A Multicentre International Randomized Parallel Group Double-blind Placebo-controlled Clinical Trial of EMPAgliflozin Once Daily to Assess Cardio-renal Outcomes in Patients With Chronic KIDNEY Disease
Phase: PHASE3
Conditions: Chronic Kidney Disease
Sponsor: Boehringer Ingelheim

 
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EMPA-KIDNEY Trial Protocol 
 
A multicentre international randomized parallel group double-
blind placebo-controlled clinical trial of EMPAgliflozin once 
daily to assess cardio-renal outcomes in patients with 
chronic KIDNEY disease 
 
 
Does inhibition of sodium-glucose co-transporter-2 with empagliflozin 
prevent kidney disease progression and cardiovascular death in 
patients with chronic kidney disease? 
 
Selective inhibition of sodium-glucose co-transporter-2 (SGLT-2) with empagliflozin causes 
urinary glucose excretion and reduces hyperglycaemia, weight, plasma circulating volume 
and blood pressure. This has been shown to translate safely into reduced clinical risk from 
cardiovascular disease (particularly heart failure and cardiovascular death) in people with 
type 2 diabetes (T2D) and established cardiovascular disease. SGLT-2 inhibition with 
empagliflozin also reduces albuminuria and slows the annual decline in estimated 
glomerular filtration rate in people with T2D who still have preserved kidney function. The 
kidney effects may result from increased sodium delivery to the kidney’s macula densa, 
which in turn causes glomerular afferent arteriolar vasoconstriction and reduced 
intraglomerular pressure. Raised intraglomerular pressure is believed to be central to the 
“final common pathway” of disease progression in chronic kidney disease (CKD). Since 
SGLT-2 inhibition with empagliflozin also causes glycosuria and acute haemodynamic 
changes in kidney function in people without diabetes, empagliflozin may also be 
nephroprotective in conditions without ambient hyperglycaemia, which collectively account 
for 50 to 70% of patients with CKD worldwide. Patients with established CKD are at 
substantial risk of progressing to end-stage kidney disease despite the use of medical 
therapies, including renin-angiotensin system inhibition, so identifying new treatments to 
delay progression is a priority. Moreover, patients with CKD are at high risk of cardiovascular 
death and heart failure, which may also be reduced by empagliflozin. 
 
A streamlined international trial 
 
This randomized trial will compare empagliflozin 10 mg once daily versus matching placebo, 
given on top of standard of care, in around 6000 participants with established CKD, with or 
without diagnosed diabetes mellitus, who are being treated (where tolerated) with an 
appropriate dose of a renin-angiotensin system inhibitor. The study is event-driven, and will 
continue until the required number of primary outcomes has occurred. Follow-up will allow 
reliable assessment of the effects of empagliflozin on kidney disease progression or 
cardiovascular mortality, and other clinical outcomes. The study design is streamlined: extra 
work for collaborating doctors and hospitals will be kept to a minimum, and only essential 
information will be collected. The trial is focused on readily identifiable and important clinical 
outcomes. Participant reported information recorded by participant interview directly into 
bespoke computer systems and centrally measured creatinine are the main means of data 
collection. 
 
Central Coordinating Office (CCO), 
 
 
Tel: 
 E-mail: 
  

 
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3.4.1 
Final check of eligibility and compliance before randomization ................................................... 28 
3.4.1.1 Collection of blood and urine samples .................................................................................... 28 
3.4.2 
Random allocation of study treatment ......................................................................................... 28 
3.5 FOLLOW-UP VISITS (2 AND 6 MONTHS AND THEN 6-MONTHLY) ..................................................... 29 
3.5.1 
Recording adverse events and adherence to study treatment .................................................... 29 
3.5.2 
Collection of blood and urine samples ......................................................................................... 29 
3.5.3 
Issuing study treatment and arranging further appointments....................................................... 30 
3.5.4 
Follow-up for randomized participants not attending study clinics ............................................... 30 
3.5.5 
Monitoring of women of child bearing potential ........................................................................... 30 
3.5.6 
Monitoring of people with diabetes mellitus ................................................................................. 30 
3.5.7 
Local Lead Investigator supervision ............................................................................................ 31 
3.6 CENTRAL MONITORING OF PARTICIPANT SAFETY, EARLY RECALL VISITS AND MODIFYING STUDY 
TREATMENT ............................................................................................................................. 31 
3.6.1 
Early Recall Visits ........................................................................................................................ 31 
3.6.2 
Monitoring liver function, potassium, creatinine and AESIs ......................................................... 31 
3.6.3 
Modifying study treatment ........................................................................................................... 31 
3.6.4 
Unblinding of study treatment ...................................................................................................... 32 
3.6.5 
Withdrawal of consent ................................................................................................................. 32 
3.7 CONFIRMATION AND VERIFICATION OF STUDY OUTCOMES (“ADJUDICATION”) .............................. 32 
3.8 CITED REFERENCES ................................................................................................................. 33 
4.1 APPENDIX 1: ORGANISATIONAL STRUCTURE AND RESPONSIBILITIES FOR STUDY DESIGN AND 
CONDUCT ................................................................................................................................ 37 
4.2 APPENDIX 2: VISIT SCHEDULE AND PROCEDURES ....................................................................... 40 
4.2.1 
Clinic procedures ......................................................................................................................... 40 
4.3 APPENDIX 3: STUDY ADDRESSES .............................................................................................. 41 
5.1 VERSION HISTORY.................................................................................................................... 42 

 
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TRIAL SYNOPSIS 
 
Trial title 
A multicentre international randomized parallel group double-blind placebo-controlled 
clinical trial of EMPAgliflozin once daily to assess cardio-renal outcomes in patients 
with chronic KIDNEY disease  
Short and lay title 
EMPA-KIDNEY (The study of heart and kidney protection with empagliflozin) 
Clinical phase  
III 
Trial design 
Randomized double-blind placebo-controlled trial 
Responsibilities 
The study was initiated by the University of Oxford and developed in a collaboration 
with Boehringer Ingelheim, which has provided funding for the trial. Boehringer 
Ingelheim, the sponsor of this trial, has delegated responsibility for the conduct, 
analysis and reporting of the trial to the University of Oxford. 
Boehringer Ingelheim ID 
1245-0137 
ClinicalTrials.gov 
NCT03594110 
EudraCT number 
2017-002971-24 
Trial participants 
Eligibility criteria: 
1. Aged ≥18 years* at Screening; and 
2. Chronic kidney disease (CKD) at risk of kidney disease progression;† 
3. A local investigator judges that the participant neither requires empagliflozin 
(or any other SGLT-2 or SGLT-1/2 inhibitor), nor that such treatment is 
definitely inappropriate; and 
4. No exclusion criteria apply 
Participants will be treated with appropriate doses of renin-angiotensin system (RAS)-
inhibition, unless such treatment is either not tolerated or not indicated. No patient 
currently being treated with empagliflozin (or other SGLT-2 or SGLT-1/2 inhibitor) 
should be taken off this therapy to meet the eligibility criteria. Throughout the study, 
the care of participants will remain the responsibility of their local doctors who will be 
asked to ensure individualized standard of care, including management of 
cardiovascular risk factors and other existing comorbidities (e.g. hypertension, 
diabetes etc.). This should be conducted in the context of prevailing local, national or 
international guidance. 
Planned sample size 
Approximately 6000 participants, including at least one-third with diabetes, one-third 
without diabetes, and up to one-third with a CKD-EPI estimated glomerular filtration 
rate (eGFR) ≥45 and <90 mL/min/1.73m2 at Screening 
Placebo Run-in 
8-12 weeks 
Treatment duration 
Event driven: the trial will continue until at least 1070 participants have experienced a 
first primary outcome after randomization  
Primary outcome 
 
Time to first occurrence of: 
 
Kidney disease progression (end-stage kidney disease‡, a sustained eGFR <10 
mL/min/1.73m², renal death, or a sustained ≥40% decline in eGFR from 
randomization) or  
 
Cardiovascular death 
Secondary outcomes 
Key secondary outcomes: 
 
Time to first hospitalization for heart failure or cardiovascular death  
 
Time to occurrences of all-cause hospitalization (first and recurrent combined) 
 
Time to death from any cause 
Other secondary outcomes: 
 
Time to kidney disease progression 
 
Time to cardiovascular death 
 
Time to cardiovascular death or end-stage kidney disease 
Medicinal Product 
Oral empagliflozin 10 mg 
Formulation, dose, route 
of administration 
Run-in: placebo film-coated tablet once daily (single-blind) for oral administration; 
From randomization: empagliflozin 10 mg film-coated tablet once daily versus 
matching placebo film-coated tablet once daily (double-blind) for oral administration 
* Or “full age” as required by local regulations (e.g. 20 years in Japan)  
† Either (i) estimated glomerular filtration rate (eGFR) ≥20, <45 mL/min/1.73m2; or (ii) eGFR ≥45, <90 
mL/min/1.73m2 with urine albumin:creatinine ratio ≥200 mg/g 
‡ End-stage kidney disease is defined as the initiation of maintenance dialysis or receipt of a kidney transplant 

 
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1.1 DOES INHIBITION OF SODIUM-GLUCOSE CO-TRANSPORTER-2 (SGLT-2) WITH EMPAGLIFLOZIN 
PREVENT KIDNEY DISEASE PROGRESSION OR CARDIOVASCULAR DEATH IN PATIENTS WITH 
CHRONIC KIDNEY DISEASE (CKD)? 
 
1.1.1 Substantial cardiovascular risk exists for CKD patients despite statin-based 
therapy and antihypertensive therapy 
In high-income countries, the prevalence of CKD is about 10% and is likely to increase as 
average population age rises and diabetes mellitus becomes more prevalent.1, 2 
Cardiovascular risk increases progressively as kidney function declines.3, 4 There is 
evidence that lowering low-density lipoprotein cholesterol and blood pressure in people with 
CKD reduces cardiovascular risk,5, 6 but substantial residual risk remains and no other 
treatments have been shown to reduce cardiovascular risk in this group of patients.  
 
A key feature of cardiovascular disease in CKD is presence of structural heart pathologies 
(e.g. left ventricular hypertrophy and/or dilatation) and heart failure (which may be 
accompanied by coronary heart disease). At least half of patients with advanced CKD (i.e. 
stages 4-5) have abnormal cardiac structure on echocardiography,7,8 increasing to over 80% 
by the time dialysis is initiated.8  
 
1.1.2 Empagliflozin reduces the risk of cardiovascular death in people with type 2 
diabetes and established cardiovascular disease 
Selective inhibition of SGLT-2 causes increased urinary glucose and transiently increased 
sodium excretion. This is associated with reductions in weight and blood pressure as well 
as haemoglobin glycation (HbA1c). Among 7020 patients with type 2 diabetes mellitus (T2D) 
and established cardiovascular disease in the EMPA-REG OUTCOME trial, empagliflozin 
reduced the primary cardiovascular composite outcome (death from cardiovascular causes, 
nonfatal myocardial infarction, or nonfatal stroke) by 14% compared to placebo (hazard ratio 
[HR] 0.86, 95% confidence interval [CI] 0.74-0.99). This was driven by a significant reduction 
in cardiovascular death (HR 0.62, 95% CI 0.49-0.77, nominal p<0.0001). A pre-specified 
secondary outcome of hospitalization for heart failure was reduced by 35% (HR 0.65, 95% 
CI 0.50-0.85).9 
 
The EMPA-REG OUTCOME trial was conducted in participants with relatively preserved 
kidney function (>90% had a baseline estimated glomerular filtration rate [eGFR] >45 
mL/min/1.73m2), and it is unclear whether empagliflozin can prevent cardiac disease in 
patients with more severe kidney impairment.  
 
1.1.3 Substantial risk of kidney disease progression in people with CKD despite 
inhibition of the renin-angiotensin system 
CKD is often a progressive condition, with proteinuria representing a significant risk factor 
for a more rapid decline in kidney function.10 Although patients with early CKD are more 
likely to die before they reach end-stage kidney disease (ESKD), the avoidance of ESKD is 
still highly desirable due to its adverse effects on quality of life and the substantial costs of 
dialysis and transplantation to healthcare providers. Inhibition of the renin-angiotensin 
system (RAS) with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor 
blockers (ARB) reduces albuminuria and slows the rate of progression in proteinuric 
nephropathies, particularly in diabetic kidney disease.11-13 However, a substantial residual 
risk of ESKD remains. Although combination therapy (i.e. ACEi plus ARB) was initially 
thought to be a promising approach, such combined regimens do not delay kidney disease 
progression and may cause hyperkalaemia or acute kidney injury.14 There is therefore a 

 
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reabsorption, thereby increasing distal sodium delivery to the macula densa, which has been 
shown to activate a tubulo-glomerular feedback leading to afferent arteriolar 
vasoconstriction, thereby reducing intraglomerular pressure and urinary albumin excretion. 
 
Empagliflozin has also been shown to have a pharmacological effect in people without 
diabetes. In healthy volunteers, empagliflozin 10 mg daily resulted in approximately 50 g/day 
glycosuria, and an initial acute decrease in GFR (an indicator of reduced intraglomerular 
pressure) has been shown to occur in overweight but otherwise healthy volunteers 
(unpublished data, BI clinical trial report 1245.66). Taken together, these observations 
suggest that empagliflozin has haemodynamic effects in the kidney in the absence of 
elevated blood glucose.  
 
It is therefore reasonable to hypothesize that empagliflozin may have beneficial effects on 
kidney disease progression and cardiovascular risk among those with CKD, irrespective of 
the presence of diabetes. Worldwide, the proportion of patients with CKD who have diabetes 
ranges from about 30 to 50% so, if empagliflozin has beneficial effects on kidney and 
cardiovascular outcomes in CKD, then its use in patients with CKD but without diabetes 
would increase the potential population who might benefit from this drug by 2-3 times.20, 21  
 
1.1.5 The safety of empagliflozin has been established in people with type 2 diabetes  
The empagliflozin clinical development programme has randomized >15,000 trial 
participants to date. About 550 healthy volunteers have been exposed to empagliflozin (up 
to 800 mg in a single dose and up to 50 mg in multiple dosing), with good tolerability. 
Approximately 8500 patients with T2D have been treated with empagliflozin in clinical 
studies, of which more than half have been treated for a year or more.22-30 In all these 
studies, empagliflozin was well tolerated. In the EMPA-REG OUTCOME trial, which had a 
median follow-up of 3.1 years, the frequency of serious adverse events (SAEs) and adverse 
events that led to discontinuation of study treatment among patients allocated empagliflozin 
was no higher than that among those allocated placebo.9, 15 There was no significant 
increase in the frequency of hypoglycaemia with empagliflozin, except when used in 
combination with a sulphonylurea or basal dose insulin.31 Electrolytes were not significantly 
different among those allocated to empagliflozin or placebo.31 Compared to placebo, there 
was an increased frequency of mycotic genital infections. By contrast with the increased risk 
of bone fracture and lower-limb amputation observed with another SGLT-2 inhibitor, 
canagliflozin,32 there was no such adverse safety signal observed when over 12,000 patients 
with T2D from placebo-controlled empagliflozin clinical trials (including EMPA-REG 
OUTCOME) were analysed together.31 Further safety analyses from EMPA-REG 
OUTCOME showed that the adverse event profile of empagliflozin in patients who had 
impaired kidney function at baseline (i.e. eGFR <60 mL/min/1.73m2), a potentially vulnerable 
population, was consistent with that reported in the overall trial population.15 In summary, 
the EMPA-KIDNEY trial aims to assess whether empagliflozin reduces the risk of kidney 
disease progression or cardiovascular death in people with CKD, irrespective of whether 
they have diabetes, and whether the benefits of treatment outweigh any adverse effects.  

 
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albumin:creatinine ratio (both based on local laboratory results at screening), and region.33 
The algorithm includes a stochastic element (treatment is assigned to the arm determined 
by the minimization algorithm with a probability of 0.9 and by a random number generator 
with a probability of 0.1). Given the stochastic element of the randomization, re-
randomization methods for the analysis are not considered necessary and only traditional 
methods of analysis are planned. Randomized participants will be issued with a 7-month 
supply of study treatment consisting of empagliflozin 10 mg or matching placebo. One tablet 
is to be taken daily with or without food. To ensure a dose interval of about 24 hours, the 
medication should ideally be taken at approximately the same time every day. 
2.3 DATA ANALYSIS PLAN 
 
2.3.1 Main and subsidiary assessments 
2.3.1.1 Primary assessment 
The primary assessment will involve an intention-to-treat comparison among all randomized 
participants, using a Cox model adjusting for each of the minimization variables (see above), 
of the effects of allocation to empagliflozin versus placebo on the time to the first occurrence 
of: 
 
(i) 
Kidney disease progression (defined as ESKD, a sustained decline in eGFR to <10 
mL/min/1.73m2, renal death, or a sustained decline of ≥40% in eGFR from 
randomization); or  
(ii) 
Cardiovascular death. 
 
ESKD is defined as the initiation of maintenance dialysis or receipt of a kidney transplant.  
 
To ensure bias is not introduced by differences between treatment arms in the extent to 
which extra eGFR measurements are made outside of scheduled follow-up visits, the term 
‘sustained’ in respect of a decline in eGFR (to <10 mL/min/1.73m2, or of ≥40% from baseline) 
is that it is either (a) measured at two consecutive scheduled study follow-up visits; or (b) 
measured at the last scheduled study follow-up visit or the last scheduled visit before death 
(or withdrawal of consent). 
 
2.3.1.2 Secondary assessments 
If the primary outcome is statistically significant (either at the interim or final analysis), the 
key secondary outcomes will then be tested. The secondary assessments will involve 
intention-to-treat comparisons among all randomized participants of the effects of allocation 
to empagliflozin versus placebo during the scheduled treatment period on: 
 
(i) 
Key secondary outcomes: 
a) 
Time to first hospitalization for heart failure or cardiovascular death; 
b) 
Time to occurrences of all-cause hospitalizations (first and recurrent 
combined); 
c) 
Time to death from any cause. 
 
 

 
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(ii) 
Other secondary outcomes: 
a) 
Time to first occurrence of kidney disease progression; 
b) 
Time to cardiovascular death; 
c) 
Time to cardiovascular death or ESKD. 
 
In testing the key secondary outcomes, their p-values will be corrected for multiple testing 
using the Hochberg “step-up” procedure that controls the familywise error rate. Other 
secondary outcomes will be assessed without adjustment for multiplicity at a nominal level 
of α = 0.05 (two-sided). 

 
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2.3.2 Safety, biochemical and exploratory assessments 
2.3.2.1 Safety assessments 
Safety assessments will involve intention-to-treat among all randomized participants and, 
where appropriate, on-treatment analyses of the effects of allocation to empagliflozin versus 
placebo during the scheduled treatment period on: 
 
(i) 
SAEs due to: 
(a) Urinary tract infection, overall and separately by sex; 
(b) Genital infection, overall and separately by sex; 
(c) Hyperkalaemia; 
(d) Acute kidney injury; 
(e) Dehydration; 
 
(ii) 
AEs of Special Interest (AESIs): 
(a) Liver injury, both overall and separately by cause (defined as ALT or AST ≥5x 
Upper Limit of Normal [ULN] or the combination of ALT or AST ≥3x ULN with 
bilirubin ≥2x ULN; measured in the same blood sample at study follow-up or early 
recall visits; see Section 3.5.2); 
(b) Ketoacidosis, both overall and, separately, by baseline diabetes status; 
(c) Lower limb amputations (overall and by level); 
 
(iii) 
Other AEs relevant to the study question: 
(a) Bone fractures, both overall and separately by site and aetiology (i.e. 
distinguishing those resulting from high and low impact trauma); 
(b) Severe hypoglycaemia (defined as low blood sugar causing severe cognitive 
impairment which requires assistance from another person for recovery);  
(c) Symptomatic dehydration (defined as whether or not a participant has 
experienced symptoms they attribute to dehydration, such as feeling faint or 
fainting); 
 
(iv) 
Hospitalization by specific causes†; 
 
(v) 
SAEs both overall and, separately, by category†; 
 
(vi) 
Discontinuation of study treatment overall and by various causes (including SAEs†, 
non-serious adverse events†, and other reasons);  
 
† based on Medical Dictionary for Drug Regulatory Activities (MedDRA) System Organ Class 
classification 

 
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(vii) 
Changes in weight and systolic and diastolic blood pressure from baseline. 
 
2.3.2.4 Health economic assessments 
The study results may, if appropriate, be used to conduct health economic assessments 
regarding the use of empagliflozin. An analysis plan will be pre-specified if any such 
analyses are considered worthwhile. 
 
2.3.3 Statistical analysis 
A full Data Analysis Plan will be finalised prior to any unblinding of study results. Briefly, all 
participants randomized to empagliflozin will be compared with all participants randomized 
to placebo, regardless of whether a participant received all, some or none of their allocated 
treatment (i.e. intention-to-treat analyses). A participant may contribute to more than one 
assessment if they have events of more than one type (e.g. hospitalization for heart failure 
followed by ESKD). For the time-to-event analyses survival analytic methods will be used to 
evaluate the time to the first event during the entire study period. For each categorical 
outcome, Cox proportional hazards regression adjusted for the prognostic variables used in 
the minimization algorithm (age, sex, prior diabetes, eGFR, urinary albumin:creatinine ratio, 
and region) will be used to estimate the hazard ratio comparing all those allocated active 
empagliflozin with all those allocated placebo. Estimates of the hazard ratio will be shown 
with 95% confidence intervals, and Kaplan-Meier estimates for the time to each of the 
primary and secondary outcomes will also be plotted. For the secondary outcome of all-
cause hospitalization, the analysis will examine all events (i.e. not just the first event in each 
participant). 

 
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The safety profile of empagliflozin has been well-studied in previous trials.9, 15, 22-31 
Therefore, in line with regulatory guidance,35 collection of safety data will be streamlined.  
 
2.5.1.1.1 Non-serious adverse events 
Non-serious AEs will only be recorded if they: 
(a) Lead to discontinuation of study treatment; or  
(b) Are one of the following: 
 Bone fracture (with additional information recorded about fracture site and aetiology 
[i.e. distinguishing those resulting from high and low impact]) 
 Severe hypoglycaemia (as defined in Section 2.3.2.1) 
 Episodes of gout 
 Symptomatic dehydration (as defined in Section 2.3.2.1) 
 An Adverse Event of Special Interest (AESI; see Section 2.5.1.1.2) 
 Events that could lead to amputation (which include diagnosis or treatment for 
peripheral arterial disease, peripheral neuropathy, diabetic foot ulcer, and lower limb 
infection or gangrene). 
 
2.5.1.1.2 Adverse Events of Special Interest (AESI) 
The following AEs will be recorded regardless of whether they fulfil the criteria for a SAE: 
 Liver injury  
 Ketoacidosis 
 Lower limb amputations (overall and by level). 
 
All new AESIs will be reviewed each working day by 
 (
) 
clinicians and relevant additional details sought promptly (see Section 3.6.2). Detailed 
reports on AESIs will be provided by the 
 to Boehringer Ingelheim at regular intervals. 
 
2.5.1.1.3 Serious Adverse Events (SAEs) 
SAEs are defined as those adverse events that: 
 Result in death 
 Are life-threatening 
 Require inpatient hospitalization or prolongation of existing hospitalization; 
 Result in persistent or significant disability or incapacity 
 Result in congenital anomaly or birth defect 
 Are important medical events in the opinion of a responsible Local Investigator (i.e. 
not life-threatening or resulting in hospitalization, but may jeopardise the participant 
or require intervention to prevent one or other of the outcomes listed above).  
 
For the purposes of this trial, certain pre-specified Preferred Terms (e.g. “agranulocytosis”, 
“interstitial lung disease”), and all cancers will always be considered Seriousa.  
 
Pregnancy will not be considered an AE in this trial, but must be reported promptly (within 
24 hours) to the Regional Co-ordinating Centre (RCC) or 
 and then followed up using 
Pregnancy Monitoring Forms. 
 
2.5.1.2 Recording and review of relevant AEs by LCC staff 
All relevant AEs (as defined in Section 2.5.1.1) reported by participants at each study visit 
interview will be recorded and assessed by trained LCC clinic staff (usually the LCC 
Research Coordinator) directly on the study computer-based data entry system (see Section 
                                            
a In accordance with the European Medicines Agency initiative on Important Medical Events.  
Note: New cancer diagnosis and recurrence of pre-existing cancer should all be recorded. 

 
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2.6.3), regardless of whether the participant continues to take study treatment or not. If the 
study team become aware of SAEs or AESIs between study visits, they are requested to 
report them within 24 hours. If LCC clinic staff cannot access the computer-based data entry 
system, they must contact their RCC to report the AE within that timeframe. After completion 
of the trial, investigators do not need to actively monitor participants, but could report SSARs 
or related AESIs through telephone contact to the RCC or 
 
 
The electronic SAE form will capture the following information for all SAEs: 
 Unique study identification number of the participant 
 Unique SAE form identification number 
 The time and date that the SAE form is completed 
 The source of the report (e.g. participant, relative, study nurse, Local Investigator, or 
other doctor) 
 A description of the event: Event descriptions will be recorded by the trained clinic 
staff using MedDRA Preferred Terms. If an appropriate term cannot be identified, 
advice can be sought from the Local Investigator or a 
 study clinician, or the 
description can be recorded as free-text and subsequently coded by 
 study 
clinician, blind to study treatment allocation 
 The reason for believing the AE to be serious (i.e. resulted in death, life-threatening, 
hospitalisation, disabling, congenital anomaly in offspring, other important medical 
event) 
 The date the event started 
 The place where the event was diagnosed or managed (e.g. hospital inpatient, 
hospital outpatient, participant’s home) 
 The name of the place where the event was diagnosed or managed (if appropriate) 
 Number of nights spent in hospital (if applicable) 
 The outcome (ongoing, recovered, death, unknown) 
 Whether the event is thought likely to be due to study treatment. In making this 
assessment, there should be consideration, based on the available information, of 
the pharmacology of the drug and drug class, probability of an alternative cause, the 
timing of the reaction with respect to study drug, the response to withdrawal of the 
study drug, and (where appropriate) the response to subsequent re-challenge or dose 
change. 
 
Such detailed information will also be collected for all AESIs. 
 
The electronic non-serious AE form will capture the following information: 
 
Unique study identification number of the participant 
 
Unique AE form identification number 
 
The time and date that the AE form is completed 
 
A description of the event (as describe above) 
 
The date the event started 
 
The outcome (ongoing, recovered, unknown) 
 
Whether the event is thought likely to be due to study treatment (as above). 
 
Local Investigators are required to review all AEs recorded by those LCC Research Co-
ordinators who have been delegated the task of recording AEs.   
 

 
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2.5.1.3 Collection of Additional Information for Suspected Serious Adverse 
Reactions (SSARs) by 
 
Any SAE that is considered, with reasonable possibility, to be due to study treatment by 
either Local Investigators, appropriately delegated LCC clinic staff or 
 study clinicians 
(or Boehringer Ingelheim staff), is potentially a SSAR. The 
study clinician will obtain 
standard information, including participant study number, identity of reporting person, 
description of event, and reason for attribution to study drug. All such reports will then be 
forwarded urgently to a 
 Clinical Coordinator (or their delegated 
 study clinician 
deputy), who will review the evidence for seriousness and relatedness (in discussion with 
the LLI if necessary), and seek any additional information required (including relevant 
information relating to medical history and treatment both prior to and following 
randomization, and prior to/at the time of onset of the SSAR).  
 
2.5.1.4 Expedited reporting of SUSARs and exemptions from expedited reporting 
SSARs that are unexpected according to the Investigator’s Brochure are subject to 
expedited reporting.36, 37 However, in line with recommendations by regulatory authorities, 
anticipated events that either are efficacy endpoints, consequences of the underlying 
disease or are events common in the study population will be exempted from expedited 
reporting in order to protect trial integrity and because based on a single case it is not 
possible to conclude that there is a reasonable possibility that the investigational drug 
caused the event.36, 38 Such events that are exempted from expedited reporting to health 
authorities in this trial are listed below. 
1. Efficacy endpoints: 
 Kidney disease progression (i.e. ESKD) 
 Myocardial infarction 
 Stroke and transient ischaemic attack 
 Heart failure 
 CV death 
 New-onset diabetes mellitus. 
 
2. Common CKD-related eventsb: 
 Acute-on-chronic kidney failure 
 Dialysis and dialysis access related events and complications 
 Bone fractures and parathyroid-related events. 
 
Any SSARs that are considered not exempt will be reported promptly by the 
 to 
Boehringer Ingelheim, and Boehringer Ingelheim will make an assessment of whether the 
event is “expected” or not (based on the latest version of the empagliflozin Investigator 
Brochure). Any SSAR that is unexpected will be considered a potential Suspected 
Unexpected Serious Adverse Reaction (SUSAR) and will be unblinded by a member of the 
 clinical staff with such privilege. 
 
All SUSARs will be reported to relevant regulatory authorities, to the Chair of the Data 
Monitoring Committee (DMC) and, as required, to ethics committees and Institutional 
Review Boards and investigators in an expedited manner in accordance with regulatory 
requirements. 
 
                                            
b The relevant MedDRA Preferred Terms which are exempt are specified in the Adverse Event Reporting 
SOP. 

 
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2.5.2 Interim analyses: role of the independent Data Monitoring Committee 
2.5.2.1 Regular unblinded analyses by the DMC 
The DMC will assess participant safety and the progress of the trial through review of 
unblinded data at specified intervals, and recommend to the Steering Committee and 
Boehringer Ingelheim whether to continue, modify, or stop the trial. Measures are in place 
to ensure blinding of Boehringer Ingelheim, University of Oxford, the Steering Committee 
and all other trial staff and participants. The tasks and responsibilities of the DMC will be 
specified in the DMC charter. The DMC will maintain written records of all its meetings. 
The DMC will request analyses at a frequency relevant to the stage of the study (typically at 
6-12 monthly intervals, with a Chair’s review every 3-6 months) or in response to emerging 
data from other trials. These unblinded analyses of all SAEs and other study outcomes (both 
overall and in key subgroups, including by region) and all expected SSARs will be supplied 
in strict confidence by a statistician not otherwise involved in the trial.  
 
The DMC would be expected to advise the Steering Committee if clear evidence emerged 
of an adverse effect on all-cause mortality (at least 2 standard deviations) or if, in the view 
of the DMC, there was other compelling evidence of hazard that seemed likely to outweigh 
any potential benefit. 
 
Unless advised by the DMC in response to clear evidence of hazard, the Steering 
Committee, collaborators, participants, representatives of the Boehringer Ingelheim, and all 
study staff will remain blind to these results until the end of the study. The DMC is 
independent of the University of Oxford and Boehringer Ingelheim. 
 
2.5.2.2 Early stopping for benefit 
In addition, the DMC may review a single formal interim efficacy analysis once 150 
participants have experienced a first ESKD event (by which time it is expected that 
approximately 60% of all first primary outcomes will have occurred). Full details of the 
stopping guidelines at this interim analysis, including the alpha spent at this analysis and 
the alpha remaining for the final analysis, will be provided in the DMC Charter. Separate 
alpha-spending functions will be used for the testing of the primary and key secondary 
outcomes to control the type I error rate across two analysis time-points, and a gatekeeping 
approach followed by the Hochberg procedure will be used to control the type I error rate 
across multiple endpoints. 
 
Briefly, in order for the DMC to recommend that the trial is stopped early for benefit at this 
formal interim analysis, both of the following conditions must be met: 
 
(1) a reduction in the primary outcome with the Hwang-Shih-DeCani alpha-spending function 
(=-8) used to define the required two-sided p-value and its corresponding critical Cox 
hazard ratio; and (2) a reduction in the secondary composite outcome of time to 
cardiovascular death or ESKD to at least the same critical Cox hazard ratio as observed in 
the primary outcome, but with the proviso that the p-value is constrained to be < 0.05. For 
example, for the scenario when 60% of the first primary outcomes (i.e. 642 first primary 
outcomes) have occurred at the time of the interim analysis, this would equate to stopping 
criteria of: (i) a two-sided p-value <0.002 with a critical Cox hazard ratio <0.78 for the primary 
outcome; and (ii) a critical Cox hazard ratio of <0.78 and a two-sided p-value <0.05 for the 
secondary outcome of time to cardiovascular death or ESKD [with 400 such events and a 
critical Cox hazard ratio of <0.78 a p-value of <0.014 would be observed]. Note the 
secondary outcome of time to cardiovascular death or ESKD is not part of the prospectively 
defined hypothesis testing strategy but is included as an additional stopping criterion to 

 
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potential to have) a substantial impact on the protection of the study participants or the 
reliability of the study results (with full details provided in a Quality Assurance Systems 
SOP). 
 
Throughout the study, the 
 will centrally monitor performance against the predefined 
critical-to-quality factors. This process will predominantly be quantitative in nature and 
remedial actions will be determined based on the detection of deviations and totality of the 
evidence.  
 
The relevant RCC and/or the 
 will arrange monitoring visits to LCCs as considered 
appropriate based on perceived training needs and the results of central process monitoring 
and statistical monitoring of study data (i.e. monitoring visits will be spaced by several 
months). The purpose of such visits will be to ensure that the study is conducted according 
to the protocol, ICH-GCP, and the applicable regulatory requirements, and by helping LCC 
clinic staff to resolve any local issues with the study and by providing additional focused 
training where necessary. Particular attention will be given to the effectiveness of strategies 
to recruit appropriate participants, the consenting process, the completeness of follow-up, 
the maintenance of participant compliance with the study treatments (which will be assessed 
by participant self-report), the reporting of study outcomes and reportable AEs (see Section 
2.5.1), and collection of relevant supporting documentation to support the adjudication 
process (see Section 3.7). With the exception of local laboratory results (where a random 
subset will be assessed), no routine source data review and verification will take place as 
such data are obtained directly from participants (or occasionally from relatives or doctors) 
by interview. Where possible, monitoring visits will include observation of a participant’s 
study visit. A report of each monitoring visit will be prepared by the study monitor and 
provided to LCC, RCC and 
 staff (including the Head of Monitoring) for review, and filed 
appropriately. Copies of these reports will be supplied to Boehringer Ingelheim on request. 
With prior arrangement, representatives of Boehringer Ingelheim may attend monitoring 
visits. Details of monitoring are provided in an On-Site Monitoring SOP. 
 
2.6.2 Supply of study treatment 
Study treatments will be manufactured, packaged, labelled and delivered to each LCC or 
RCC by Boehringer Ingelheim (or their subcontractor) under the direction of the 
 and 
according to Good Manufacturing Practices. An inventory of study drug supplies will be 
maintained on the study computer-based system and monitored at the 
. LCC Local 
Investigators will be responsible for making appropriate arrangements for the storage and 
issuing of study treatments, and for the disposal of unused study drug in accordance with 
study SOPs. 
 
2.6.3 Data management 
All data in the study will be processed electronically using a set of custom-written 
applications developed to meet the requirements of the protocol and to comply with 21 CFR 
Part 11 and other relevant regulatory, legal and information security requirements. The LCC 
staff (usually the LCC Research Coordinator) will use bespoke web-based applications for 
local study management and to enter participant data (including study visit forms and AE 
information) directly into the database. These source data will be held in central databases 
located both at the 
 and at an independent third party where it will remain under the 
control of the Local Investigators (i.e. no paper case report forms exist). Any data queries 
reported by LCCs to the 
or RCC (as per regional arrangements) during the study will 
be recorded onto the computer-based study management system. Data queries will be 
reviewed and managed by the 
 in accordance with an Internal Operating Procedure, 

 
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with data changes only made to pre-defined critical-to-quality data points. Clear electronic 
documentation will be maintained so the original data entry is not obscured and there is an 
audit trail for each entered data error and data change. 
 
RCC and 
 staff will use the suite of administration applications on the computer-based 
system to manage LCCs and study participants, including central clinical supervision (review 
of AEs and laboratory results) by the 
, management of follow-up and compliance, 
tracking of samples for central analysis, collection of supporting documentation for relevant 
events, and clinical outcome adjudication. 
 
All data accesses will require a unique username and password, and any changes to data 
will require the user to enter their username and password as an electronic signature. Staff 
will have access restricted to only the functionality and data that are appropriate to their role 
in the study. 
  
2.6.4 Biological sample assay, transport and storage 
2.6.4.1 Local analysis of eligibility and safety bloods 
Local laboratories will be used in all LCC study clinics for eligibility checks at the Screening 
visit (urine albumin:creatinine ratio [or protein:creatinine ratio, according to local practice], 
and blood creatinine plus liver transaminases [AST or ALT]), at the Randomization visit 
(blood creatinine, potassium, liver transaminases, bilirubin and haematocrit) and for clinical 
safety oversight at each follow-up visit (including blood creatinine, potassium and liver 
transaminases with bilirubin; see Section 4.2.1).  
 
Haematocrit, haemoglobin, phosphate, sodium and corrected calcium will also be measured 
locally at 18 months of follow-up in a subset of about 20% (e.g. UK participants) of the 
surviving population.  
 
2.6.4.2 Central assessment of samples collected at the randomization visit and 
during follow-up 
Samples of both blood and urine are to be collected from all participants at the 
Randomization visit for central analysis and storage, including subsequent DNA extraction 
(subject to relevant consent, see Section 2.6.4.3) at a central ISO 17025 accredited 
laboratory. Central samples will not be used to assess eligibility. Further samples of both 
blood and urine are to be collected from all participants at the 2 month, 18 month (i.e. the 
approximate study midpoint) and Final Follow-up visits. Blood will be collected for central 
analysis of creatinine at the time of every scheduled Follow-up visit (see Section 4.2.1). 
RCCs will supply LCC staff with kits to collect these blood and urine samples. Blood is to be 
kept cool before centrifugation, separation into bar-coded cryovials, and storage at below -
18°C within a day of the study clinic visit. Samples are to be transferred to below -40°C 
within 4 weeks. At appropriate intervals, samples will be collected from the LCCs (by the 
RCC or 
) and transferred to the central laboratory for analysis (see Section 4.2.1) and 
for long-term frozen storage. Full details of sample collection, transport, storage and analysis 
are provided in a separate SOP.  
 
2.6.4.3 Consent approval for unspecified analyses on blood and urine samples 
Sample tubes will be labelled with a unique Sample ID which will be linked to the participant 
and the study visit using the study computer-based data entry system (i.e. samples will be 
pseudonymised). Outside the study clinic, staff involved in the transport, storage and 
analysis of these samples will have no means of linking tubes to an identifiable participant. 
Consent for protocol-specified analyses will be included in the main consent form. In 
addition, all participants will be asked if they would provide Supplementary Consent to allow 

 
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samples that have been collected for central laboratory analyses to be retained and used 
for unspecified analyses in the future. Similarly, Supplementary Consent will be sought to 
permit genetic material in the blood samples to be analysed. In all cases, participants will be 
free to opt in or out of any part of the Supplementary Consent without affecting their eligibility 
for the trial. 
 
2.6.5 Administrative details 
2.6.5.1 Source documents and archiving 
Source documents for the study constitute the clinic visit records held in the study main 
database, results of protocol-mandated local laboratory blood and urine analyses, the 
additional information obtained on reported adverse events that are relevant to the outcome 
measures (see Section 3.7), death certificates, and drug supply records. These will be 
retained for at least 25 years from the completion of the study. Boehringer Ingelheim and 
regulatory agencies will have the right to commission a confidential audit of such records in 
the 
, RCCs, and LCCs provided this does not result in unblinding while the study is in 
progress. 
 
2.6.5.2 Funding 
This study was initiated by 
 University of Oxford and developed as an academic 
collaboration with clinical scientists at Boehringer Ingelheim. Boehringer Ingelheim is the 
sponsor, and will perform regulatory submissions and interactions. It will also provide 
funding and packaged study medication (empagliflozin and matching placebo) for the study. 
Boehringer Ingelheim has delegated other roles to the University of Oxford, which is 
responsible for leading the trial scientifically and methodologically worldwide, including its 
conduct and statistical analysis. It is intended that the study will be conducted in the US in 
collaboration with independent scientists from the 
 
. Data will be collected and analysed independently from the source of funding. 
 
2.6.5.3 Indemnity 
Boehringer Ingelheim will, at all times, indemnify the study investigators and study staff from 
claims that may be made against them for any injury sustained by a study participant as a 
consequence of participation in the study in accordance with this protocol. The indemnity 
will be outlined in detail in the agreements between the 
, RCCs and LCCs (and in a 
letter from Boehringer Ingelheim). 
 
2.6.5.4 End of the within-trial period 
When the minimum number of required study outcomes has accrued (see Section 2.4.1.2), 
or the DMC advises the trial should be stopped early, participants will be invited to Final 
Follow-up visits. This visit may occur earlier than their planned next 6-monthly visit. The end 
of the trial is then defined as the latest of the following two dates: 7 days after the last 
participant’s Final Follow-up visit, or the date of the last 4-week post-Final Follow-up blood 
draw. 
 
2.6.5.5 Publications and reports 
The Steering Committee (which includes representatives from University of Oxford, 
 
 and Boehringer Ingelheim, as well as other individuals with relevant expertise) 
will be responsible for drafting the primary manuscript from the study and will establish a 
publication plan for secondary and supplementary analyses. In general, papers initiated by 
the Steering Committee (including the primary manuscript) will be written in the name of the 
Collaborative Group, with individual investigators named personally at the end of the report 
(or, to comply with journal requirements, in web-based material posted with the report). Draft 
copies of any manuscripts relating to the effects of empagliflozin from this trial will be 

 
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provided to Boehringer Ingelheim for review prior to publication but the decision to submit 
for publication will rest with the Steering Committee. 
 
The Steering Committee will also institute a process by which proposals for additional 
publications (including from clinician scientists within Boehringer Ingelheim seeking to 
further evaluate the benefit-risk profile of empagliflozin and from independent external 
researchers) are considered by the Steering Committee before they begin. The Steering 
Committee will facilitate the use of the study data and approval will not be unreasonably 
withheld. However, the Steering Committee will need to be satisfied that any proposed 
publication is of high quality, honours the commitments made to the study participants in the 
consent documentation and ethical approvals, and is compliant with relevant legal and 
regulatory requirements (e.g. relating to data protection and privacy). The Steering 
Committee will have the right to review and comment on any draft manuscripts prior to 
publication. 
 
2.6.5.6 Substudies 
Proposals for substudies must be approved by the Steering Committee before they begin. 
In considering such proposals, the Steering Committee will need to be satisfied that the 
proposed substudy is of a high quality, and that it will not compromise the main study in any 
way (e.g. by reducing the recruitment rate or compliance with study treatment or overuse of 
stored biological samples). 
 

 
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3.1 ELIGIBILITY FOR THE STUDY 
 
Consenting individuals are eligible for randomization if: 
(i) 
Age is ≥18 yearsc at Screening; 
(ii) 
There is evidence of chronic kidney disease at risk of kidney disease progression 
(see Section 3.1.1); 
(iii) 
A local Investigator judges that the participant neither requires empagliflozin (or 
any other SGLT-2 or SGLT-1/2 inhibitor), nor that such treatment is inappropriate; 
and 
(iv) 
None of the exclusion criteria apply (see Section 3.1.2). 
 
Participants will be treated with appropriate doses of single agent RAS-inhibition with either 
ACEi or ARB unless such treatment is either not tolerated or not indicated (see Section 
3.3.4).  
 
No potential participant currently being treated with empagliflozin (or other SGLT-2 or SGLT-
1/2 inhibitor) should be taken off this therapy to meet the eligibility criteria. 
 
3.1.1 Inclusion criteria 
Evidence of progressive CKD at risk of kidney disease progression is defined on the basis 
of local laboratory results recorded at least 3 months before and at the time of the Screening 
visit, and requires that: 
(a) CKD-EPI eGFR ≥20 <45 mL/min/1.73m²; or 
(b) CKD-EPI eGFR ≥45 <90 mL/min/1.73m2 with urinary albumin:creatinine ratio 
≥200 mg/g (or protein:creatinine ratio ≥300 mg/g)  
 
Note: the number of participants with or without diabetes mellitus (of any type) will be at 
least one-third of each, and the number of participants with an eGFR >45 mL/min/1.73m2 
limited to about one-third. The Steering Committee will monitor these proportions and will 
limit recruitment of particular categories of participant in whom sufficient numbers have 
already been screened or randomized. 
 
3.1.2 Exclusion criteria 
None of the following must be fulfilled: 
(i) 
Currently receiving SGLT-2 or SGLT-1/2 inhibitord; 
(ii) 
Diabetes mellitus type 2 and prior atherosclerotic cardiovascular diseasee with an 
eGFR >60 mL/min/1.73m2 at Screening; 
(iii) 
Receiving combined ACEi and ARBf treatmentd; 
(iv) 
Maintenance dialysis, functioning kidney transplant, or scheduled living donor 
transplantd; 
(v) 
Polycystic kidney disease; 
(vi) 
Previous or scheduled bariatric surgery; 
(vii) 
Ketoacidosis in the past 5 years; 
(viii) 
Symptomatic hypotensiond, or systolic blood pressure <90 or >180 mmHg at 
Screening; 
(ix) 
ALT or AST >3x ULN at Screening; 
(x) 
Hypersensitivity to empagliflozin or other SGLT-2 inhibitor; 
                                            
c Or “full age” as required by local regulation (e.g. 20 years in Japan).  
d Based on self-reports at Screening and Randomization visits. 
e Myocardial infarction, angina, stroke or peripheral arterial disease (including lower limb amputation) 
f Or renin-inhibitor combined with ACEi or ARB. 

 
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(xi) 
Any intravenous immunosuppression therapy in last 3 months; or anyone currently 
on >45 mg prednisolone (or equivalent)d;  
(xii) 
Use of an investigational medicinal product in the 30 days prior to Screening visit; 
(xiii) 
Known to be poorly compliant with clinic visits or prescribed medicationd; 
(xiv) 
Medical history that might limit the individual’s ability to take trial treatments for the 
duration of the study (e.g. severe respiratory disease; history of cancer or evidence 
of spread within last 4 years, other than non-melanoma skin cancer; or recent history 
of alcohol or substance misuse)d; 
(xv) 
Current pregnancy, lactation or women of childbearing potential (WOCBP), unless 
using highly-effective contraceptiong; 
(xvi) 
Type 1 diabetes mellitus. 
 
In addition, individuals will be excluded at the Randomization visit if the participant: 
(i) 
Does not adhere to Run-in treatment; 
(ii) 
Is no longer willing to be randomized and followed for at least 3 years; 
(iii) 
Is considered by a local investigator not to be suitable for randomization (see Section 
3.3.4); or 
(iv) 
Experiences ketoacidosis, heart attack, stroke, or hospitalization for heart failure, or 
hospitalization for urinary tract infection or acute kidney injury during Run-in. 
 
Note that individuals who do not fulfil one or more inclusion criteria, or who fulfil one or more 
exclusion criteria, may be re-screened and later become eligible.  
 
3.2 
 IDENTIFICATION AND INVITATION 
3.2.1 Identification and invitation of potentially eligible participants 
Extensive pre-screening efforts will be made to identify large numbers of potential 
participants at each LCC. The exact methods will vary by centre and by country, and in all 
cases will be subject to appropriate institutional review board approval and compliance with 
data privacy regulations. In general, potentially eligible participants (based on age, blood 
and urine results) will be identified from clinical records (including electronic health care 
records) and contacted to seek their provisional agreement to attend a Screening visit. 
Potential participants will be given information about the study. 
 
3.3 SCREENING VISIT AND PRE-RANDOMIZATION RUN-IN 
3.3.1 Assessment of relevant medical history and eligibility 
LCC clinic staff will recheck basic inclusion criteria are met (e.g. age and the blood/urine 
results used to identify potential participants) then take written informed consent. 
 
3.3.2 Written consent 
Individuals who appear initially to be eligible will have the study explained to them by the 
clinic staff, using the Participant Information Leaflet and Consent Form as a basis for 
discussion. Where relevant, supplementary Consent will also be sought (see Section 
2.6.4.3). Each individual will have an opportunity to initiate discussion, and have time to think 
about their participation in the study, perhaps after discussing it with their family or a local 
doctor. Individuals who choose to do this will be asked to attend a repeat Screening visit 
                                            
d Based on self-reports at Screening and Randomization visits. 
g Highly effective methods of contraception include implants, injectables, combined oral contraceptives (the 
participant must have been on a stable dose for at least 3 months prior to entering the trial), intrauterine device, 
vasectomised partner, or true sexual abstinence (when this is the preferred and usual lifestyle of the patient 
and does not include periodic abstinence [e.g. calendar, ovulation, symptothermal or post-ovulation methods]). 
Use of such methods must be maintained throughout the trial and for 7 days after the end of the trial. 

 
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within a few weeks. Attendees will be discouraged from participating if it is thought unlikely 
that they would be willing and able to continue attending Follow-up visits for at least 3 years.  
 
3.3.3 Confirmation of eligibility and collection of blood and urine samples 
After providing written consent, blood/urine test results will be recorded. Other medical 
history (including primary renal diagnosis and other co-morbidity), non-study medication, 
blood pressure and other factors pertinent to eligibility will be obtained directly from 
participants (rather than from hospital record review) and recorded directly into the 
Screening Form. These inclusion and exclusion criteria will be checked with the assistance 
of the study computer-based system.  
 
A non-fasting blood sample will be taken for local analysis of creatinine and liver 
transaminases (AST or ALT), and a urine sample will be taken for local analysis of urinary 
albumin:creatinine ratio (or, if albuminuria measurement unavailable in local laboratory, 
protein:creatinine ratio). The LCC clinic staff will issue a 15 week supply of placebo tablets 
to eligible participants. 
 
WOCBP, defined as women less than 55 years of age unless surgically sterile or with history 
of a postmenopausal state, will be requested to use highly effective methods of 
contraception. A pregnancy test will be offered if, after questioning about recent menses and 
regularity of menstrual cycle, pregnancy is considered reasonably possible (or if a 
pregnancy test is required by local regulation). 
 
Participants with diabetes will be educated about the risks of diabetic ketoacidosis and the 
actions they should take if they suspect it, and will be provided with a specific information 
card (see Section 3.5.6). 
 
An appointment will be made for the Randomization visit in 8-12 weeks. The participant’s 
doctor(s) will be informed that the participant has entered Run-in. 
 
Following the Screening visit, the locally analysed blood and urine results will be recorded 
onto the study computer-based system, which will provide another assessment of eligibility 
(see Section 3.1). If these results indicate that the participant is not eligible for the trial, they 
may be repeated once if in the opinion of a Local Investigator they were spurious, otherwise 
the participant will be withdrawn from the Run-in period and asked to stop and return all 
placebo Run-in medication. 
 
3.3.4 Review of eligibility and renin-angiotensin system inhibition by a Local 
Investigator 
During Run-in, the LLI (or authorised delegate) will be given a description of the participant’s 
medical history (including primary renal diagnosis), single agent RAS-inhibition treatment 
and blood and urine results all based on the Screening visit, and asked to indicate whether, 
in their view, these results (or any other factor) make the participant unsuitable for entry into 
the randomized phase of the study. Additionally, participants should be randomized only if 
a Local Investigator judges that the participant does not require empagliflozin (or any other 
SGLT-2 or SGLT-1/2 inhibitor), and neither is such treatment inappropriate. No patient 
currently being treated with empagliflozin (or other SGLT-2 or SGLT-1/2 inhibitor) should be 
taken off this therapy to meet the eligibility criteria. 
 
For eligible participants, the LLI (or authorized and medically qualified delegate) will also be 
asked to confirm that the participant is prescribed, in their opinion, an appropriate dose of 

 
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single agent RAS-inhibition (i.e. ACEi or ARB, but not both). Those participants for whom 
RAS inhibition is not considered indicated (e.g. due to concomitant medication or co-
morbidity), or who cannot tolerate RAS inhibition, will still be eligible to enter the trial, but the 
reason for not using RAS-inhibition will be documented. Those participants who, in the 
opinion of the LLI, need to start RAS inhibition or are not on an appropriate dose will be 
excluded from the study (but may be rescreened later, e.g. once established on an 
appropriate dose). 
 
Additionally, throughout the study, the care of participants will remain the responsibility of 
their local doctors, who are asked to ensure appropriate and individualized care. This 
includes appropriate management of risk of kidney disease progression, risk of 
cardiovascular disease, and other conditions which are common in CKD (such as mineral-
bone disorder, renal anaemia, metabolic acidosis). Modifiable risk factors include but are 
not limited to glycaemic control in participants with diabetes, blood pressure control, and 
treatment of dyslipidaemia. It is advised that this is conducted in the context of prevailing 
local, national or international guidance. 
 
3.4 
 RANDOMIZATION VISIT (0 MONTHS) 
3.4.1 Final check of eligibility and compliance before randomization 
For individuals who attend their Randomization Clinic appointment, study eligibility will be 
confirmed (see Section 3.1). The participant will also be asked if they have experienced any 
SAE or significant problems during the Run-in period. Information on other relevant factors 
will also be collected, such as prior history of urosepsis, heart failure and New York Heart 
Association (NYHA) functional classification, history of peripheral neuropathy, diabetic foot 
ulcer, lower limb infection or gangrene, smoking history and alcohol intake, and an 
assessment of health related quality of life is to be made (using the EQ5D-5L questionnaire). 
Details of all non-study treatments will be sought, compliance with Run-in treatment 
checked, and consent information checked. Blood pressure, height, weight, and hip and 
waist circumference will be measured. The participant’s willingness to take study medication 
and attend follow-up visits for at least 3 years will be confirmed. Details will be recorded 
directly onto the Randomization Form on the study computer-based system (which is 
designed to obtain complete information, assess eligibility, and to prompt appropriate 
actions). 
 
3.4.1.1 Collection of blood and urine samples 
Eligible participants will have a blood sample taken for local measurement of creatinine, 
potassium, liver function (ALT or AST, and bilirubin), and haemoglobin/haematocrit. Blood 
and urine samples will also be processed in preparation for subsequent transportation to the 
central laboratory (see Section 2.6.4). 
 
3.4.2 Random allocation of study treatment 
Eligible and consenting individuals will be allocated empagliflozin or matching placebo using 
a minimized randomization program on the study computer-based system (see Section 
2.2.2).33 Participants will be allocated a numbered treatment pack containing a 7-month 
supply of one tablet daily of either active empagliflozin 10 mg or matching placebo. 
 
The numbered treatment packs will be issued to the participant by the LCC clinic staff or 
their local hospital pharmacy. An appointment for the first post-randomization Follow-up visit 
will then be made by the study staff, with guidance from the study computer-based system. 
The participant’s doctor(s) will be informed that the participant has been randomized. 

 
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Following the Randomization visit, the locally analysed blood results will be recorded onto 
the study computer-based system by the LCC. 
 
3.5 
 FOLLOW-UP VISITS (2 AND 6 MONTHS AND THEN 6-MONTHLY) 
3.5.1 Recording adverse events and adherence to study treatment 
Following randomization, all participants are scheduled to attend Follow-up visits at 2 and 6 
months, and then 6-monthly until the end of the study. 
 
At each visit, details of all hospital admissions and any other SAEs will be sought from 
participants, and questions will specifically be asked about SAEs due to urinary tract 
infection, genital infection, hyperkalaemia, acute kidney injury and dehydration. Information 
about new-onset of diabetes, gout, AESIs (i.e. liver injury, ketoacidosis and lower limb 
amputation), bone fractures, severe hypoglycaemia and symptomatic dehydration will also 
be recorded. The source of the information/data is the report from the participant (or where 
unavailable a relative or other doctor) entered directly into the electronic case report form. 
In this study, paper or electronic hospital notes are not routinely reviewed to identify AEs. 
Any SAE considered to be due to study treatment (i.e. a possible SSAR) is to be discussed 
as soon as possible with a RCC/
 study clinician in order that additional information can 
be collected (see Section 2.5.1.3).  
 
Key changes to non-study medication will be sought, and adherence to study treatment will 
be reviewed. Adherence will be assessed and documented by LCC clinic staff at every study 
visit by asking participants about missed doses and visual inspection of remaining tablets (a 
pill count will not be performed). The amount of study treatment taken since the last visit will 
be estimated and recorded as “most”, “some” or “little/none” (with further guidance on these 
categories provided in the LCC Clinic Manual). The LCC clinic staff will discuss any reasons 
for non-adherence with the participant (and with their LLI or with 
clinical staff if 
necessary) and encourage the participant to take study treatment regularly whenever 
appropriate. For participants who discontinue study treatment, the reason for doing so will 
be sought.  
 
Blood pressure and weight will be measured at each Follow-up visit. At the 18 month and 
the Final Follow-up visit, hip and waist circumference will be measured and health related 
quality of life (using EQ5D-5L questionnaire) will be assessed. Details are to be recorded 
directly onto the electronic Follow-up form on the study computer-based system.  
 
Local Research Co-ordinators will be trained to ask participants to report any relevant AEs 
(related or not) occurring up to 7 days after their Final Follow-Up Visit directly to LCC clinic 
staff. 
 
3.5.2 Collection of blood and urine samples 
At each Follow-up visit, a non-fasting blood sample will be taken for local analysis for 
creatinine, potassium and liver function (ALT or AST, and bilirubin). Results are ideally 
entered onto the computer-based system within 2 working days. At 18 months of follow-up, 
a 20% subset of participants (e.g. UK participants) will also have haematocrit, haemoglobin, 
phosphate, sodium and corrected calcium measured locally.  
 
Four weeks after the Final Follow-up visit, a subset of about 20% of participants (who have 
not started dialysis or have a functioning kidney transplant) will provide a further non-fasting 
blood sample for local analysis of creatinine (known as the 4-week post-Final Follow-up 
blood draw) and a urine sample for local analysis of urine albumin and creatinine.  

 
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At each scheduled follow-up visit a central blood sample will be collected. At the 2 and 18 
month and Final Follow-up visits, urine samples will also be collected (see Section 2.6.4.2).  
 
3.5.3 Issuing study treatment and arranging further appointments 
Provided continuing study treatment remains appropriate, participants will be given a further 
7-month supply of their randomly allocated study treatment (empagliflozin 10 mg or 
matching placebo), and any previously allocated treatment will be retrieved (except at the 
2-month visit). An appointment will then be made for their next scheduled Follow-up visit. 
 
3.5.4 Follow-up for randomized participants not attending study clinics 
Follow-up information is to be collected from all study participants, irrespective of whether 
they continue to take study treatment, usually at routine Follow-up clinic visits, unless they 
withdraw consent (see Section 3.6.5). If, however, a participant becomes unwilling or unable 
to attend study clinic visits then LCC staff will telephone the participant (or, where 
appropriate, their relative or carer) at the time of each of their scheduled Follow-up 
appointments and complete the necessary Follow-up form on the study computer-based 
system. If monitoring of blood is no longer possible (e.g. because the participant no longer 
attends clinic visits and no other means of measuring creatinine/liver function can be 
arranged), then the participant will be asked to discontinue all study treatment and advised 
to see a local doctor. All efforts will be made to continue to follow-up such participants (as 
described above), and those being followed by telephone or other remote method will be 
encouraged to provide blood samples for central analysis at relevant time points. If this is 
not possible, then LCC or RCC staff will attempt to check a participant’s progress by 
interview or direct correspondence with the participant’s own local doctors or (where 
appropriate consent and approvals are in place) by reviewing available information on 
routine healthcare systems (including local blood result systems) and registries. (In the UK, 
for example, there are registries for treated ESKD, hospital admissions, cancers, and 
deaths.) Such information could also be used for long-term follow-up, alongside participant 
questionnaires administered by telephone, mail or electronically.  
 
3.5.5 Monitoring of women of child bearing potential 
Animal studies show that empagliflozin crosses the placenta during late gestation to a very 
limited extent, but it is considered preferable to avoid its use during pregnancy. WOCBP will 
therefore have to agree to use highly effective methods of contraception during the trial. At 
each visit, a pregnancy test will be offered if, after questioning about recent menses and 
regularity of menstrual cycle, pregnancy is considered reasonably possible (or if a 
pregnancy test is required by local regulation). LCC clinic staff will also reinforce the need 
for highly effective contraception at each visit. If a participant becomes pregnant during the 
trial, the trial medication will be stopped and the participant will be followed up until birth or 
termination of the pregnancy (see further details for reporting of pregnancy in Section 
2.5.1.1). 
 
3.5.6 Monitoring of people with diabetes mellitus 
LCC clinic staff will receive training on the specific risk of ketoacidosis (which can present 
with lower than anticipated blood glucose levels in people with diabetes treated with SGLT-
2 inhibitors) and will be asked to provide additional written information about ketoacidosis to 
participants with diabetes (e.g. a trial information card). Testing equipment and materials to 
detect blood ketones will be available to people with type 1 diabetes before Randomization. 
 

 
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3.5.7 Local Lead Investigator supervision 
LLI will meet regularly with the other LCC staff to review study progress, the delegation of 
duties log and approve listings of reported adverse events. The RCC or 
 will be 
contacted if adverse event information needs to be refined. 
  
3.6 CENTRAL MONITORING OF PARTICIPANT SAFETY, EARLY RECALL VISITS AND MODIFYING 
STUDY TREATMENT 
 
3.6.1 Early Recall Visits 
An Early Recall visit may be arranged for any participant who requires review outside their 
planned visit schedule. Examples of circumstances where this may be necessary include 
the assessment of abnormal values in safety blood results from routine Follow-up visits, or 
if symptoms of liver disease (e.g. icterus) develop between scheduled Follow-up visits, or 
an extra visit is required a few weeks after the Randomization Visit (e.g. if requested by local 
regulators or Local Investigator). As at routine study visits, the results of blood tests 
performed at Early Recall visits will be entered by LCC clinic staff into the study computer-
based system (which is designed to prompt appropriate actions) and these results will be 
monitored centrally by clinical staff at the 
and RCCs in accordance with the study 
procedures.  
 
3.6.2 Monitoring liver function, potassium, creatinine and AESIs 
 study clinicians will be responsible for reviewing local results on liver function, 
potassium and creatinine, and all reports of AESIs. They will advise on the need for (and 
timing of) Early Recall visits and whether study treatment should be stopped or restarted. In 
so doing, 
study clinicians will collaborate with the LLI and other LCC clinic staff (or 
RCC in certain regions), as necessary, and will generally initiate contact if there have been 
results that fulfil the definition of liver injury or a 50% increase in creatinine since the 
preceding Follow-up visit. Management strategies include ascertainment of a more detailed 
clinical picture, additional investigations, more frequent study visits, or a lower threshold for 
stopping study treatment. 
 
3.6.3 Modifying study treatment 
If adverse events occur that are believed to be due to empagliflozin, including significant 
elevation of liver transaminases, the study treatments may be temporarily or permanently 
discontinued. The following events are also sufficient reason to discontinue the study 
empagliflozin or placebo: 
 
 SAE considered likely to be due to the study treatment (i.e. SSAR, see Section 
2.5.1.3) 
 Kidney transplantation 
 New reason to prescribe empagliflozin or another SGLT-2 or SGLT-1/2 inhibitor (e.g. 
a local doctor of the opinion that it should be included as part of the current standard 
of care for prevention of cardiovascular events); or new reason not to use an SGLT-
2 inhibitor (e.g. local doctors may choose to stop study treatment on initiation of 
maintenance dialysis or after ketoacidosis) 
 Pregnancy or suspected pregnancy 
 At the request of the participant or their doctors (for whatever reason) or any other 
situation where continuing study treatment is not considered to be in the participant’s 
best interests by their own doctors or the study clinical team (including cessation of 
use of reliable contraception in WOCBP or use of high potency immunosuppression). 

 
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Whenever possible, the study computer-based system will prompt LCC clinic staff to 
consider whether there are specific reasons to discontinue or to restart study treatment (if 
appropriate, i.e. if reasons for discontinuation do not exist any longer). 
 study clinicians 
will provide advice if required. 
 
3.6.4 Unblinding of study treatment 
There are two main situations in which unblinding of the treatment allocation (empagliflozin 
or placebo) for an individual participant may be warranted: 
 
 When knowledge of the treatment allocation could materially influence the immediate 
medical management (e.g. after overdose) 
 When unblinding is necessary as part of Safety Reporting (see Section 2.5.1.4). 
 
Urgent unblinding is available by contacting a 
 study clinician on a 24-hour basis via 
the 
 Freefone telephone service. For the avoidance of doubt, if an investigator or local 
doctor requests the unblinded treatment allocation, it will be provided. All unblinding 
episodes are logged within the study computer-based system. 
 
3.6.5 Withdrawal of consent 
Participants may decide that they no longer wish to take study treatment or are no longer 
willing to attend study visits. LCCs may be able to help participants overcome problems 
associated with personal circumstances (e.g. provide transport support to attend clinics). 
These decisions are not considered to be withdrawals of consent, and appropriate 
procedures for dealing with them are described elsewhere in this protocol (e.g. for 
discontinuation of study treatment see Section 3.6.3 and for alternative methods of follow-
up see Section 3.5.4). However, participants are free to withdraw consent for some or all 
aspects of the study at any time. In order to ensure that relevant safeguards are put in place 
to maintain the individual’s safety (e.g. if an important safety issue comes to light that might 
affect a participant who has previously withdrawn from the study) and to prevent a breach 
of the individual’s decision to withdraw (e.g. to prevent re-invitation of an individual who had 
previously withdrawn consent), the decision to withdraw should ideally be put in writing and 
a copy maintained at the LCC (with key data items being recorded on the study computer-
based system). This written information should specify which aspect(s) of the study consent 
is being withdrawn: for example, direct contact from study staff; collection of information from 
a relative or friend; collection of information from local doctors or routine data sources; or 
the storage and analysis of samples for protocol-specified future unspecified assays. (In 
accordance with regulatory guidance, data that have already been collected and 
incorporated into the study database, including the results of laboratory assays, will continue 
to be processed.) 
 
3.7 CONFIRMATION AND VERIFICATION OF STUDY OUTCOMES (“ADJUDICATION”)  
 
Outcomes (and components) purely based on laboratory values (e.g. sustained ≥40% 
decline in eGFR,) will not be adjudicated and analyses will emphasize the results of 
measurements made at central laboratories. Wherever possible, eGFR will be calculated 
using centrally measured serum creatinine (with local results substituted if central results 
are unavailable). eGFR will be calculated using the CKD-EPI creatinine formula.40 
 
Receipt of a kidney transplant or initiation of maintenance dialysis will also not be 
adjudicated. Instead, LCC reports will be cross-checked by the 
 with information at 

 
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subsequent follow-up visits or (where available) with additional medical information collected 
for adjudication of deaths.  
 
Additional medical information will be sought for AEs that undergo adjudication. In general, 
these will be limited to all deaths and events initially reported as hospitalization for heart 
failure, myocardial infarction, stroke, liver injury, ketoacidosis, lower limb amputation and 
acute kidney injury. Other events may be added to the adjudication list if considered 
necessary to ensure a reliable assessment of the clinical effects (and particularly safety) of 
empagliflozin. Most hospitalizations will not be adjudicated and so analyses of 
hospitalizations will mainly be based on LCC reports. 
 
Relevant information needed for adjudication may come from the records held at the LCCs 
and other hospitals, from participant’s own doctors, or from electronic sources and registries. 
In some cases it may be necessary to obtain information that predates randomization into 
the study. A central panel of clinicians based at, or overseen by, the 
 will provide the 
adjudication. Review, processing and adjudication of AEs will be conducted in accordance 
with the study SOPs and will be blinded to study treatment allocation (empagliflozin or 
placebo). The relevant SOP will detail a quality control process where the first events 
adjudicated by each adjudicator and a random subsample thereafter (about 5%) will be 
reviewed by a second adjudicator (blind to original adjudication). 
 
3.8 
CITED REFERENCES 
 
1. 
Levey AS, Coresh J. Chronic kidney disease. Lancet 2012; 379(9811): 165-80. 
2. 
Stevens PE, O'Donoghue DJ, de Lusignan S, et al. Chronic kidney disease 
management in the United Kingdom: NEOERICA project results. Kidney Int 2007; 72(1): 92-
9. 
3. 
Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular 
filtration rate and albuminuria with all-cause and cardiovascular mortality in general 
population cohorts: a collaborative meta-analysis. Lancet 2010; 375(9731): 2073-81. 
4. 
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and 
the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351(13): 
1296-305. 
5. 
Cholesterol Treatment Trialists Collaboration. Impact of renal function on the effects 
of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual 
participant data from 28 randomised trials. The lancet Diabetes & endocrinology 2016; 4(10): 
829-39. 
6. 
Ninomiya T, Perkovic V, Turnbull F, et al. Blood pressure lowering and major 
cardiovascular events in people with and without chronic kidney disease: meta-analysis of 
randomised controlled trials. BMJ 2013; 347: f5680. 
7. 
Park M, Hsu CY, Li Y, et al. Associations between kidney function and subclinical 
cardiac abnormalities in CKD. J Am Soc Nephrol 2012; 23(10): 1725-34. 
8. 
Foley RN, Parfrey PS, Kent GM, Harnett JD, Murray DC, Barre PE. Long-term 
evolution of cardiomyopathy in dialysis patients. Kidney Int 1998; 54(5): 1720-5. 
9. 
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and 
Mortality in Type 2 Diabetes. N Engl J Med 2015; 373(22): 2117-28. 

 
Page 34 of 42 
EMPAKIDNEY2.0 2020-01-13 
 
 
 
 
EuDRACT: 2017-002971-24 
10. 
Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures 
with mortality and end-stage renal disease in individuals with and without diabetes: a meta-
analysis. Lancet 2012; 380(9854): 1662-73. 
11. 
Jafar TH, Schmid CH, Landa M, et al. Angiotensin-converting enzyme inhibitors and 
progression of nondiabetic renal disease. A meta-analysis of patient-level data. Ann Intern 
Med 2001; 135(2): 73-87. 
12. 
Lewis EJ, Hunsicker LG, Clarke WR, 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. 
13. 
Brenner BM, Cooper ME, de Zeeuw D, 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. 
14. 
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the 
treatment of diabetic nephropathy. N Engl J Med 2013; 369(20): 1892-903. 
15. 
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney 
Disease in Type 2 Diabetes. N Engl J Med 2016; 375(4): 323-34. 
16. 
Schnaper HW. Remnant nephron physiology and the progression of chronic kidney 
disease. Pediatric nephrology 2014; 29(2): 193-202. 
17. 
Ruggenenti P, Porrini EL, Gaspari F, et al. Glomerular hyperfiltration and renal 
disease progression in type 2 diabetes. Diabetes Care 2012; 35(10): 2061-8. 
18. 
Tonneijck L, Muskiet MH, Smits MM, et al. Glomerular Hyperfiltration in Diabetes: 
Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 2017; 28(4): 1023-
39. 
19. 
Haynes R, Staplin N, Emberson J, et al. Evaluating the contribution of the cause of 
kidney disease to prognosis in CKD: results from the Study of Heart and Renal Protection 
(SHARP). Am J Kidney Dis 2014; 64(1): 40-8. 
20. 
Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and 
perspectives. Lancet 2013; 382(9888): 260-72. 
21. 
USRDS. International Comparison. 2014 Annual Data Report: Atlas of End-Stage 
Renal Disease in the United States. , National Institutes of Health, National Institute of 
Diabetes and Digestive and Kidney Diseases, Bethesda, MD. 2014; 2. 
22. 
Ridderstrale M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and 
glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, 
active-controlled, double-blind, phase 3 trial. The lancet Diabetes & endocrinology 2014; 
2(9): 691-700. 
23. 
Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin 
in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled 
trial. Diabetes Care 2014; 37(6): 1650-9. 

 
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24. 
Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin 
plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, 
placebo-controlled trial. Diabetes Care 2013; 36(11): 3396-404. 
25. 
Kovacs CS, Seshiah V, Swallow R, et al. Empagliflozin improves glycaemic and 
weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients 
with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 
2014; 16(2): 147-58. 
26. 
Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an 
active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-
controlled, phase 3 trial. The lancet Diabetes & endocrinology 2013; 1(3): 208-19. 
27. 
Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, 
lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated 
multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes 
care 2014; 37(7): 1815-23. 
28. 
Rosenstock J, Jelaska A, Zeller C, et al. Impact of empagliflozin added on to basal 
insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, 
double-blind, placebo-controlled trial. Diabetes Obes Metab 2015; 17(10): 936-48. 
29. 
Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients 
with type 2 diabetes and hypertension. Diabetes Care 2015; 38(3): 420-8. 
30. 
Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to 
existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: 
a randomised, double-blind, placebo-controlled trial. The lancet Diabetes & endocrinology 
2014; 2(5): 369-84. 
31. 
Kohler S, Zeller C, Iliev H, Kaspers S. Safety and Tolerability of Empagliflozin in 
Patients with Type 2 Diabetes: Pooled Analysis of Phase I-III Clinical Trials. Advances in 
therapy 2017; 34(7): 1707-26. 
32. 
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal 
Events in Type 2 Diabetes. N Engl J Med 2017; 377(7): 644-57. 
33. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics 1975; 31(1): 103-15. 
34. 
Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials 
requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer 
1977; 35(1): 1-39. 
35. 
U.S. Department of Health and Human Services Food and Drug Administration. 
Guidance for Industry Determining the Extent of Safety Data Collection Needed in Late 
Stage Premarket and Postapproval Clinical Investigations. 2015. 
36. 
U.S. Department of Health and Human Services Food and Drug Administration. 
Guidance for Industry. Safety Assessment for IND Reporting. Dec 2015. 
37. 
ICH Harmonised tripartite guideline  Clinical safety data management: definitions and 
standards for expedited reporting E2A. Oct 1994. 

 
Page 36 of 42 
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38. 
Risk proportionate approaches in clinical trials. Recommendations of the expert 
group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical 
trials on medicinal products for human use. Apr 2017. 
39. 
Meeker-O'Connell A, Glessner C, Behm M, et al. Enhancing clinical evidence by 
proactively building quality into clinical trials. Clinical trials 2016; 13(4): 439-44. 
40. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular 
filtration rate. Ann Intern Med 2009; 150(9): 604-12. 

 
 
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4.1 APPENDIX 1: ORGANISATIONAL STRUCTURE AND RESPONSIBILITIES FOR STUDY DESIGN AND 
CONDUCT 
 
Boehringer Ingelheim 
Boehringer Ingelheim has delegated certain responsibilities to the independent Principal 
Investigators and 
 at the University of Oxford, and to the Steering Committee. 
Boehringer Ingelheim remains fully responsible for: 
 
 Provision of study funding 
 Provision and distribution (but not allocation) of manufactured and labelled study drug 
 Regulatory submissions and interactions (with support from the Principal 
Investigators) 
 Auditing of investigational sites, facilities, study setup, study processes, etc. as per 
the Audit Plan. 
 
Responsibility for oversight of the quality and integrity of the trial data remains with 
Boehringer Ingelheim. 
 
Principal Investigators 
The Principal Investigators have overall responsibility for: 
 
 Design of the study (in collaboration with Boehringer Ingelheim) 
 Preparation of the Protocol and subsequent revisions 
 Managing the 
  
 Development of computer-based systems and study SOPs.  
 
Steering Committee 
The Steering Committee is responsible for: 
 
 Agreeing the Data Analysis Plans  
 Reviewing progress of the study and, if necessary, suggesting and agreeing changes 
to the Protocol 
 Reviewing new scientific evidence that may be of relevance 
 Drafting, review and approval of study main publication(s) 
 Review and approval of proposals for subsequent analyses and publications 
 Approval of substudy proposals  
 Reviewing study quality and risk management approaches, and ensuring that the 
focus is always on issues that have (or the potential to have) a substantial impact on 
the safety of the study participants or the reliability of the study results 
 Monitoring participant characteristics and limiting recruitment of particular categories 
of participant when sufficient numbers have already entered the trial. 
 
Data Monitoring Committee 
The independent Data Monitoring Committee is responsible for: 
 
 Reviewing unblinded interim data according to the schedule outlined in the Protocol 
 Advising the Steering Committee if, in their view, the randomized data provide 
evidence that may warrant early termination of all or part of the study for either 
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 Review of the formal interim analyses (see Section 2.5.2.2). 
 
Central Coordinating Office 
The 
 is responsible for the overall coordination of the Study, including: 
 
 Study planning and organisation of Steering Committee meetings 
 Agreement of each regional recruitment plan (including countries, number of LCCs, 
number of participants, and timelines) 
 Contractual issues with RCCs and budget administration 
 Co-ordination of Ethics Committee applications 
 Supporting Boehringer Ingelheim in their interactions with regulatory authorities and 
other outside agencies as appropriate 
 Design, implementation and maintenance of computer-based systems for the study 
(including 
/RCC computer-based system for administration and study computer-
based system for direct data entry) 
 Provision of study materials to RCCs and LCCs, and provision of IT support to RCCs 
 Monitoring of drug supply in liaison with Boehringer Ingelheim (who will be 
responsible for drug distribution to each LCC) 
 Central laboratory assay and long-term storage of blood and urine samples 
 Monitoring of overall progress of the study, with a focus on critical-to-quality factors 
 Clinical safety monitoring, including reporting of SSARs to the Chair of the Data 
Monitoring Committee and to Boehringer Ingelheim 
 Responding to technical, medical, data and administrative queries from the RCCs 
 Manage data queries and data changes (with a clear audit trail) 
 Management of outcome adjudication 
 Liaison with the Data Monitoring Committee. 
 
Regional Coordinating Centres 
Each RCC is responsible, under the direction of its Regional Coordinator, for: 
 
 Identification of potential LCCs and agreement of their recruitment plans (including 
number of participants and timelines) 
 Contractual issues with LCCs and regional budget administration 
 Obtaining any central Ethics Committee approval (where appropriate) and assisting 
LCCs with local Ethics Committee applications  
 Training of LCC staff and assistants 
 Distribution of study materials to LCCs 
 Responding to technical, medical and administrative queries from the LCCs 
 Perform LCC on-site monitoring visits by trained study monitors 
 “Process” monitoring of LCCs by responding to regular or occasional reports on 
regional progress prepared by the 
 
 Ensuring appropriate follow-up of abnormal safety blood results 
 Collection and initial processing of relevant documentation to confirm reported events 
in line with study SOPs  
 Collection and short-term storage of blood and urine samples from LCCs, and 
subsequent transport of them to the 
  
 Organisation of meetings of collaborators within the region 
 Entering data entry errors reported by LCCs 
 Supporting Boehringer Ingelheim in their interactions with regulatory authorities as 
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 Ensuring that trial-related activities are performed according to local regulations. 
 
Local Clinical Centres 
The LCC lead investigator and LCC staff are responsible for: 
 
 Meeting regularly as a team to review study progress locally, the delegation of duties 
log and for Local Investigators to review and approve listings of locally reported 
adverse events (i.e. provide LLI oversight) 
 Obtaining local Ethics Committee approval were necessary (aided by the RCC) 
 Obtaining local management approval where necessary 
 Performing trial-related activities according to local regulations 
 Provision of adequate clinic space and access to appropriate systems for the 
identification of potentially eligible individuals 
 Conducting clinic procedures: managing and distributing study drugs (in conjunction, 
if required, with the hospital pharmacy), and maintaining relevant study equipment in 
accordance with the Protocol and SOPs 
 Ensuring adequate local laboratory facilities for safety monitoring and, if necessary, 
processing and temporarily storing samples for central analysis 
 Reviewing Screening Form data, confirm appropriate dose of RAS-inhibition (where 
relevant), confirm no reasons to prescribe or not prescribe empagliflozin (or other 
SGLT-2 or SGLT-1/-2 inhibitor), and approving participants for randomization (Local 
Investigators only) 
 Providing individualized care, including management of cardiovascular risk factors 
and other existing comorbidities (e.g. hypertension, diabetes) according to relevant 
guidelines 
 Dealing with routine enquiries from participants and their families in collaboration with 
the RCC where necessary 
 Obtaining clinical information when requested to confirm potential primary and 
secondary, tertiary and safety study outcomes 
 Informing the RCC or 
 of any possible data entry errors. 
 

 
 
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4.2 APPENDIX 2: VISIT SCHEDULE AND PROCEDURES 
4.2.1 Clinic procedures 
 
 
Task
Activity
Registration
Screening
Randomization
- 12 to -8 weeks
0 months
2 months
6 months
6 monthly visits
Final visit**
Demographics
Record contact details
X
check
check
check
check
check
check
Relevant medical history (incl. inclusion criteria & an dose of RAS inhibitor)
X
X
Exclusion criteria (incl. relevant non-study medication)
X
X
Other information (smoking, alcohol)
X
Use of non-study medication
X
X
X
X
X
X
Consent
Obtain consent
X
Confirm consent
X
Safety & outcomes reporting
Adverse events (incl. Suspected Serious Adverse Reactions)
X
X
X
X
X
Self-reported compliance
X
X
X
X
X
Reasons for stopping study treatment (incl. SAEs, non-serious adverse events, other reasons)
X
X
X
X
X
Remote follow-up using routine data sources and/or participant surveys*
(X)*
(X)*
(X)*
(X)*
Quality of life (by EQ5D-5L)
X
18 month only
X
Physical measurements
Blood pressure
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Hip & waist circumference
X
18 month only
X
Local laboratory assessments
Creatinine and liver function tests (transaminases and bilirubin)
X
X
X
X
X
X**
Potassium
X
X
X
X
X
Haematocrit, haemoglobin
X (all)
18 month only (in about a 20% subset)
Sodium, corrected calcium, phosphate (in about a 20% subset)
18 month only
Urinary albumin and creatinine
X
Pregnancy test***
X
X
X
X
X
X
Central sample collection
Blood samples for central analysis of creatinine & storage****
X
X
X
X
X
Urine for central analysis of albumin & creatinine, and storage
X
X
18 month only
X
Issue placebo
X
Randomize eligible & willing participants
X
Issue randomized treatment (empagliflozin 10 mg or placebo; 210 day supply)
X
X
X
Retrieve unused treatment
X
X
X
X
Create appointment
X
X
X
X
X
X
Provide advice
X
X
X
X
X
X
*** If pregnancy reasonably possible as indicated by participant's history (or if required by local regulation)
In-trial follow-up
* Remote follow-up may be used for some participants who are unwilling or unable to attend study visits, and for all surviving participants for several years after the final visit; ** Additional local blood creatinine 
**** NT-pro BNP measured at 0 months and HbA1c measured at 0, 2, 18 months and final visit.
and urine albumin:creatinine ratio measurement 4 weeks after final follow-up (~20% subset). Final follow-up timing is determined by the Steering Committee in response to numbers of events & DMC recommendations.
Medical history & eligibility 
 assessment
Randomization & study treatment
 handling
Appointment management 
& advice
 

 
Page 42 of 42 
EMPAKIDNEY2.0 2020-01-13 
 
 
 
 
EuDRACT: 2017-002971-24 
5.1 VERSION HISTORY 
 
EDMS #5434 
 
Version 
Version date 
Summary 
1.0 
8th January 2018 
Version 1.0 finalized 
1.1 
8th January 2018 
Footnote update 
1.2 
25th January 2018 
Formal interim analysis update 
1.3 
26th March 2018 
Update following MHRA review 
1.4 
25th April 2018 
Update following FDA review of formal interim analysis 
2.0 
13th January 2020 
Recruitment target increase to 6000 participants;  
exclusion of further participation from people with type 1 
diabetes after introduction of a cap; clarification on the 
subdivisions of cardiovascular death; reducing tertiary 
subgroup analyses solely to the primary outcome and 
highlighting the subgroups of key interest; section 3.1.2 
exclusion criterion (ix) modified; substituting local 
creatinine results when central creatinine results are 
missing; and clarification in table 4.2.1 that Hb/Hct is 
measured in all participants at randomization (to be 
consistent with the protocol text in section 3.4.1.1)