version 3.0 dated 07-FEB-2023 
Changes and additions to SAP version 2.0. 
 Sensitivity analyses using retrieved dropouts have been added for the primary and confirmatory 
secondary endpoints (section 2.3.2, 2.4.1 and Table 7) 
 Subgroup analysis based on age: <65, 65≤ to <75, ≥75 years and eGFR: < 30, 30 ≤ to < 45, 45 ≤ 
to < 60, ≥ 60 mL/min/1.73m2 (CKD-EPI) have been added (section 2.3.4) 
 The alpha-spending function on the confirmatory secondary endpoints (section 2.4.1) has been 
updated to the same alpha-spending function as for the primary endpoint. 
 Two sensitivity analyses have been added for the confirmatory secondary endpoint annual rate 
of change in eGFR (total eGFR slope) (section 2.4.1 and Table 7) 
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Date: 
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Trial ID: NN9535-4321 
Version: 
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Status: 
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 The supplementary analysis for the primary endpoint using the CKD-EPI eGFR equation 
without race was taken out of the equation (primary endpoint) has been added to Table 7. 
 
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Statistical Analysis Plan 
 
Date: 
09 February 2023 Novo Nordisk 
Trial ID: NN9535-4321 
Version: 
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UTN: U1111-1217-6259 
Status: 
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Table 8 
Additional exploratory analyses 
Endpoint 
Time frame 
Unit 
Analysis 
Time to first occurrence of 
ESRD defined as a composite 
endpoint consisting of: 
- Initiation of chronic renal 
replacement therapy 
- Onset of persistent eGFR 
<15 mL/min/1.73 m2 
From randomisation to end-
of-trial  
Months 
Stratified Cox model as 
for the primary endpoint 
(primary analysis) 
Time to first occurrence of a 
4-component CKD endpoint 
consisting of: 
- Renal death 
- Initiation of chronic renal 
replacement therapy 
- Onset of persistent eGFR 
<15 mL/min/1.73 m2 
- Onset of persistent ≥50 % 
reduction in eGFR 
Time to first occurrence of a 
composite endpoint consisting 
of: 
- Onset of persistent ≥57 % 
reduction in eGFR (doubling 
of serum creatinine) 
- Renal death 
- Initiation of chronic renal 
replacement therapy 
- Onset of persistent eGFR 
<15 mL/min/1.73 m2 
Time to first occurrence of a 
composite endpoint consisting 
of: 
- Renal death 
- Initiation of chronic renal 
replacement therapy 
- Onset of persistent eGFR 
<15 mL/min/1.73 m2 
- Onset of persistent ≥40 % 
reduction in eGFR 
Time to first occurrence of a 
composite endpoint consisting 
of: 
- All-cause death 
- Initiation of chronic renal 
replacement therapy 
- Onset of persistent eGFR 
<15 mL/min/1.73 m2 
- Onset of persistent ≥50 % 
reduction in eGFR 
Time to first insulin initiation 
(in subjects who are insulin 
naïve at randomisation)  
Time to first occurrence of all-
cause hospitalisation 
Change in total cholesterol 
mg/dL 
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Change in LDL cholesterol 
From randomisation to year 
3*. 
 
mg/dL 
ANCOVA (change in 
insulin dose) /log-
ANCOVA (rest) as for the 
continuous supportive 
secondary endpoints 
Change in HDL cholesterol 
mg/dL 
Change in Triglycerides 
mg/dL 
Change in Urea 
mg/dL 
Change in bicarbonate 
mmol/L 
Change in hsCRP  
mg/L 
Change in insulin dose (for 
subjects using insulin at 
baseline) (absolute and 
relative change) 
IU and IU/kg 
*If 10% or more of subjects from FAS have missed the relevant visit due to trial termination earlier than planned. the endpoints will be evaluated as 
change to 2 years. 
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Date: 
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Version: 
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6 
References 
1. 
Zhao Y, Herring AH, Zhou H, Ali MW, Koch GG. A multiple imputation method for 
sensitivity analyses of time-to-event data with possibly informative censoring. J 
Biopharm Stat. 2014;24(2):229-53. 
2. 
He J, Crackel R, Koh W, Chen LW, Li F, Zhang J, et al. Retrieved-Dropout-Based 
multiple imputation for time-to-event data in cardiovascular outcome trials. J Biopharm 
Stat. 2022:1-19. 
3. 
Andersen PK, Perme MP. Pseudo-observations in survival analysis. Stat Methods Med 
Res. 2010;19(1):71-99. 
4. 
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. New creatinine- 
and cystatin C-based equations to estimate GFR without race. N Engl J Med. 
2021;385(19):1737-49. 
5. 
Glimm E, Maurer W, Bretz F. Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med. 2010;29(2):219-28. 
6. 
Vonesh EF, Greene T, Schluchter MD. Shared parameter models for the joint analysis of 
longitudinal data and event times. Stat Med. 2006;25(1):143-63. 
7. 
Ghosh D, Lin DY. Nonparametric analysis of recurrent events and death. Biometrics. 
2000;56(2):554-62. 
8. 
Ghosh D, Lin D. Marginal regression models for recurrent and terminal events. 
Statistica Sinica. 2002;12:663-88. 
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