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

                                                                                      
 
 
EMPA-KIDNEY MRI substudy justification and design (protocol supplement) 
V2.0 – 25-FEB-2021   
Page  1 of 5      EDMS #7083 
 
 
EMPA-KIDNEY Magnetic Resonance Imaging Substudy Protocol Supplement 
 
Study 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  
Sponsor protocol number: 1245-0137 
Protocol identifier: 
 
CTSUEMPA-KIDNEY1.4 2018-04-25 
EudraCT number:     
2017-002971-24 
 
Summary 
This document is a substudy protocol supplement which provides the rationale, design and key 
operation details of an EMPA-KIDNEY substudy to image a subset of participants‘ hearts and kidneys 
using multi-parametric magnetic resonance imaging. This protocol substudy document is only relevant 
to sites participating in the substudy and does not alter the main protocol in any respect. The 
procedures in the main protocol should be followed irrepsective of whether a participant joins this 
substudy or not. 
 
Background 
The EMPA-KIDNEY study is investigating whether empagliflozin 10 mg daily reduces the risk of a 
cardiorenal composite outcome among patients with established chronic kidney disease. Trials in 
other populations indicate that sodium-glucose co-transporter-2 inhibitors (SGLT-2i, like 
empagliflozin) do reduce the risk of progression of kidney disease and heart failure (including 
cardiovascular death) among people with diabetes, diabetic kidney disease and – more recently – 
heart failure with reduced ejection fraction (including patients with and without diabetes). However, 
substantial uncertainty remains for many types of patients with chronic kidney disease (CKD) and 
diabetes excluded from these trials and for patients with CKD but without diabetes. 
 
EMPA-KIDNEY and the other SGLT-2i trials will provide clear evidence of the clinical safety and 
efficacy of SGLT-2i, but the mechanisms by which these effects occur remain uncertain. Many 
different mechanisms have been proposed to explain the observed benefits to date, but much of this 
work relies on animal models and whether these mechanisms operate in humans has not been 
confirmed. Magnetic resonance imaging (MRI) offers an opportunity to assess the effects on structure 
and function of the heart and kidneys in patients with CKD. 
 

                                                                                      
 
 
EMPA-KIDNEY MRI substudy justification and design (protocol supplement) 
V2.0 – 25-FEB-2021   
Page  2 of 5      EDMS #7083 
 
MRI allows detailed imaging of organs without ionizing radiation. Cardiac MRI is well-established both 
in research and clinical care and provides accurate assessment of cardiac structure and function. It 
has frequently been used to assess the effects of treatments on cardiac structure (e.g. left ventricular 
mass) and function (e.g. cardiac output) for patients with cardiac disease. Patients with CKD develop 
abnormal cardiac structure and function early in their disease and it is likely that such abnormalities 
underlie some of the large excess risk of cardiovascular morbidity and mortality observed in this 
population. However, few studies to date have tested the effect of treatment in a randomized 
comparison on cardiac MRI among patients with CKD. 
 
MRI of the kidney is a newer discipline and is currently a research tool only. There are many different 
MRI methods that can visualize different aspects of kidney structure and function and their 
combination is called “multiparametric” MRI. Examples of methods and what they assess are shown 
in Table 1. 
MRI method 
Target measure 
Volumetry 
Kidney size, cortical thickness 
T1 mapping 
Fibrosis (scarring) and inflammation of kidney 
Blood oxygen level dependent (BOLD) 
Kidney oxygenation 
Arterial spin labelling (ASL) 
Kidney perfusion 
Diffusion-weighted imaging (DWI) 
Fibrosis of kidney 
Modified Dixon (mDIXON) 
Fat content 
Table 1: Examples of MRI methods and what they assess 
 
Small studies have demonstrated that kidneys in healthy volunteers have different measurements to 
kidneys in patients with CKD. For example, one study found that the mean T1 time among healthy 
volunteers was 1432 (SD 87) ms, whereas among patients with CKD it was 1574 (SD 74) (p<0.001).1 
Cortical perfusion (measured by arterial spin labelling) was lower among patients with CKD (71 [SD 
49] mL/100g/min) than healthy volunteers (200 [SD 56] mL/100g/min) (p<0.001). It is therefore 
plausible that treatments that retard the progression of kidney disease may also delay changes in MRI 
parameters. Furthermore, such MRI parameters could be used to either stratify risk or provide 
additional early data on new drugs during their development. MRI is safe and none of the planned 
measurements require injection of any contrast or other agents. 
 
UK capability 
The UK has a Renal Imaging Network (RIN; https://kidneyresearchuk.org/research/research-
networks/uk-renal-imaging-network/) which is funded by the UK Medical Research Council and is 
undertaking a project to standardize approaches to renal MRI. This collaboration of centres (most of 

                                                                                      
 
 
EMPA-KIDNEY MRI substudy justification and design (protocol supplement) 
V2.0 – 25-FEB-2021   
Page  3 of 5      EDMS #7083 
 
whom are collaborating in the EMPA-KIDNEY trial) mean the UK is ideally placed to host this research. 
This proposal has been written by a collaboration of EMPA-KIDNEY investigators and members of 
the UK RIN. In addition, it may be possible to involve some other international centres although this 
has not been discussed yet. 
 
Aims 
The primary aim of this substudy is to use multiparametric MRI to assess, in a subset of EMPA-
KIDNEY participants, the effect of empagliflozin 10mg versus matching placebo on kidney cortical T1 
at 18 months after randomization. 
 
Secondary aims are to use multiparametric MRI to assess: 
1. The effects of empagliflozin 10mg versus matching placebo at 18 months on: 
o Kidney size and cortical thickness 
o Kidney perfusion (measured by arterial spin labelling) 
o Kidney oxygenation (measured by BOLD) 
o Kidney fat content (measured by mDIXON) 
o Cardiac structure (left ventricular mass, standard volumes) 
o Cardiac function (left ventricular ejection fraction, cardiac output) 
o Cardiac fibrosis (measured by T1) 
2. Whether any effects of empagliflozin 10mg versus matching placebo on kidney fibrosis are 
modified by baseline factors, in particular by level of kidney function, glycosylated haemoglobin, 
body mass index, age, sex and RAS inhibitor use 
 
Exploratory aims are to assess the effects of empagliflozin 10mg versus matching placebo at 18 
months on less well-established MRI measurements (for example diffusion tensor imaging) which 
may only be measured in a subset of participants. 
 
Sample size estimates 
The original plan was to perform two scans in each participant: one at baseline and one at about 18 
months after Randomization. Because of the COVID-19 pandemic it was not possible to perform 
baseline scans and recruitment to the main trial is now very nearly complete. However, it is still 
feasible to make the planned comparisons using a single scan during Follow-up (at least 18 months  
after Randomization). Instead of using the planned ANCOVA analysis (where the 18 month 
measurements are adjusted for baseline), we will use unadjusted measurements. This reduces the 
precision somewhat so a larger sample size is required.  

                                                                                      
 
 
EMPA-KIDNEY MRI substudy justification and design (protocol supplement) 
V2.0 – 25-FEB-2021   
Page  4 of 5      EDMS #7083 
 
It was estimated that at least 64 (of the 6000) EMPA-KIDNEY participants with baseline and 18 
months follow-up MRI data will provide ample power (>90%, 2p=0.05) to detect at least a 50 ms 
difference in T1 (assumed reference range in healthy adults is  1500 ms with a standard deviation of 
100 ms and intra-individual correlation of 0.8) based on analysis of covariance (ANCOVA). By 
changing the design to a single scan, approximately 172 participants are required for equivalent 
statistical power. 
 
Data Analysis Plan  
The primary analysis will estimate the differences in cortical T1 between treatment groups at ~18 
months, regardless of whether a participant received all, some or none of their allocated treatment 
(i.e. intention-to-treat analyses). Secondary outcomes include kidney volumes, perfusion and 
oxygenation and cardiac structure and function. Differences in cortical T1 and the secondary 
outcomes between treatment groups will be adjusted (or stratified) for the elements included in the 
main trial’s minimization algorithm. Missing measurements will be imputed. Results from the imputed 
analyses will be compared with those from equivalent “complete-case” analyses, but primary 
emphasis will be placed on the results after multiple imputation. More complete details of statistical 
methods, including definitions of subgroups, methods of any imputation, approaches to adjustments 
and weighting of averages will be set out in a separate full Data Analysis Plan which will be consistent 
with the main study Data Analysis Plan.  
 
Flowchart of Substudy Activities 
 
INVITATION 
 Invite potential participants after Screening visit complete and participant has entered pre-
randomization Run-in phase; OR 
 Invite potential participants around time of 18 or 24 month Follow-up visit (when a baseline scan 
was not possible) 
INFORMED CONSENT AND BASELINE SCAN 
 Written informed consent is sought from willing individuals when they attend for first MRI scan  
18 MONTHS OF FOLLOW-UP 
 Second MRI scan performed around time of 18-24 month follow-up visit 
 
Design 

                                                                                      
 
 
EMPA-KIDNEY MRI substudy justification and design (protocol supplement) 
V2.0 – 25-FEB-2021   
Page  5 of 5      EDMS #7083 
 
Eligibility: In selected regions, EMPA-KIDNEY Local Clinical Centres (LCCs) with access to an 
appropriate MRI scanner will be invited to join this optional substudy. The only exclusion criteria are 
those for a standard MRI scan: 
 
Cardiac pacemaker 
 
Any unfixed metallic implant or metallic fragments 
 
Excessive tattoos 
 
Fear of closed spaces or claustrophobia 
 
Absence of one kidney 
 
Invitation: Potential participants will be invited to join this substudy before the time of their 
Randomization Visit. If baseline scans were not possible (eg, due to COVID-19), participants will be 
invited around the time of their 18 or 24 month Follow-up visit for a single scan. If participants are 
interested the Research Coordinator will explain the substudy to potential participants using the 
Participant Information Leaflet and Consent Form. Consenting participants will then have an 
appointment made to attend for their MRI scan. 
 
Methods: The MRI scanning staff will double-check the suitability of the patient for an MRI scan and 
explain what it will involve. The participant will need to hold their breath at certain points during the 
process. The planned MRI scans take about 1 hour to complete. 
 
Analysis: The MRI data from all sites will be uploaded to an online secure platform (as used by other 
NHS services such as the Dementias Platform UK) and analysed by a standard pipeline. No 
participant data are required to be transferred with the scan (except for their de-identified unique study 
ID). The results will then be provided to the study statisticians at the University of Oxford for analysis. 
Patients from Oxford may have some of their MRI data also transferred to Perspectum Diagnostics 
who will process the data and provide results to University of Oxford staff. Basic demographic, medical 
history and laboratory details will be provided to staff at the University of Oxford and Perspectum 
Diagnostics to facilitate analysis of the exploratory aims. The primary analyses will not be conducted 
until the end of the main trial because only at this time will the unblinded treatment allocation become 
available. 
 
References 
1. 
Buchanan CE, Mahmoud H, Cox EF et al. Nephrol Dial Transplant 2019; doi 
10.1093/ndt/gfz219