Conditions: Heart Failure Type 2 Diabetes Mellitus
Keywords: Heart Failure Type 2 Diabetes Mellitus Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors Natriuresis Diuresis
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 23
Healthy volunteers: no

Brief summary:
The RECEDE-CHF trial is a single centre phase IV, randomised, double-blind, placebo-controlled, crossover trial conducted in NHS Tayside, Scotland comparing empagliflozin 25mg, to placebo in patients with Type 2 Diabetes and mild Chronic Heart Failure with left ventricular systolic dysfunction who are already on a loop diuretic. Renal physiological testing will be performed at two points on each arm to assess the effect of empagliflozin, on urinary volume, compared to placebo. The secondary outcomes are to assess the effect of empagliflozin in addition to loop diuretics on natriuresis, to assess the safety of add-on SGLT2 inhibitor therapy as measured by changes to serum creatinine and eGFR, to assess effects of empagliflozin on urinary protein/creatinine ratio, albumin/creatinine ratio and cystatin C when compared to placebo.

Detailed description:
Type 2 Diabetes (T2D) and Heart Failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose co-transporter 2 (SGLT2) inhibitors and their use in patients with HF. This is following publication of EMPA-REG OUTCOME trial that reported a 14% reduction in the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and \>30% reductions in cardiovascular mortality, overall mortality and HF hospitalisations in patients randomised to the SGLT2 inhibitor, empagliflozin, when compared to placebo. Data on the effect of SGLT2 inhibitor use with diuretics is limited. We hypothesize that, in the diabetic CHF population, SGLT2 inhibition may augment the effects of loop diuretics.

Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. The investigational medicinal product will be administered, followed by an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose.

This proof of concept trial will aim to shed light on the mechanism of the cardiovascular and renal outcomes demonstrated in the recent EMPA-REG study by documenting the influence of the SGLT2 inhibitors when used in combination with a loop diuretic on diuresis and natriuresis when compared to placebo.

The RECEDE-CHF trial is funded by the British Heart Foundation (BHF grant number: 807998). NAM is a BHF funded clinical research fellow.

Arms:
arm 1: Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks, minimum of a 2 week washout period, then 6 weeks placebo arm 2: Placebo for 6 weeks, minimum of a 2 week washout period, followed by Empagliflozin (SGLT2 inhibitor) 25mg capsules once daily for 6 weeks

Interventions: intervention 1: Empagliflozin 25mg intervention 2: Placebo oral capsule intervention 3: Frusemide
Intervention descriptions: intervention 1: Empagliflozin (SGLT2 inhibitor) 25 mg once daily for 6 weeks intervention 2: Capsules containing microcrystalline cellulose Ph Eur over encapsulated in a hard gelatine capsule shell to match the active comparator once daily for 6 weeks intervention 3: Renal Physiology Test (RPT) days will be performed at week 1 and week 6 on each arm of this crossover trial. On these RPT days participants will undergo oral water loading (15mls/kg) and frequent urination at 30 minute intervals to gain a steady state diuresis. At a set time point, an intravenous bolus of furosemide at a dose of half the participant's usual loop diuretic dose will be administered.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 1 of 55 
Trial Protocol 
REnal and Cardiovascular Effects of SGLT2 inhibition in combination with loop 
DiurEtics in diabetic participants with Chronic Heart Failure.  
 
Trial Acronym 
RECEDE-CHF 
Sponsor 
University of Dundee-NHS Tayside  
Sponsor R&D Number 
2015CA02 
Funder 
British Heart Foundation 
Chief Investigator 
Professor Chim Lang 
Principal 
Investigator/Research Fellow 
Dr Natalie Mordi 
EudraCT Number 
2016-003968-39 
CTA Number 
 
REC Number 
16/ES/0137 
ISRCTN Number 
 
Version Number and Date 
Version 4.0 22nd January 2018 
 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 2 of 55 
CONTENTS  
CONTENTS .............................................................................................................. 2 
PROTOCOL APPROVAL .......................................................................................... 5 
LIST OF ABBREVIATIONS ....................................................................................... 7 
SUMMARY ................................................................................................................ 9 
1 
INTRODUCTION ....................................................................................... 12 
1.1 
BACKGROUND ................................................................................ 12 
1.2 
RATIONALE FOR TRIAL .................................................................. 13 
2 
TRIAL OBJECTIVES ................................................................................ 16 
2.1 
OBJECTIVEs .................................................................................... 16 
2.1.1 
Primary Objective .................................................................... 16 
2.1.2 
Secondary Objectives .............................................................. 16 
2.2 
OUTCOMES ..................................................................................... 16 
2.2.1 
Primary Outcome .................................................................... 16 
2.2.2 
Secondary Outcomes .............................................................. 16 
3 
TRIAL DESIGN ......................................................................................... 17 
3.1 
TRIAL DESCRIPTION ...................................................................... 17 
3.2 
Trial investigations ............................................................................ 19 
3.2.1 
Blood Tests ............................................................................. 19 
3.2.2 
Urine Tests .............................................................................. 20 
3.2.3 
Renal Physiological Tests........................................................ 20 
3.3 
TRIAL FLOWCHART ........................................................................ 21 
4 
TRIAL POPULATION ................................................................................ 22 
4.1 
NUMBER OF PARTICIPANTS ......................................................... 22 
4.2 
INCLUSION CRITERIA .................................................................... 22 
4.3 
EXCLUSION CRITERIA ................................................................... 23 
5 
PARTICIPANT SELECTION AND ENROLMENT ..................................... 23 
5.1 
IDENTIFYING PARTICIPANTS ........................................................ 23 
5.2 
CONSENTING PARTICIPANTS ....................................................... 24 
5.3 
SCREENING FOR ELIGIBILITY ....................................................... 26 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS .................... 26 
5.5 
RANDOMISATION ........................................................................... 26 
5.5.1 
Randomisation ........................................................................ 26 
5.5.2 
Treatment Allocation ................................................................ 26 
5.5.3 
Emergency Unblinding Procedures ......................................... 27 
5.5.4 
Withdrawal procedures ............................................................ 27 
6 
INVESTIGATIONAL MEDICINAL PRODUCT ........................................... 28 
6.1 
TRIAL DRUG .................................................................................... 28 
6.1.1 
Trial Drug Identification ............................................................ 28 
6.1.2 
Trial Drug Manufacturer ........................................................... 28 
6.1.3 
Marketing Authorisation Holder ............................................... 28 
6.1.4 
Labelling and Packaging ......................................................... 28 
6.1.5 
Storage .................................................................................... 28 
6.1.6 
IMP Safety Information ............................................................ 29 
6.1.7 
Accountability procedures........................................................ 29 
6.2 
TRIAL COMPARATOR ..................................................................... 29 
6.2.1 
Comparator Identification......................................................... 29 
6.2.2 
Comparator Manufacturer........................................................ 29 
6.2.3 
Labelling and Packaging ......................................................... 29 
6.2.4 
Storage .................................................................................... 29 
6.3 
DOSING REGIME ............................................................................ 30 


                             
                         
     
 
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6.4 
DOSE CHANGES ............................................................................. 30 
6.5 
PARTICIPANT COMPLIANCE ......................................................... 30 
6.6 
OVERDOSE ..................................................................................... 30 
6.7 
OTHER MEDICATIONS ................................................................... 31 
6.7.1 
Permitted Medications ............................................................. 31 
6.7.2 
Prohibited Medications ............................................................ 31 
6.7.3 
Concomitant Medications ........................................................ 31 
6.8 
Discontinuation ................................................................................. 31 
7 
TRIAL ASSESSMENTS ............................................................................ 32 
7.1 
TRIAL ASSESSMENTS .................................................................... 32 
7.2 
SAFETY ASSESSMENTS ................................................................ 32 
8 
DATA COLLECTION& MANAGEMENT ................................................... 32 
8.1 
Data Collection ................................................................................. 32 
8.2 
Data Management SysteM ............................................................... 33 
9 
STATISTICS AND DATA ANALYSIS ....................................................... 33 
9.1 
SAMPLE SIZE CALCULATION ........................................................ 33 
9.1.1 
POWER CALCULATIONS ....................................................... 33 
9.2 
PROPOSED ANALYSES ................................................................. 34 
9.2.1 
STATISTICAL ANALYSIS ....................................................... 34 
9.3 
Missing data ..................................................................................... 34 
10 
ADVERSE EVENTS .................................................................................. 34 
10.1 
DEFINITIONS ................................................................................... 34 
10.2 
Detecting aes and saes .................................................................... 35 
10.3 
RECORDING AND REPORTING AEs AND SAEs ........................... 36 
10.4 
Evaluation of aes and saes. .............................................................. 36 
10.4.1 
Assessment of Seriousness .................................................... 37 
10.4.2 
Assessment of Causality ......................................................... 37 
10.4.3 
Assessment of Severity ........................................................... 37 
10.4.4 
Assessment of Expectedness .................................................. 38 
10.5 
reporting of SAEs/surs/susars .......................................................... 38 
10.6 
Regulatory REPORTING REQUIREMENTS ..................................... 38 
10.7 
annual reporting requirements .......................................................... 39 
10.8 
URGENT SAFETY MEASURES ....................................................... 39 
11 
PREGNANCY............................................................................................ 39 
11.1 
CONTRACEPTIVE ADVICE TO PARTICIPANTS ............................ 40 
12 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS................ 40 
12.1 
TRIAL MANAGEMENT GROUP ....................................................... 40 
12.2 
TRIAL MANAGEMENT ..................................................................... 40 
12.3 
TRIAL STEERING COMMITTEE ...................................................... 41 
12.4 
DATA MONITORING COMMITTEE .................................................. 41 
12.5 
INSPECTION OF RECORDS ........................................................... 41 
12.6 
RISK ASSESSMENT ........................................................................ 41 
12.7 
TRIAL MONITORING ....................................................................... 41 
12.7.1 
Potential Risks ......................................................................... 42 
12.7.2 
Minimising Risk ....................................................................... 42 
13 
GOOD CLINICAL PRACTICE ................................................................... 42 
13.1 
ETHICAL CONDUCT OF THE TRIAL ............................................... 42 
13.2 
regulatory compliance of the trial ...................................................... 42 
13.3 
ci respobsibilities .............................................................................. 42 
13.3.1 
Informed Consent .................................................................... 43 
13.3.2 
Trial Staff ................................................................................. 44 


                             
                         
     
 
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13.3.3 
Data Recording ....................................................................... 44 
13.3.4 
GCP Training ........................................................................... 44 
13.3.5 
Confidentiality .......................................................................... 44 
13.3.6 
Data Protection ........................................................................ 45 
13.3.7 
Insurance and Indemnity ......................................................... 45 
14 
TRIAL CONDUCT RESPONSIBILITIES ................................................... 45 
14.1 
PROTOCOL AMENDMENTS ........................................................... 45 
14.2 
PROTOCOL DEVIATIONS, BREACHES AND WAIVERS ................ 46 
14.3 
TRIAL RECORD RETENTION ......................................................... 46 
14.4 
END OF TRIAL ................................................................................. 46 
14.5 
CONTINUATION OF DRUG FOLLOWING THE END OF TRIAL ..... 47 
15 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ....... 47 
15.1 
AUTHORSHIP POLICY .................................................................... 47 
15.2 
PUBLICATION ................................................................................. 47 
15.3 
PEER REVIEW ................................................................................ 47 
16 
REFERENCES .......................................................................................... 48 
17 
APPENDIX 1: TRIAL SCHEDULE ............................................................ 51 
18 
APPENDIX 2: TRIAL DAY TIMELINE ....................................................... 54 
 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 5 of 55 
PROTOCOL APPROVAL 
REnal and Cardiovascular Effects of SGLT2 inhibition in combination with loop 
DiurEtics in diabetic patients with Chronic Heart Failure. (RECEDE-CHF) 
EudraCT number 2016-003968-39 
 
Signatures 
By signing this document I am confirming that I have read, understood and approve 
the protocol for the above trial. 
 
Professor Chim Lang 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
Dr Natalie Mordi 
 
 
 
Individual Responsible for 
Statistical Review 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 6 of 55 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 7 of 55 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AR 
Adverse Reaction 
BNP 
Brain Natriuretic Peptide 
BP 
Blood Pressure 
CHF 
Chronic Heart Failure 
CI 
Chief Investigator 
CNORIS 
Clinical Negligence and Other Risks Scheme 
CRC 
Clinical Research Centre 
CRF 
Case Report Form 
CTIMP 
Clinical Trials of Investigational Medicinal Product 
DM 
Diabetes Mellitus 
DPPIV 
Dipeptidyl peptidase inhibitor 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 
FBC 
Full Blood Count 
GCP 
Good Clinical Practice 
GP 
General Practitioner  
HbA1c 
Glycated Haemoglobin 
HF 
Heart Failure 
HIC 
Health Informatics Centre 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
LFTs 
Liver Function Tests 
LPLV 
Last Participant Last Visit 
LVSD 
Left Ventricular Systolic Dysfunction 
MHRA 
Medicines and Healthcare Products Regulatory 
Agency 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
NYHA 
New York Heart Association 
PI 
Principal Investigator 
PSF 
Pharmacy Site File 
QC 
Quality Control 
R&D 
Research & Development 
REC 
Research Ethics Committee 
RPT 
Renal Physiological Test 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 
SDRN 
Scottish Diabetes Research Network 
SGLT2 
Sodium-Glucose co-Transporter-2 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 8 of 55 
SU 
Sulphonylureas 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2D 
Type 2 Diabetes 
TASC 
Tayside Medical Sciences Centre 
TCTU 
Tayside Clinical Trials Unit 
TG 
Tubulo-glomerular 
TMF 
Trial Master File 
U&Es 
Urea & Electrolytes 
UAR 
Unexpected Adverse Reaction 
UoD 
University of Dundee 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 9 of 55 
SUMMARY 
Lay Summary 
People with diabetes are at increased risk of developing Heart Failure (HF). Symptoms 
of HF include increased shortness of breath, reduced ability to exercise and in some 
cases premature death as the heart becomes less efficient at pumping blood around 
the body. Many of these symptoms are caused by fluid retention. 
Drug options to treat HF in diabetes are currently limited as many of the drugs used 
are not suitable in diabetic participants as they cause unpleasant or harmful side 
effects. Many participants are given water tablets to help reduce or prevent fluid 
retention. 
A new class of anti-diabetic drugs may have some benefit in HF with diabetes as they 
may reduce workload on the heart. It has been shown that they may also promote 
weight loss and increase exercise capacity in previous studies.  
This trial will test if there is any benefit from using a drug called empagliflozin, (an 
SGLT2 inhibitor), to boost the effects of water tablets in diabetic participants with heart 
failure, by increasing sodium and urine output. 
The findings of this trial may help to find out if this class of drugs, SGLT2 inhibitors, are 
useful in diabetic participants with HF.  
In this trial, the aim is to recruit participants who have diabetes and heart failure. 
Participants will undergo investigations of kidney function, renal physiological tests, by 
measuring urine and sodium excretion.  
As this is a two-way cross over clinical trial, participants will be randomly allocated to 
either empagliflozin 25mg (6 weeks) or a dummy medication (placebo) (6 weeks), with 
a two week wash-out period between each arm. This will allow the researchers to 
compare if there is a difference between normal treatment and the addition of 
empagliflozin. Participants will undergo renal physiological testing at the end of week 
1 and week 6 during each arm. Participants will continue as normal with currently 
prescribed medication for their diabetes and heart failure. 
 
 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 10 of 55 
Professional Summary 
Men and women with diabetes have a 2-5 fold increased risk of heart failure (HF). The 
prevalence and incidence of HF is increasing in diabetes and mortality rates remain 
alarmingly high. This highlights the need for novel therapies in diabetes that will reduce 
HF risk and/or delay disease progression.  
Type 2 Diabetes Mellitus (T2DM) and Chronic Heart Failure (CHF) is a common but 
lethal combination where therapeutic options are limited.  
In CHF loop diuretics are a mainstay of therapy and are required to treat fluid retention. 
However, following their chronic use many people develop diuretic resistance leading 
to a worsening of CHF. Combining thiazide-like diuretics with loop diuretics is a 
commonly used but ineffective strategy to overcome diuretic resistance. Thus, new 
treatment strategies are urgently needed.  
SLGT2 inhibitors, the newest class of anti-diabetic drugs, may have additional 
beneficial cardio-renal effects in participants with concomitant DM and CHF. SGLT2 
inhibitors have an osmotic diuretic effect by reducing sodium and glucose absorption 
in the proximal tubules of the nephrons. We hypothesize that these effects could 
potentially be beneficial in treatment of participants with HF who are prone to sodium 
and fluid retention. 
The aim of this trial is to assess the safety and efficacy of empagliflozin, an SGLT2 
inhibitor, when prescribed in participants with DM and CHF who are on loop diuretics. 
We will conduct a double-blind, randomised controlled crossover trial of 34 participants 
with DM and stable CHF who are on furosemide. Participants will be randomised to 
either empagliflozin 25mg once daily or placebo for six weeks before crossing over to 
receive either placebo or empagliflozin for a further six weeks (after a 2 week washout 
period). 
Participants will undergo detailed renal physiological assessment after 1 week of 
treatment and end of each treatment period to assess renal physiological parameters 
to ascertain whether the addition of empagliflozin in conjunction with an intravenous 
bolus of furosemide improves urine output without any significant adverse 
consequences. The primary endpoint of the trial is a change in urinary volume in 
response to furosemide with empagliflozin when compared to placebo. 


                             
                         
     
 
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If our hypothesis is confirmed, it may position SGLT2 inhibitors such as empagliflozin 
as a mainstay of treatment in participants with DM and CHF. Additionally, it may help 
to provide an understanding of some of the mechanisms that may provide an 
improvement in cardiovascular outcome with SGLT2 inhibitors shown in the recently 
published EMPA-REG15 trial. 


                             
                         
     
 
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1 
 
INTRODUCTION 
1.1 
 BACKGROUND 
Chronic heart failure (CHF) and type 2 diabetes (T2D) frequently coexist. In population 
based studies and in CHF trials, the prevalence of T2D among participants with 
symptomatic heart failure (HF) is estimated to be between 12% and 41%.1 Among all 
participants hospitalised for CHF, it has been reported that up to 40% have T2D.2, 3 
This association can be lethal since T2D has consistently been shown to be an 
independent predictor of increased morbidity and mortality in participants with CHF.4  
However, treating participants with concomitant HF and T2D can be challenging. In the 
treatment of T2D, European Association for the Study of Diabetes/American Diabetes 
Association guidelines recommend tailoring therapeutic approaches to individual 
needs and/or risks.5   For most participants, metformin is the first choice anti-diabetic 
drug in all T2D participants including those with coincidental HF.6 This is underpinned 
by observational population cohort studies including our own observation in the 
Scottish population 7, 8. However metformin alone is often not enough to keep 
glycaemia under control and there is a substantial need for a second line anti-diabetic 
drug in HF participants. Unfortunately, the choices are very limited for the participants 
in this group. Sulphonylureas (SU) are commonly prescribed in T2D however they are 
associated with weight gain and hypoglycaemia, while there remain concerns that SUs 
may increase all-cause and cardiovascular-mortality,9 although this link is not fully 
established.  Glitazones are contra-indicated in New York Heart Association III or IV 
HF, while their role in milder degrees of HF remains to a certain extent controversial 
with some observational studies indicating increased hospitalisation or readmission 
due to HF.10  Insulin use has also been associated with increased mortality in 
participants with CHF.11 More recent agents such as the DPPIV inhibitors have also, 
disappointingly, failed to show cardiovascular benefit with some concerns raised 
following the publication of SAVOR-TIMI-53, that they increased HF hospitalisations, 
although these trials have only been of short duration12 and may not apply to all DPPIV 
inhibitors (http://www.medscape.com/viewarticle/843830). Therefore, it can be 
concluded that therapeutic options in T2D and HF are very limited and there is a critical 
need for agents that will both improve overall glycaemic control and HF outcomes. 
 


                             
                         
     
 
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1.2 
RATIONALE FOR TRIAL 
In this trial it is proposed that there may be unique features of the SGLT2 inhibitors 
that exhibit renoprotective effects alongside cardioprotective effects in participants with 
mild-CHF with left ventricular systolic dysfunction and diabetes.  
SGLT2 inhibitors have recently been licensed for use in participants with T2D. This 
oral anti-diabetic agent achieves its effect by blocking the low affinity, high capacity 
Type 2 Sodium-Glucose Linked co-Transporter, predominantly found in the proximal 
convoluted tubules of the kidneys, thus causing glycosuria, resulting in lowered blood 
glucose levels.  SGLT2 inhibitors cause weight reduction following the caloric loss from 
glycosuria. They have also been shown to improve insulin resistance in ZDF rats13 and 
in a small clinical trial among T2D participants.14 Exercise intolerance is a cardinal 
symptom of participants with HF and improving insulin sensitivity has been shown to 
improve exercise capacity. Thus, SGLT2 inhibition has the potential to improve 
exercise capacity in SGLT2 inhibition and to have beneficial effects on adverse left 
ventricular (LV) remodelling that occurs in participants with DM and HF by reducing 
the load on the heart through its diuretic and blood pressure lowering actions. The 
recent landmark EMPA-REG outcome trial that reported a striking 35% relative risk 
reduction in HF hospitalisations with empagliflozin may provide supportive evidence 
for beneficial effects of SGLT2 inhibition in the setting of CHF.15, 16  However, it should 
be noted that in the EMPA-REG trial, only 10% of trial participants had HF. The 
currently recruiting, European Foundation for the Study of Diabetes funded REFORM 
Trial is examining the potential LV remodelling benefits of SGLT2 inhibitors in 
participants with T2D and HF (clinical trials.gov identifier NCT02397421). 
A significant problem among participants with T2D and concomitant HF is diuretic 
resistance.17 It occurs frequently and can increase the length of stay in hospital and is 
associated with increased morbidity and mortality.18 The pathophysiology of diuretic 
resistance is varied and remains the subject of much debate.19  As a result, it is unclear 
how to treat diuretic resistance. At this time, sequential nephron blockade with thiazide-
like diuretics used in combination with loop diuretics is often used to overcome diuretic 
resistance in acute decompensated CHF.20  However this strategy does not always 
work and is associated with the hazards of hypokalaemia, hyponatraemia, hypotension 
and renal failure. A new strategy is needed. It is believed that SGLT2 inhibitors may 
be able to address this issue by its novel mechanism of action in the proximal part of 


                             
                         
     
 
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the renal tubules. It is hypothesized that its osmotic diuretic effects may augment the 
diuretic effects of furosemide in participants with T2DM and CHF. 
There is data to support the potential for direct renoprotective actions arising from 
SGLT2 inhibition including actions to attenuate type 1 diabetes associated hyper 
filtration through an effect on tubulo-glomerular (TG) feedback which may have renal-
protective effects by decreasing glomerular hydrostatic pressure.23, 24 SGLT2 inhibition 
has also been shown to attenuate tubular hypertrophy and reduce the tubular toxicity 
of glucose.22 They may also have indirect renoprotective effects through its blood 
pressure lowering effects and glycaemia lowering effects which could decrease the 
renal inflammatory and fibrotic response by blocking glucose entry into the cell.22 
Consequently, there are now several on-going SGLT2 inhibitor renal outcome trials in 
T2D, including the CANVAS-R trial (clinicaltrials.gov identifier NCT01989754) and the 
CREDENCE trial (clinical trials.gov identifier NCT02065791). However, neither trial 
specifically looks at T2DM participants with CHF.  
We contend that these effects, albeit modest, of SGLT2 inhibitors may potentially 
augment the diuretic effect of loop diuretics. It is noteworthy that osmotic diuretics such 
as mannitol have been used alone or in combination with loop diuretics such as 
furosemide to promote diuresis in participants undergoing intra-cranial surgery28 and 
in the postoperative period to prevent acute kidney injury.29 In CHF, mannitol was 
reported to promote effective diuresis in a single centre trial in the US.30 Importantly, 
in all these settings, mannitol, which is a potent osmotic diuretic when used in 
combination with furosemide, was shown to be safe and did not result in renal failure 
or electrolyte disturbances. 
It is known that increased sodium delivery to the macula densa following SGLT2 
inhibition may intensify TG feedback and lead to a decline in glomerular filtration rate 
at least in T2D individuals.25, 26 A meta-analysis on the effect of dapagliflozin on renal 
function that included 12 placebo controlled randomized studies and involved more 
than 4000 participants with preserved renal function showed that dapagliflozin caused 
a fall in estimated glomerular filtration rate (eGFR) at week 1 that slowly returned to 
baseline.31 This pattern of acute eGFR decline followed by stabilization suggests that 
the acute eGFR decline reflects a (reversible) haemodynamic change rather than 
worsening of structural renal function. 


                             
                         
     
 
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The renal effects of SGLT2 inhibitors in combination with furosemide in T2D with CHF 
are not known. The recent EMPA-REG trial demonstrated a beneficial effect of the 
SGLT2 inhibitor empagliflozin on cardiovascular outcomes, particularly heart failure 
hospitalisation in T2D.15 It is thought that the most likely explanation for this positive 
result is the improvement in loading conditions caused by the osmotic diuresis.33 
Therefore, there is an urgent need for a trial to provide detailed acute and long-term 
information regarding the renal effects of the SGLT2 inhibition in combination with 
furosemide, in T2D participants with stable CHF.  
The intent of this proposed trial is to obtain data that might be relevant to the design of 
future studies in which SGLT2 inhibitors may be considered as an adjunctive agent to 
loop diuretics in this vulnerable participant group. There is currently no data on 
combining SGLT2 inhibitors and diuretics, which is why this combination is not 
recommended at this point in time. However, it should be noted that in EMPA-REG 
43% of participants were on loop diuretics.15 Since HF and T2D are frequent co-
morbidities, it is possible that physicians may find participants requiring both SGLT2 
inhibitor therapy and furosemide concurrently. Only by trialling this, can these 
fundamental issues be addressed and, perhaps, inspire a change in practise.  
We will recruit diabetic HF participants taking stable doses of furosemide, or, 
alternative loop diuretics, with eGFR greater than 45ml/min. Whilst SmPC states that 
empagliflozin should not be administered with an eGFR < 60 ml/min, EMPA-REG 
recruited participants with an inclusion criteria of eGFR ≥ 30 ml/min.15 Within the total 
number of participants, n = 1819 (25%), with an EGFR < 60 mls/min, 1,212 were 
randomised to empagliflozin15. There was no reported increase in renal adverse events 
(acute kidney injury or hyperkalaemia) in those with eGFR < 60 mls/min regardless of 
whether the patients had impaired kidney function at baseline. Further analysis in the 
EMPA-REG renal outcome, demonstrated that in patients with T2D at high risk for 
cardiovascular events, those who received empagliflozin in addition to standard care 
had a significantly lower risk of microvascular outcome events than did those receiving 
placebo, a difference that was driven by a lower risk of progression of kidney disease 
(as defined by incident or worsening nephropathy).32 Furthermore the Dapa-HF trial 
(clinical trials.gov identifier NCT03036124) will set an inclusion of eGFR > 30mls/min 
to further evaluate the effect of dapagliflozin on the incidence of worsening HF or 
cardiovascular death in patients with CHF. 


                             
                         
     
 
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As there will be administration of intravenous furosemide of half the participant's usual 
daily dose with the RECEDE-CHF protocol, an eGFR ≥ 45 ml/min will be taken as a 
cut off for inclusion. 
This trial will, with careful monitoring, begin the process of uncovering the unrealised 
potential of this new class of drug, and for the reasons given above, it is poised to 
become the 2nd line anti-diabetic agent of choice in HF participants.  
2 
TRIAL OBJECTIVES 
2.1 
OBJECTIVES 
2.1.1 Primary Objective 
The primary aim/objective will be to assess whether empagliflozin (SGLT2 Inhibitor) 
can augment the diuretic effect of loop diuretics in diabetic participants with mild CHF 
with left ventricular systolic dysfunction (LVSD), as measured by urinary volume, when 
compared to placebo. 
2.1.2 Secondary Objectives 
The secondary aims/objectives are to assess the effect of empagliflozin (SGLT2 
inhibitor) on natriuresis when used with loop diuretics in diabetic patients with mild CHF 
with LVSD as measured by urinary sodium excretion, to measure the safety of add-on 
SGLT2 inhibitor therapy versus placebo on top of loop diuretics as measured by serum 
creatinine and eGFR, to assess effects of empagliflozin on protein/creatinine ratio, 
albumin/creatinine ratio and on the renal biomarker, cystatin C.  
2.2 
OUTCOMES 
2.2.1 Primary Outcome 
The primary outcome for this trial is: 
• 
To assess the effect of empagliflozin versus placebo on urine output  
2.2.2 Secondary Outcomes 
The secondary outcomes for this trial are: 
• 
To assess the effect of empagliflozin versus placebo on urinary sodium 
excretion 
• 
To assess the change in glomerular filtration rate (safety endpoint) 


                             
                         
     
 
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• 
To assess the change in creatinine (safety endpoints) 
• 
To assess the effect of empagliflozin on protein/creatinine ratio  
• 
To assess the effect of empagliflozin on albumin/creatinine ratio 
• 
To assess the effect of empagliflozin on the renal biomarker, cystatin C. 
3 
TRIAL DESIGN 
3.1 
TRIAL DESCRIPTION 
The RECEDE-CHF Trial is a single centre randomised, double-blind, placebo-
controlled, crossover, trial conducted in NHS Tayside to compare the SGLT2 inhibitor 
empagliflozin 25mg, to placebo. Participants will be enrolled in the trial for a period of 
between 14 to 16 weeks.  
At the screening visit, following informed consent, an initial medical history and clinical 
examination will be performed and concomitant medication will be recorded. 
Participants will have bloods taken for safety analysis and vital signs will be checked 
to confirm eligibility prior to enrolment. An assessment of suitability of the trial for the 
potential participant will be undertaken by the principal investigator or medically 
qualified delegate.  
Should the participant meet the inclusion criteria and have no exclusion criteria 
identified, they will return for the baseline/randomisation visit at the Clinical Research 
Centre (CRC), Ninewells Hospital, Dundee, within four weeks post screening visit. 
Where possible the screening visit and randomisation visits will be combined.  
At the randomisation visit participants will undergo safety blood tests, vital signs and 
trial medication will be dispensed (either empagliflozin 25mg or placebo).  
Participants will continue on trial medication, empagliflozin 25mg or placebo, once 
daily, for a period of 6 weeks. Participants will be educated on the symptoms of 
hypoglycaemia which includes a written action plan on how to manage it in the unlikely 
event that it occurs.  
Participants will return to the CRC 3-days (±2 days) post-randomisation, for a trial day, 
lasting approximately 5 hours, where they will have safety and research bloods drawn, 
vital signs recorded and will undergo renal physiological tests (RPT). Participants will 
be required to provide several urine samples throughout the course of the visit.  


                             
                         
     
 
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Participants will then return again at week 6 for a trial day, lasting approximately 5 
hours, where they will undergo RPT again, safety and research bloods will be drawn 
and vital signs recorded. Participants will be again required to provide several urine 
samples throughout the course of this visit. Participants will terminate trial drug, either 
empagliflozin 25mg or placebo, at this visit and will return to the CRC at the end of the 
two week wash out period (week 9) 
At week 9, participants will have safety and research bloods drawn, vital signs 
recorded, new trial medication dispensed, educated on the symptoms of 
hypoglycaemia and given a written action plan on how to manage it in the unlikely 
event that it occurs. 
Participants will subsequently return to the CRC after 3 days (±2 days), for a trial day, 
lasting approximately 5 hours, where they will have safety and research bloods drawn 
again, vital signs recorded and will undergo renal physiological tests (RPT). 
Participants will be required to provide several urine samples throughout the course of 
the visit.  
Participants will then return again at week 14 for the final trial day, lasting 
approximately 5 hours, where they will undergo RPT again, safety and research bloods 
will be drawn and vital signs recorded. Participants will be required to provide several 
urine samples throughout the course of the visit. Participants will terminate trial drug, 
either empagliflozin 25mg or placebo. 
Further details of trial visits are detailed in section 7.1. 
Participants not on insulin will continue with all usual medications, these remain 
unchanged throughout unless clinically indicated. Participants who are already on 
insulin at time of recruitment will be advised of the likelihood of having to reduce their 
total daily dose of insulin by for example by a reduction of 10% on the day they are 
randomised with an increase in the frequency of their blood sugar monitoring. Further 
dose titration will be done by the trial team, Diabetic Consultant, or GP with or without 
instruction from either the trial team or Diabetic Consultant, based on the participant’s 
symptoms, home and laboratory-based blood sugar levels. Down-titration of therapy 
will be done in a stepwise manner starting with insulin. Other anti-diabetic agents will 
only be down-titrated once insulin has been discontinued. Up-titration of therapy can 
be done at the treating physician’s discretion. There will be no titration of the IMP. 


                             
                         
     
 
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Acute exacerbations of CHF are likely to occur in the course of this trial. These will be 
treated as per usual practice and the empagliflozin or placebo will not need to be 
stopped unless the participant or their clinician specifically requests stopping or there 
are sound clinical reasons to do so. Anti-hyperglycaemic medications may be adjusted 
by the participants GP, hospital care consultant or PI as necessary during the trial; 
changes will be recorded in the concomitant medications. 
It is expected that the number of participants requiring therapy changes will be equal 
between the two groups. Participants experiencing two or more severe hypoglycaemic 
episodes, requiring medical assistance, despite down titration or discontinuation of 
other anti-hyperglycaemic medications will have trial medication discontinued.  
3.2 
TRIAL INVESTIGATIONS 
3.2.1 Blood Tests  
Screening blood samples will be taken for routine haematology and biochemistry tests 
including full blood count, renal function, (U&Es), liver function (LFTs), blood glucose, 
haemoglobin A1c, lipids, pro-NT BNP and cystatin C levels.  
Routine safety bloods will be taken at visits throughout the trial: at each visit, in pre-
screening, baseline/randomisation, visits 3 (day 2), visits 5 (week 6) visit 6 (week9) 
visit 7 (week 9 + 3) and the final visit week 15.  
Research bloods will be taken at randomisation visit, day 3, week 6, week 9 (post-
wash out), week 9 day 3, and week 15. BNP, inflammatory markers and other markers 
of interest such as oxidative stress will be measured. Additional blood markers may be 
tested on surplus samples at a later date. The total amount of research blood taken at 
each visit will be no more than 20ml.  
Consent will also be sought for future ethically approved genetic analysis using 
research blood samples. This can be declined without affecting participation in the trial. 
If agreement is given for this, 10ml of extra blood will be taken at the randomisation 
visit and anonymously stored in the Division of Molecular and Clinical Medicine, 
University of Dundee: any subsequent analysis of these samples will be subject to 
approval of a Research Ethics Committee (REC) prior to analysis.  


                             
                         
     
 
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3.2.2 Urine Tests 
Participants will provide a spot urine sample for quantification of albumin/creatinine 
ratio and protein/creatinine ratio at 4 of the trial days. As well as four 24 hour urinary 
collections on the days prior to the renal physiological tests days.  
3.2.3 Renal Physiological Tests 
Participants will attend the Clinical Research Centre (CRC) on 4 separate trial days (2 
while in each arm of the trial).  On each trial day, participants will present themselves 
to the CRC, following an overnight fast. Two days before presenting to the CRC, 
participants will be required to follow a 2gm sodium and 2L fluid/day controlled diet. A 
24-hour urine collection will be made in the 24 hours prior to the day of the renal 
physiological test. Participants will be asked to take their morning usual medications 
except their IMP (empagliflozin or placebo) and furosemide (or equivalent loop 
diuretic). 
An intravenous cannula will be placed in each arm for subsequent infusion and blood 
sampling. Bloods will be drawn for measurement of plasma NT-proBNP (a biomarker 
of wall stress and will be measured as a discovery variable in this proof of concept trial) 
using standard protocols. Firstly, a 15 ml/kg oral water load will be administered over 
approximately a 15-minute period. Thereafter, at approximately 30 minute intervals, 
participants will be requested to void urine until the end of the trial day. The volume of 
urine passed will be measured and an aliquot stored for later analysis. On each 
occasion, the volume of urine passed will be measured, and an equal volume of water 
given to drink. In this way, a steady state diuresis will be established over 
approximately 3 hours. The last urine collection during this stabilization period will be 
taken as baseline. Approximately 3 hours after initiation of the test, each participant 
will receive an oral tablet of either empagliflozin 25mg or placebo. After the seventh 
urine sample, participants will be given a bolus of IV furosemide at half their total daily 
dose. Heart rate will be displayed continuously on an ECG oscilloscope and the blood 
pressure measured approximately every 60 minutes. Venous blood will be obtained at 
the midpoint of each clearance period for measurement of serum sodium, osmolality 
and creatinine. At the end of the RPT, light refreshments in the form of tea, coffee or 
juice with biscuits will be provided. A lunch will then be provided at the CRC. 


                             
                         
     
 
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Day 0  
   Day 3 
Week 3  
Week 6 
Weeks 7-9  
 
    Week 9 
         Week 9 + Day 3  Week 12     Week 15 
Randomisation   RPT  
Televisit 
RPT 
 
Washout period 
    Drug dispensing      RPT 
              Televisit 
RPT 
Up to 4 weeks before 
randomisation.  
3.3 
TRIAL FLOWCHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please refer to Section 7 and Appendix 1 for more detailed information regarding study specific tests being performed at each visit.  
 
Screening: 
From sources listed 
in protocol.  
Empagliflozin 25 mg (n=17) 
Placebo (n=17) 
Two-week washout period 
Randomise (n=34) 


                             
                         
     
 
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4 
TRIAL POPULATION 
4.1 
NUMBER OF PARTICIPANTS 
34 participants with underlying diabetes and well-controlled chronic heart failure (CHF) 
will be recruited from a range of sources as listed below in 5.1.  
The PI will be responsible for recruitment but may delegate to other named individuals 
within the trial team. Any such delegation will be recorded on the trial delegation log 
and authorised by the CI.  
It is anticipated it will take up to 18 months to recruit the 34 participants for 
randomisation with approximately 80-100 being consented into the screening trial. We 
anticipate a screen failure rate of 20% and a dropout rate of 35% after recruitment due 
to the high intensity and frequent renal physiological tests.  
4.2 
INCLUSION CRITERIA 
Participants will be eligible if they: 
• 
Aged 18 to 80 years with previously diagnosed Type 2 Diabetes Mellitus.  
• 
Are 
diagnosed 
with 
NYHA 
Functional 
class 
II-III 
HF 
with 
prior 
echocardiographic evidence of LVSD.  
• 
On stable doses of furosemide, or alternative loop diuretic for at least one 
month. 
• 
Type 2 Diabetes  
• 
eGFR ≥ 45 ml/min. 
• 
Have stable HF symptoms for at least three months prior to consent 
• 
On stable HF therapy for at least three months prior to consent 
• 
Have not been hospitalised for HF for at least three months prior to consent.  
• 
Women of childbearing potential* (WoCBP) must agree to take precautions to 
avoid pregnancy throughout the trial and for 4 weeks after intake of the last 
dose. 
 


                             
                         
     
 
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4.3 
EXCLUSION CRITERIA 
Participants will be excluded if they: 
• 
A diagnosis of chronic liver disease and/or liver enzymes that are twice the 
upper limit of normal 
• 
Systolic BP of <95mmHg at screening visit.  
• 
HbA1c < 6.0% 
• 
Participants on thiazide diuretics. 
• 
Participants receiving renal dialysis 
• 
Participants who have previously had an episode of diabetic ketoacidosis. 
• 
Participants with type 1 diabetes mellitus 
• 
Malignancy (receiving active treatment) or other life threatening disease.  
• 
Pregnant or lactating women 
• 
Participants with difficulty in micturition e.g. severe prostate enlargement 
• 
Allergy to any SGLT2 inhibitor or lactose or galactose intolerance 
• 
Past or current treatment with any SGLT2 inhibitor 
• 
Participants who have participated in any other clinical interventional trial of an 
investigational medicinal product within 30 days. 
• 
Participants who are unable to give informed consent 
• 
Any other reason considered by the physician to be inappropriate for inclusion.  
*Women of child bearing potential (WoCBP) are defined as premenopausal women 
who have not been surgically sterilised or had a hysterectomy, bilateral salpingectomy 
or bilateral oophorectomy. Women over 45 years old, who have not had a menstrual 
period for at least 12 months, without an alternative medical cause, will be considered 
post-menopausal. 
5 
PARTICIPANT SELECTION AND ENROLMENT 
5.1 
IDENTIFYING PARTICIPANTS 
Participants will be recruited from the sources identified as: 


                             
                         
     
 
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1. From the HF (BIOSTAT) database in Tayside of research participants who 
have taken part in previous HF studies in the Department of Clinical 
Pharmacology, University of Dundee. 
2. From the Diabetes and Cardiology clinics at any of the four NHS Tayside 
locations (Ninewells Hospital, Arbroath Royal Infirmary, Stracathro Hospital 
and Perth Royal Infirmary).  
3. From SHARE, the Scottish Health Research Register, where participants have 
pre-consented to be invited for research. 
4. From the Scottish Diabetes Research Network (SDRN), where patients have 
previously been involved in diabetes trials and have consented to being 
approached for future research, including those registered on the GoDARTS 
Database.  
The PI will be responsible for recruitment but may delegate to other named individuals 
within the trial team. The PI or delegate may remotely screen electronic records to 
identify potentially suitable people and appropriate approvals will be in place to allow 
them to do so.   
5.2 
CONSENTING PARTICIPANTS 
The PI, research nurse or delegate will either approach directly suitable participants at 
the clinical areas specified above or they will be approached indirectly by letter. 
Medical notes, which can be accessed via online systems such as Clinical Portal, will 
be reviewed to initially assess a participant’s suitability. A review of the medical notes 
will be made to assess inclusion criteria (as listed in 4.2), and to identify if exclusion 
criteria (listed in 4.3) are met, prior to being approached. The letter will be sent either 
from their clinical consultant responsible for their care or from the Cl, either directly or 
on his behalf by the UoD Health Informatics Centre (HIC), if required. Prior consent for 
contact is in place for participants registered to the research databases described 
above. Those registered with SHARE have also provided consent for access to and 
use of their electronic health records in order to identify them as potentially eligible 
participants for the trial.  
When first contact is via letter (or telephone/e-mail if it is via SHARE, as per participant 
choice), a brief Participant Information Sheet (bPIS) will be sent which gives a general 
overview of the trial. Participants will be asked to contact the research team if they are 


                             
                         
     
 
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interested in the trial. All participants will be given at least 24 hours to consider their 
response and will be asked to return an expression of interest in a stamped, addressed 
envelope.  
Should participants express an interest in taking part in the trial from the bPIS they will 
be provided with a full participant information sheet (PIS) by post. They will be given 
at least 24 hours to consider participation before they are scheduled to attend the 
research clinic at the CRC, Ninewells Hospital. When first contact is directly via a Clinic, 
potential participants will be given full PIS. All participants will be given at least 24 
hours to consider participation before a screening visit is arranged by the research 
fellow or delegate. 
Participants will have the opportunity to ask questions about the trial when the 
screening visit is being arranged and at the screening visit, where the informed consent 
discussion will take place. If they decide to participate, written informed consent will be 
taken and eligibility assessed by confirming all inclusion/exclusion criteria – medical 
notes will also be reviewed again at this stage. The CI, PI, research nurse or 
appropriately trained and qualified delegate will carry out informed consent.  
Where a participant requests to speak with a physician from the trial team the consent 
process will not be completed until the participant has spoken to the physician and had 
all their questions answered to their satisfaction. 
Participants will be asked for their consent for a member of the Research team (CI, PI 
or research nurse) to inform the GP of the individual’s intent to participate in this study. 
Those participants who do not agree to their GP being informed of participation in this 
study will be excluded from the study.  
All individuals taking informed consent will have received training in Good Clinical 
Practice (GCP) and will adhere to the TASC SOP07 on informed consent.  It will be 
explained to participants that they are under no obligation to enrol in the trial and that 
they can withdraw at any time during the trial, without having to give a reason. A copy 
of the signed informed consent form (ICF) along with a copy of the PIS will be given to 
the trial participant. The original signed consent form will be retained at the trial site 
(filed in the TMF) and one copy filed in the medical notes. 


                             
                         
     
 
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5.3 
SCREENING FOR ELIGIBILITY 
Participants must have documented Type 2 Diabetes Mellitus and CHF with LVSD. 
Post consent, screening bloods will be performed to ensure renal function and HbA1c 
meet the inclusion criteria. Blood pressure and heart rate will also be measured. 
Women of child bearing potential will have a pregnancy test. Participants will be 
consented prior to screening and a screening log will be maintained.  
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS  
The reason(s) for ineligibility will be explained to participants and any questions they 
have will be answered. They will be thanked for their participation in screening and any 
relevant information from this will be added to their hospital notes and be 
communicated to their GP and consultant, where the participant consents for this to 
happen.  
5.5 
RANDOMISATION 
5.5.1 Randomisation 
After successful screening for eligibility and safety, participants will be randomised to 
either empagliflozin 25mg/ placebo or placebo/empagliflozin 25 mg in a double blind 
fashion in this crossover study. 
The double blind medication (empagliflozin or placebo) will be prepared, packaged and 
labelled by Tayside Pharmaceuticals. Randomisation will be carried out by Tayside 
Pharmaceuticals, using block randomisation using a validated randomisation 
programme, and will securely backup both the randomisation seed and the 
randomisation allocation. 
The Clinical Trials Pharmacy, Ninewells Hospital will be provided with a copy of the 
randomisation allocation for the purposes of 24h emergency unblinding. 
5.5.2 Treatment Allocation 
Participants will be given blinded medication. At the randomisation visit they will be 
dosed with either empagliflozin 25mg (6 weeks) or matched placebo (6 weeks) to 
continue once daily, with a 2-week washout period between each arm.  Participants 
and their bloods (including U&Es and LFTs, FBC) will be monitored as per trial 
schedule and medication stopped if concerns arise.  If trial drug needs to be stopped 


                             
                         
     
 
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due to intolerance or adverse events, they will remain in the trial in order to do an 
“intention to treat” analysis.  They will be invited to attend all future trial visits. 
5.5.3 Emergency Unblinding Procedures 
A clinician familiar with the research (and named on the delegation log) will be available 
each workday for contact by all participants. This will include the CI, the PI/ a research 
fellow based within the Division of Cardiovascular and Diabetes Medicine Department 
at Ninewells Hospital.  
Any other clinician who sees participants during trial participation will be free to stop 
the trial drug if they feel it is clinically indicated and be asked to inform the trial team. 
The Clinical Trials Pharmacy, Ninewells Hospital will be provided with a copy of the 
randomisation allocation for the purposes of 24h emergency unblinding. During office 
hours the Clinical Trial Pharmacy, Ninewells Hospital, should be contacted if unblinding 
is required, out of hours the On-call Pharmacist should be contacted via Ninewells 
Hospital switchboard. 
 
5.5.4 Withdrawal procedures 
Participants are free to withdraw from the trial at any time. Although a participant is not 
obliged to give reason(s) for withdrawing prematurely, if the participant appears lost to 
follow up, the CI will make a reasonable effort to ascertain the reason(s), while fully 
respecting the individual’s rights, and will demonstrate that everything possible was 
done in an attempt to find any participant lost to follow-up. Those lost to follow-up or 
withdrawn will be identified and a descriptive analysis of them provided, including the 
reasons for their loss and its relationship to treatment and outcome. 
Participants who withdraw will be replaced if possible within the trial time frame. Those 
that withdraw from trial drug will be encouraged to attend future trial visits and where 
possible the final visit for the outcome measures. Participants who withdraw will be 
invited to a final ‘early discontinuation’ visit. At this visit, the tests that would be taken 
at week 15 the final study visit, including vital signs and blood samples for  NT-proBNP, 
serum sodium, osmolality and creatinine, for safety, research and genetic bloods 
(without undergoing the detailed renal physiological testing), to allow the investigators 
to obtain further information on the safety of the drug. 


                             
                         
     
 
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If withdrawal is due to an adverse event (AE), contact will be maintained by the PI or 
delegate with the individual to ensure resolution of the AE; this will also be logged in 
the AE log and participant’s hospital case notes.   
Reasons for treatment discontinuation due to safety and/or tolerability are listed in 
section 6.8. There is an increased risk of hypoglycaemia, as discussed in section 10.2  
Participants’ anti-hyperglycaemic medications may be adjusted as deemed necessary 
by a trial doctor, local NHS clinic or GP in order to achieve an appropriate individualised 
glycaemic control according to local guidelines without them having to stop the trial 
medication. Medications will be reconciled at all 9 patient visits (see Appendix 1) so 
that documentation can be made of any changes to participants’ other regular 
medication. Where medication has been adjusted, the Emergency Care Summary, an 
online patient record used to document repeat and acute prescriptions will be used to 
clarify the start and stopping date for any medication changes. Changes made by 
Hospital based doctors will be seen on Medical documentation and clinic letters. If 
clarification is required for changes made in the community, then the GP Practice may 
be contacted directly to clarify the date and indication for change.  
6 
INVESTIGATIONAL MEDICINAL PRODUCT 
6.1 
TRIAL DRUG 
6.1.1 Trial Drug Identification 
Jardiance tablet (25mg) over-encapsulated in hard gelatine capsule shell. 
6.1.2 Trial Drug Manufacturer 
Tayside Pharmaceuticals, Ninewells Hospital, Dundee.  
6.1.3 Marketing Authorisation Holder 
Not applicable. IMP dossier to be formulated by Tayside Pharmaceuticals 
6.1.4 Labelling and Packaging 
Tayside Pharmaceuticals, Ninewells Hospital, Dundee.  
6.1.5 Storage 
IMP will be stored in the Clinical Trial Pharmacy (Ninewells Hospital, Dundee). IMP 
accountability logs will be held in the Pharmacy Site File (PSF).  


                             
                         
     
 
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6.1.6 IMP Safety Information 
The Summary of Product Characteristics (SmPC) will be held in the PSF and TMF. 
Section 4.8 will be used to assess the causality of any adverse event in relation to the 
IMP. The CI will check at least annually for any changes to the SmPC. Where changes 
to Section 4.8 impact on the assessment of causality of adverse events, the new 
version of the SmPC will be submitted as an amendment prior to being used as 
reference safety information (RSI) and the updated SmPC will be provided to 
Pharmacy. 
Common side effects of empagliflozin include, increased urination and vaginal yeast 
infection. Women who take empagliflozin may get vaginal yeast infections hence 
participations will be encouraged to approach either the PI or the GP if they experience 
vaginal odour, white or yellowish vaginal discharge and/or vaginal itching. Increased 
urination may be reported by the participant in the absence of any infection. 
Less common side effects include, dehydration and subsequent acute kidney injury, 
ketoacidosis (which has been reported in the absence of hyperglycaemia), urinary tract 
infections, hepatic injury and for men taking empagliflozin, yeast infection of the penis.  
6.1.7 Accountability procedures 
These will be overseen by the Clinical Trials Pharmacist in the Clinical Trials Pharmacy 
Department (Ninewells Hospital) and will be documented in an Accountability Log held 
in the PSF. Accountability will be in compliance with TASC SOP 37. 
6.2 
TRIAL COMPARATOR 
6.2.1 Comparator Identification  
Hard gelatine capsule shell containing Microcrystalline Cellulose Ph. Eur. 
6.2.2 Comparator Manufacturer 
Tayside Pharmaceuticals, Ninewells Hospital, Dundee. 
6.2.3 Labelling and Packaging 
Tayside Pharmaceuticals, Ninewells Hospital, Dundee. 
6.2.4 Storage 
Drugs will be stored in the Clinical Trial Pharmacy (Ninewells Hospital). 


                             
                         
     
 
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6.3 
DOSING REGIME 
Participants will be given blinded medication. At the randomisation visit, they will be 
dosed with either oral empagliflozin 25mg OD or matched placebo to continue for 6 
weeks, if tolerated. This will be followed by a two-week washout period. The participant 
will then cross over to be given either placebo or empagliflozin 25mg OD for a further 
6 weeks. 
No additional lifestyle restrictions will be imposed on the participant and we will ask 
them to carry on as normal except in the 48 hours preceding the renal physiological 
tests where we would request a 2gm sodium and 2L fluid/day controlled dietDOSE 
CHANGES 
No dose change is planned in this trial. If the participant is taken off the trial, their GP 
and/or consultant will be informed of the reason for that. 
6.5 
PARTICIPANT COMPLIANCE 
Compliance will be checked and documented using tablet counts at both trial visits 
during each arm. A telephone visit is scheduled for week 3 and week 12 where 
compliance will be checked verbally and participants will be advised by the research 
nurse or PI on the importance of correct compliance.  
6.6 
OVERDOSE 
This is unlikely given the simple once daily dosing but there is no specific antidote.  
In the event of an overdose, appropriate supportive treatment should be initiated as 
dictated by the participant’s clinical status. The removal of empagliflozin by 
haemodialysis has not been studied.  
Overdose with empagliflozin is rare, however it has been noted that there is an 
increased risk of hypoglycaemia when given with insulin and/or sulphonylureas. The 
majority of the hypoglycaemic events are mild (defined as not requiring any 
assistance). In the case of any overdose, the patient will be advised to stop the 
medication and the event will be reported. If symptomatic, the patient (or their carer) 
will be advised to take an oral glucose load (sugary drink, fruit etc.) and if necessary 
to seek medical attention at their GP or hospital. 


                             
                         
     
 
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6.7 
OTHER MEDICATIONS 
6.7.1 Permitted Medications 
Other medications, apart from those listed in 6.7.2, will be allowed. All concurrent 
medication(s) will be recorded.  
6.7.2 Prohibited Medications 
Repaglinide, and other anti-diabetic drugs in this class are contra-indicated due to the 
increased risk of hypoglycaemia. Thiazide diuretics due to increased risk of hyper 
diuresis. These medications are prohibited in this trial. The GP information letter and 
PIS will contain information on all the above points.  
6.7.3 Concomitant Medications 
Details of all concomitant medications will be discussed and recorded in the CRF at all 
study visits, including telephone visits.  
6.8 
DISCONTINUATION 
The trial medication will be discontinued due to safety and/or tolerability in the following 
circumstances: 
• 
Participant becomes pregnant 
• 
LFTs rise to greater than twice the normal range 
• 
Participant develops symptoms of NYHA class IV heart failure 
• 
Participant has vomiting and diarrhoea for 48 hours and volume depletion is 
suspected 
• 
Participant develops symptomatic postural hypotension 
• 
Participant develops signs of vulvovaginitis, balanitis and related genital 
infections or urinary tract infections which do not respond to treatment.  
• 
Participant has suspected or diagnosed Diabetic Ketoacidosis  
• 
Participant develops a sustained eGFR < 45 mls/min despite alteration of dose 
of furosemide or alternative loop diuretic  


                             
                         
     
 
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7 
TRIAL ASSESSMENTS 
7.1 
TRIAL ASSESSMENTS 
As outlined in section 5.2, participants will be provided with a full PIS and are given at 
least 24 hours to consider their response before a screening visit will be arranged for 
consent to be taken and to check their eligibility by all the criteria. On discussion with 
the participant, if they are willing to wait for the results of their safety blood tests, visit 
1 (screening) and visit 2 (baseline/randomisation) will be offered to be combined. 
For details of assessments carried out at each visit see Appendix 1  
 
7.2 
SAFETY ASSESSMENTS 
Safety 
assessments 
will 
be 
carried 
out 
at 
visits 
1 
(screening), 
2 
(baseline/randomisation) 
or 
where 
visits 
1 
and 
2 
(screening 
and 
baseline/randomisation) are combined, visit 3 (Day 3), visit 5 (week 10), visit 6 (week 
9), visit 7 (week 9 +3) and visit 9 (week 15). Participants will be asked to return for visit 
10 (final visit/week 19 ± 7 days) to ensure diuretic medication is at an adequate dose 
following discontinuation of study medication. These safety assessments include: 
• 
Safety bloods: including U&Es, LFTs, Glucose, Magnesium, Calcium, 
Cholesterol, Urate and FBC 
• 
Vital signs including BP, participants will be asked about any symptoms of 
postural hypotension and hypoglycaemia 
• 
Assessment of any adverse events (specifically genital infection as this is the 
most common side effect of empagliflozin and may present as an adverse 
reaction). 
8 
DATA COLLECTION& MANAGEMENT 
8.1 
DATA COLLECTION 
The data will be collected by the PI or delegate on a paper case report form (CRF) with 
subsequent transcription to an electronic CRF. Electronic storage will be in an 
encrypted form on a password protected device.  


                             
                         
     
 
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The medical notes will act as source data for past medical history and blood results. 
Any data relating to general medical history will be documented in the notes. 
8.2 
DATA MANAGEMENT SYSTEM  
Excel will be used as the data management system (DMS) with adherence to TASC 
SOP 48 Data Management in CTIMPs using Excel, by the trial team doing the data 
entry and analysis.  
The DMS will be based on the protocol and CRF for the trial and individual 
requirements of the investigators. Development and validation of the trial database and 
QC will be done according to TASC SOP 48.  
9 
STATISTICS AND DATA ANALYSIS 
9.1 
SAMPLE SIZE CALCULATION 
9.1.1 POWER CALCULATIONS 
Power calculations are based on our previous data in participants with CHF36-40 as well 
as more contemporary data.41 The sample size is based on the mean furosemide-
induced urinary volume (SD=250). A 20% increase is expected in this parameter 
following SGLT2 inhibition. This increase in urinary volume is based on published 
percentage increases in urinary volume in T2D patients that range from 11%-33% 
depending on the dose of the SGLT2 inhibitor as shown by List and colleagues42 in the 
available data with dapagliflozin (dapagliflozin 2.5 mg: 11% increase in 24-hr urine 
volume; dapagliflozin 5 mg: 22% 11% increase in 24-hr urine volume; dapagliflozin 10 
mg: 24% 11% increase in 24-hr urine volume; dapagliflozin 20 mg: 27% 11% increase 
in 24-hr urine volume and dapagliflozin 50 mg: 33% 11% increase in 24-hr urine 
volume). There is no data of SGLT inhibition together with loop diuretics apart from the 
previously discussed case report of a diuretic resistant HF patient in whom the fluid 
overload was successfully treated with the SGLT2 inhibitor, ipragliflozin. The authors 
reported a striking 50% increase in urinary volume (following treatment with 50 mg 
daily of oral ipragliflozin for 5 days).34 Based on the above, it was determined that a 
20% increase in furosemide induced increase in urinary volume will be reasonable. 
With an alpha 0.05 and power of 90%, 22 participants per arm are required, assuming 
35% drop out. Since this trial is using an AB/BA crossover design, a total of 34 
participants will be required, as each participant will be exposed to both arms of the 


                             
                         
     
 
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trial. The rationale for the high dropout rate, is due to the high intensity renal 
physiological tests that will occur on 4 occasions for the participants, from 0730 to 1230 
we feel that anything less than a 35% drop out rate would be conservative. 
9.2 
PROPOSED ANALYSES 
9.2.1 STATISTICAL ANALYSIS 
Participants will be allocated to treatment groups at random. Descriptive statistics will 
be calculated for all data and reported as mean (SD) for continuous data and N (%) for 
categorical data. For statistical evaluation of repeated measurements, analysis of 
variance will be used. P<0.05 will be taken as the level of statistical significance. 
A detailed statistical analysis plan will be prepared during the trial by the trial 
statistician.  
9.3 
MISSING DATA 
The primary analysis will be based on the intention-to-treat principle. The extent of 
missing data will be examined and the reason for the dropout ascertained. Multiple 
imputation may be used to impute missing values if necessary and where assumptions 
for missing at random (MAR) data are met. Complete case analysis where missing 
participants are excluded will be carried out as a secondary analysis. Pre-specified 
sub-group analyses will be completed by fitting the appropriate interaction term in the 
regression model and- if significant outcomes will be presented separately by level of 
sub-group.  
With regards to participant medication, this will be recorded at baseline and at each 
trial visit with a secondary analysis adjusting for changes in trial medications planned.  
10 ADVERSE EVENTS 
Adverse event reporting will be carried out in accordance with TASC SOP 11: 
Identifying, Recording and Reporting Adverse Events for Clinical Trials of 
Investigational Medicinal Products. The CI (or delegate) is responsible for detection 
and documentation (and reporting, where required) of adverse events.  
10.1 DEFINITIONS 
An adverse event (AE) is any untoward medical event affecting a clinical trial 
participant. Each initial AE will be considered for severity, causality or expectedness 


                             
                         
     
 
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and may be reclassified as a serious event or reaction based on prevailing 
circumstances. 
An adverse reaction (AR) is where it is suspected that an AE has been caused by a 
reaction to a trial drug. 
A serious adverse event (SAE), serious adverse reaction (SAR) or suspected 
unexpected serious adverse reaction (SUSAR) is any AE, AR or UAR that at any dose: 
• 
results in death 
• 
is life threatening  
• 
requires hospitalisation or prolongation of existing hospitalisation 
• 
results in persistent or significant disability or incapacity 
• 
is a congenital anomaly or birth defect 
• 
Or is otherwise considered serious 
Note: Hospitalisations for treatment planned prior to randomisation and hospitalisation 
for elective treatment of a pre-existing condition will not be considered as an SAE. 
However, any adverse events occurring during such hospitalisation will be recorded. 
10.2 DETECTING AES AND SAES 
The CI is responsible for the detection and documentation of events meeting the 
criteria and definitions below. 
Full details of contraindications and side effects that have been reported following 
administration of the trial drug can be found in the SmPC. Adverse reactions in 
association with empagliflozin are rare in the overall treated population and mostly of 
a minor nature. The incidence may be higher in the presence of renal and/or hepatic 
disorder.  
Common non-serious side effects are: Runny or stuffy nose; sore throat.  
Severe side effects that may occur and which immediate attention should be sought 
are: Severe allergic reactions (rash; hives; itching; difficulty breathing or swallowing; 
tightness in the chest; swelling of the mouth, face, lips, throat, or tongue; unusual 
hoarseness); fainting; fast or irregular heartbeat; increased urination; muscle 
weakness; penis discharge, redness, rash, itching, pain, or swelling; severe or 


                             
                         
     
 
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persistent headache, dizziness, or light-headedness; sluggishness; symptoms of low 
blood sugar (e.g. confusion, increased sweating, weakness, tremors, dizziness, 
fainting, drowsiness, headache, irritability, chills, fast heartbeat, vision changes, 
increased hunger); symptoms of kidney problems or urinary tract infection (e.g. blood 
in the urine, change in the amount of urine produced, difficult or painful urination, 
unusual or persistent pain in the mid to lower back, unexplained swelling); unusual 
tiredness or weakness; vaginal discharge, itching, or odour, very dry mouth or eyes. 
Participants should be instructed to contact a member of the trial team at any time after 
consenting to join the trial if any of the above symptoms develop. All reported adverse 
events (AEs) that occur after joining the trial will be recorded in detail in the CRF AE 
log. In the case of an AE, the Investigator should initiate the appropriate treatment 
according to their medical judgement. Participants with AEs present at the last visit 
must be followed up until resolution of the event.  
10.3 RECORDING AND REPORTING AES AND SAES 
All AEs and SAEs will be recorded from the time a participant consents to join the trial 
until the last trial visit.  Participants with unresolved AEs at their last trial visit will be 
followed up until resolution or 30 days after their last visit, whichever is sooner. SAEs 
and SUSARS will be followed until resolution. 
The CI or delegate will ask about the occurrence of AEs and hospitalisations at every 
visit during the trial. AEs will be recorded on the AE Log in the CRF. SAEs will be 
submitted 
on 
an 
SAE 
form 
to 
the 
TASC 
Pharmacovigilance 
Section 
(pharmacovigilance.tayside@nhs.net) within 24 hours of becoming aware of the SAE. 
SAEs will be initially assessed for causality and expectedness by the Investigator. The 
Sponsor will make the definitive assessment on expectedness. The evaluation of 
expectedness will be made based on the knowledge of the reaction and the relevant 
product information (SmPC). Refer to TASC SOP 11 “Identifying, Recording and 
Reporting Adverse Events for CTIMPs”. 
10.4 EVALUATION OF AES AND SAES. 
Seriousness, causality, severity and expectedness will be evaluated as though the 
participant is taking an active drug.  


                             
                         
     
 
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10.4.1 Assessment of Seriousness 
The CI or delegate will make an assessment of seriousness as defined in section 10.1. 
10.4.2 Assessment of Causality 
The CI or delegate will make an assessment of whether the AE is likely to be related 
to treatment according to the following definitions.  
Unrelated: where the AE is not considered to be related to the trial drug.  
Possibly: although a relationship to the trial drug cannot be completely ruled out, the 
nature of the event, underlying disease, concomitant medication or temporal 
relationship make other explanations more likely. 
Probably: the temporal relationship and absence of a more likely explanation suggest 
the event could be related to the trial drug.  
Definitely: the known effects of the trial drug or its therapeutic class, or based on 
challenge testing, suggest that the trial drug is the most likely cause.  
All AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. 
possibly, probably, definitely) to the trial drug will be considered as ARs/SARs. All 
AEs/SAEs judged as being related (e.g. possibly, probably, definitely) to an interaction 
between the trial drug and another drug will also be considered to be ARs/SARs.  
Alternative causes such as natural history of underlying disease, concomitant therapy, 
other risk factors and the temporal relationship of the event to the treatment will be 
considered. The blind will not be broken for the purpose of making this assessment.  
10.4.3 Assessment of Severity  
The CI or delegate will make an assessment of severity for each AE according to one 
of the following categories: 
Mild: an event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with every day activities.  
Moderate: an event that is sufficiently discomforting to interfere with normal everyday 
activities.  
Severe: an event that prevents normal everyday activities.  


                             
                         
     
 
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Note: the term ‘severe’, used to describe the intensity, should not be confused with 
‘serious’ which is a regulatory definition based on participant/event outcome or action 
criteria. For example, a headache may be severe by not serious, while a minor stroke 
is serious but may not be severe.  
10.4.4 Assessment of Expectedness 
If an event is judged to be an AR/SAR, the evaluation of expectedness will be made 
based on knowledge of the reaction and the relevant product information documented 
in the SmPC Section 4.8.  
ARs/SARs may be classed as either: 
Expected: The AR is consistent with the toxicity of the trial drug listed in the SmPC. 
Unexpected: The AR is not consistent with the toxicity in the SmPC. 
10.5 REPORTING OF SAES/SURS/SUSARS 
SAEs 
must 
be 
reported 
to 
the 
TASC 
Pharmacovigilance 
Section 
pharmacovigilance.tayside@nhs.net within 24 hours of the CI or delegate becoming 
aware of the event. The TASC SAE form must be completed as thoroughly as possible 
with all available details of the event and signed by the Investigator. If any of the 
information is not available at the time of reporting, the Investigator will ensure that any 
missing information is provided on a follow-up SAE form as soon as this becomes 
available. It will be indicated on the form that this information is follow-up information 
of a previously reported event.  
All SAEs must be followed up to resolution and any additional information reported to 
the TASC Pharmacovigilance Section pharmacovigilance.tayside@nhs.net using the 
TASC SAE form.  
10.6 REGULATORY REPORTING REQUIREMENTS 
The Sponsor is responsible for reporting SUSARs to the competent authority, the 
MHRA, the Research Ethics Committee (REC) and any other competent authorities. 
Fatal or life threatening SUSARs will be reported within 7 days and non-fatal and non-
life threatening SUSARs within 15 days.  


                             
                         
     
 
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10.7 ANNUAL REPORTING REQUIREMENTS 
The following reports will be submitted each year as a condition of the authorisation to 
undertake a clinical trial or as a condition of a favourable opinion from REC.  
The Development Safety Update Report (DSUR) will be prepared by the Sponsor - 
TASC Pharmacovigilance Section - and CI and submitted to the MHRA on the 
anniversary date of Clinical Trial Authorisation (CTA).  
An NRES CTIMP Safety Report Form will be sent to REC along with the DSUR. 
Reports of SUSARs in the UK, urgent safety measures and any other safety reports 
submitted, for example reports of a data monitoring committee, will also be 
accompanied by a Safety Report Form.  
A NRES Annual Progress Report for CTIMPs will be prepared and submitted by the CI 
to REC and copied to sponsor on the anniversary date of the REC favourable opinion.  
10.8 URGENT SAFETY MEASURES 
The CI or other clinician may take appropriate immediate urgent safety measures in 
order to protect the participants of a CTIMP against any immediate hazard to their 
health or safety. The MHRA, REC and Sponsor will be notified in writing within three 
days. 
11 PREGNANCY 
Pregnancy is not considered an AE or SAE, unless there is a congenital abnormality 
or birth defect. If a pregnancy occurs, the participant will be advised to stop trial 
medication immediately. The CI or delegate will collect pregnancy information for 
female trial participants who become pregnant, or female partners of male trial 
participants who become pregnant while participating in a trial.  
For female partners of male trial participants who become pregnant while participating 
in a trial, additional consent should be obtained to follow up the pregnancy.  
The CI or delegate should complete the TASC Pregnancy Notification Form and submit 
to the TASC Pharmacovigilance section pharmacovigilance.tayside@nhs.net within 14 
days of being made aware of the pregnancy.  


                             
                         
     
 
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Any pregnancy should be followed to outcome. Pregnancy follow up information must 
be recorded on the TASC Pregnancy Follow up form and submitted to the TASC 
Pharmacovigilance section.  
11.1 CONTRACEPTIVE ADVICE TO PARTICIPANTS 
Women of child bearing potential must be willing to have pregnancy testing prior to trial 
entry, prior to administration of trial medication and during trial treatment. In addition, 
women of child bearing potential, who are sexually active, must be willing to use a form 
of a medically approved birth control method 7.1 e.g.: 
• 
Combined Oral Contraceptive Pill 
• 
Placement of an intrauterine device – ‘coil’ 
• 
Barrier methods of contraception: male condom only 
• 
Established use of oral, injected, transdermal or implanted hormonal methods 
of contraception 
• 
Male partner sterilisation (followed by the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate). 
Men who are sexually active with female partners of child bearing potential will also be 
advised to use a form of medically approved birth control method as listed above.  
12 TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
12.1 TRIAL MANAGEMENT GROUP 
The trial will be co-ordinated by a Trial Management Group, consisting of the grant-
holders including the CI, the PI and the trial manager.  
12.2 TRIAL MANAGEMENT 
The PI will oversee the trial on a day-to-day basis and will be accountable to the CI. 
The PI will be responsible for checking the CRFs for completeness, plausibility and 
consistency. However, this will remain the overall responsibility of the CI. Any queries 
will be resolved by the CI or delegated member of the trial team.  
A trial-specific Delegation of Responsibilities & Signature Log will be prepared and 
maintained throughout the trial, detailing the responsibilities of each member of staff 
working on the trial.  


                             
                         
     
 
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12.3 TRIAL STEERING COMMITTEE 
The Trial Management Group (TMG) will also act as the Trial Steering Committee 
(TSC). 
12.4 DATA MONITORING COMMITTEE  
This is not considered necessary as this is a relatively small trial. Close supervision of 
the PI/Clinical Research Fellow will be conducted by an experienced Chief Investigator 
supported by a senior trial manager from the TCTU. 
12.5 INSPECTION OF RECORDS 
The CI, PI and all institutions involved in the trial will permit trial related monitoring, 
audits, REC review, and regulatory inspection(s). In the event of an audit, the CI will 
allow the Sponsor, representatives of the Sponsor or regulatory authorities direct 
access to all trial records and source documentation. 
12.6 RISK ASSESSMENT 
A trial risk assessment was carried out by the TASC Research Governance Manager 
prior to Sponsorship approval being granted. 
12.7 TRIAL MONITORING 
Trial monitoring will be in accordance with TASC SOP 03. 
The purpose of trial monitoring is to verify that: 
• 
The rights and well-being of human subjects are protected 
• 
The reported trial data are accurate, complete and verifiable from source 
documents 
• 
The conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory 
requirement(s).  
The Sponsor will determine the appropriate extent and nature of monitoring for the trial 
and will appoint appropriately qualified and trained monitors. 
The monitor will communicate any monitoring findings to both the CI and PI and the 
Sponsor.  


                             
                         
     
 
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12.7.1 Potential Risks 
Potential adverse reaction to empagliflozin are outlined in the SmPC and discussed in 
section 10.2.  
The participants will undergo venepuncture and cannulation which may cause some 
mild transient pain and bruising at the visits outlined in Appendix 1. Care will be taken 
by the doctor or nurse to minimise any distress to the participant. Needle stick injury 
during venepuncture remains a risk to the medical or nursing staff involved, and 
universal precautions will be taken. During the renal physiology tests, staff at the CRC 
will be handling urine collections, again universal precautions will be taken.  
12.7.2 Minimising Risk 
Careful monitoring of participant’s blood results throughout the trial and dedicated care 
and adverse event monitoring will be undertaken as required. Participants who are on 
contraindicated medications will be excluded and those at higher risk of adverse events 
will also be prohibited from participating, as specified in the exclusion criteria.  
13 GOOD CLINICAL PRACTICE 
13.1 ETHICAL CONDUCT OF THE TRIAL 
The trial will be conducted in accordance with the principles of good clinical practice 
(GCP). 
In addition to Sponsorship approval, a favorable ethical opinion will be obtained from 
an appropriate REC. Authorisation from an appropriate competent authority(s) and 
appropriate NHS R&D permissions(s) will be obtained prior to commencement of the 
trial. 
13.2 REGULATORY COMPLIANCE OF THE TRIAL 
Regulatory approval will be obtained from the MHRA. The protocol and trial conduct 
will comply with the Medicines for Human Use (Clinical Trials) Regulations 2004, and 
any relevant amendments.  
13.3 CI RESPOBSIBILITIES 
The CI will be responsible for the overall conduct of the trial at the site and compliance 
with the protocol and any protocol amendments. In accordance with the principles of 
GCP, the following areas listed in this section are also the responsibility of the CI. 


                             
                         
     
 
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Responsibilities may be delegated to an appropriate member of trial staff at each site. 
Delegated tasks must be documented on the Delegation Log and signed by all those 
named on the list and by the CI. The CI will supervise the clinical research fellow who 
will act as PI on the trial.  
13.3.1 Informed Consent 
The CI will be responsible for ensuring informed consents is obtained before any 
protocol specific procedures are carried out as the decision of a participant to 
participate in clinical research is voluntary and should be based on a clear 
understanding of what is involved.  
Participants will receive adequate oral and written information-appropriate Participant 
Information Sheet (PIS) and Informed Consent Form (ICF) will be provided. The oral 
explanation to the participant will be performed by the PI (research fellow) or delegate 
and will cover all the elements specified in the PIS and ICF.  
The participant will be given every opportunity to clarify any points they do not 
understand and, if necessary, ask for more information. The participant will be given 
sufficient time to consider the information provided. It will be emphasised that the 
participant may withdraw their consent to participate at any time without loss of benefits 
to which they otherwise would be entitled.  
The participant will be informed and must agree to their medical records being 
inspected by regulatory authorities, REC and monitors but it will be explained that their 
name will not be disclosed outside the trial site.  
The ICF will request permission that data collected from the participant by the 
Researcher and/or research team in this study will be used to support other research 
in the future, and may be shared anonymously with other researchers collaborating 
with the research team. The data will be stored electronically, anonymously and 
securely.  
The ICF will request permission that any tissue (referring to urine and serum samples) 
collected by the Researcher and/or research team in this study will be stored and that 
any excess may be shared anonymously with other researchers collaborating with the 
research team to support future research projects. Any residual urine or serum 
samples would be stored anonymously in the secure University of Dundee laboratory 
in the Division of Cardiovascular and Diabetes Medicine for up to 10 years.  


                             
                         
     
 
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In the sharing of tissue (in this study which would be urine and blood samples) any 
future projects would require collaboration with the researchers and would require 
scrutiny from further Research Ethics Committee review.  
The CI or delegate and the participant will sign and date the ICF to confirm that consent 
has been obtained. The participant will receive a copy of this document and a copy will 
be filed in their medical case notes and TMF as appropriate.  
13.3.2 Trial Staff  
The CI, PI and other appropriate trial staff will be familiar with the IMP, protocol and 
the trial requirements. The CI will ensure that all staff assisting with the trial are 
adequately informed and trained about the IMP, protocol and their trial related duties 
as appropriate. The CI will provide supervision of the PI, who is a research fellow on 
this trial.  
13.3.3 Data Recording 
The CI is responsible for the quality of the data recorded in the CRF.  
13.3.4 GCP Training 
All trial staff will hold evidence of appropriate valid GCP training or undergo GCP 
training and maintain this throughout the duration of the trial, in line with the TASC 
Good Clinical Practice Training Policy for Personnel Involved in Clinical Research.  
13.3.5 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified 
in a manner designed to maintain participant confidentiality. All records will be kept in 
a secure storage area with limited access to trial staff only. Clinical information will not 
be released without the written permission of the participant, except as necessary for 
monitoring and auditing by the Sponsor, its designee or Regulatory Authorities. The CI 
and trial staff involved with this trial will not disclose or use for any purpose other than 
performance of the trial, any data, record, or other unpublished, confidential 
information disclosed to those individuals for the purpose of the trial. Prior written 
agreement from the Sponsor or its designee will be obtained for the disclosure of any 
said confidential information to other parties. 


                             
                         
     
 
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13.3.6 Data Protection 
The CI and trial staff involved with this trial will comply with the requirements of the 
Data Protection Act 1998 with regard to the collection, storage, processing and 
disclosure of personal information and will uphold the Act’s core principles. The CI and 
trial staff will also adhere, if appropriate, to the current version of the NHS Scotland 
Code of Practice on Protecting Participant Confidentiality.  Access to collated 
participant data will be restricted to the CI and appropriate trial staff. 
Computers used to collate the data will have limited access measures via user names 
and passwords. 
Published results will not contain any personal data that could allow identification of 
individual participants. 
13.3.7 Insurance and Indemnity 
The University of Dundee and Tayside Health Board are Co-Sponsoring the trial. 
Insurance. – The University of Dundee will obtain and hold Professional Negligence 
Clinical Trials Insurance cover for legal liabilities arising from the trial.  
Tayside Health Board will maintain its membership of the Clinical Negligence and 
Other Risks Insurance Scheme (“CNORIS”) which covers the legal liability of Tayside 
in relation to the trial]. 
Where the trial involves University of Dundee staff undertaking clinical research on 
NHS participants, such staff will hold honorary contracts with Tayside Health Board 
which means they will have cover under Tayside’s membership of the CNORIS 
scheme. 
Indemnity. Co-Sponsors do not provide trial participants with indemnity in relation to 
participation in the Trial but have insurance for legal liability as described above. 
14 TRIAL CONDUCT RESPONSIBILITIES 
14.1 PROTOCOL AMENDMENTS 
The CI will seek Sponsor approval for any amendments to the Protocol or other trial 
documents. Amendments to the protocol or other trial docs will not be implemented 
without approval from the Sponsor and subsequent approval from the appropriate REC 


                             
                         
     
 
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and/or Regulatory Authority, as appropriate, and NHS R&D Office(s). Refer to TASC 
SOP 26 “Amendments to CTIMPs” 
14.2 PROTOCOL DEVIATIONS, BREACHES AND WAIVERS 
The CI will not implement any deviation from the protocol without agreement from the 
Sponsor, except where necessary to eliminate an immediate hazard to trial 
participants. 
In the event that the CI needs to deviate from the protocol, the nature of and reasons 
for the deviation will be recorded in the CRF, documented in a TASC Deviation & 
Breach Log and notified to the Sponsor. If this necessitates a subsequent protocol 
amendment, this will be submitted to the Sponsor for approval and then to the 
appropriate REC, Regulatory Authority and local NHS R&D for review and approvals 
as appropriate. It is Sponsor policy that waivers to the Protocol will not be approved. 
In the event that a serious breach of the protocol or GCP is suspected, this will be 
reported to the Sponsor immediately using the form “Notification to Sponsor of 
Potential Serious Breach or Serious Deviation”. Refer to TASC SOP 25 “Escalation 
and Notification of Serious Breaches of GCP or the Trial Protocol for CTIMPs”.  
14.3 TRIAL RECORD RETENTION 
Archiving of trial documents will be carried out as specified in TASC SOP 13: Archiving 
Clinical Research Data for Clinical Trials of Investigational Medicinal Products, (unless 
otherwise agreed with the Sponsor and by contract). As the data from this trial does 
not form part of an application for a Marketing Authorisation (MA) all trial 
documentation, including medical case notes, will be kept for at least 5 years.  
14.4 END OF TRIAL 
The end of trial is defined as last participant last visit (LPLV). The Sponsor and, CI 
have the right at any time to terminate the trial for clinical or administrative reasons.  
The end of the trial will be reported to the Sponsor, REC, Regulatory Authority and 
NHS R&D Office(s) within 90 days, or 15 days if the trial is terminated prematurely. 
The CI will ensure that any appropriate follow up is arranged for all participants. 
A final report of the trial will be provided to the Sponsor, REC and Regulatory Authority 
within 1 year of the end of the trial. 


                             
                         
     
 
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14.5 CONTINUATION OF DRUG FOLLOWING THE END OF TRIAL 
This is not appropriate since confirmatory studies are necessary before guidelines for 
this condition would recommend this particular therapy.  
15 REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS 
15.1 AUTHORSHIP POLICY 
Ownership of the data arising from this trial resides with the trial team and their 
respective employers. On completion of the trial, the trial data will be analysed and 
tabulated, and a clinical trial report will be prepared.  
15.2 PUBLICATION 
The clinical trial report will be used for publication and presentation at scientific 
meetings. Trial investigators have the right to publish orally or in writing the results of 
the trial. Summaries of results will also be made available to Investigators for 
dissemination within their clinical areas (where appropriate and according to their 
discretion). 
15.3 PEER REVIEW 
This trial has been funded by the British Heart Foundation who have peer reviewed the 
grant application. Additional peer review of the protocol occurs via the Sponsorship 
Committee. Resulting publications will be reviewed by the referees of the journal to 
which the paper (and its protocol) will be submitted.  
 
 


                             
                         
     
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 48 of 55 
16 REFERENCES 
1. 
MacDonald MR, Petrie MC, Hawkins NM, Petrie JR, Fisher M, McKelvie R, Aguilar D, 
Krum H and McMurray JJ. Diabetes, left ventricular systolic dysfunction, and chronic heart 
failure Eur Heart J England; 2008(29): 1224-40. 
2. 
Deswal A, Petersen NJ, Souchek J, Ashton CM and Wray NP. Impact of race on health 
care utilization and outcomes in veterans with congestive heart failure. Journal of the 
American College of Cardiology. 2004;43:778-784. 
3. 
Rathore Ss FJMWY and et al. RAce, quality of care, and outcomes of elderly patients 
hospitalized with heart failure. Jama. 2003;289:2517. 
4. 
Murcia AM, Hennekens CH, Lamas GA, Jimenez-Navarro M, Rouleau JL, Flaker GC, 
Goldman S, Skali H, Braunwald E and Pfeffer MA. Impact of diabetes on mortality in patients 
with myocardial infarction and left ventricular dysfunction. Arch Intern Med. 2004;164:2273-
9. 
5. 
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, 
Tsapas A, Wender R and Matthews DR. Management of hyperglycemia in type 2 diabetes: a 
patient-centered approach: position statement of the American Diabetes Association (ADA) 
and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-
79. 
6. 
Krum H, Jelinek MV, Stewart S, Sindone A and Atherton JJ. 2011 update to National 
Heart Foundation of Australia and Cardiac Society of Australia and New Zealand Guidelines for 
the prevention, detection and management of chronic heart failure in Australia, 2006. Med J 
Aust. 2011;194:405-9. 
7. 
Evans JMM, Doney ASF, Al Zadjali MA, Ogston SA, Petrie JR, Morris AD, Struthers AD, 
Wong AKF and Lang CC. Effect of Metformin on Mortality in Patients With Heart Failure and 
Type 2 Diabetes Mellitus. The American Journal of Cardiology. 2010;106:1006-1010. 
8. 
Andersson C, Olesen JB, Hansen PR, Weeke P, Norgaard ML, Jørgensen CH, Lange T, 
Abildstrøm SZ, Schramm TK, Vaag A, Køber L, Torp-Pedersen C and Gislason GH. Metformin 
treatment is associated with a low risk of mortality in diabetic patients with heart failure: a 
retrospective nationwide cohort study. Diabetologia. 2010;53:2546-2553. 
9. 
Forst T, Hanefeld M, Jacob S, Moeser G, Schwenk G, Pfützner A and Haupt A. 
Association of sulphonylurea treatment with all-cause and cardiovascular mortality: A 
systematic review and meta-analysis of observational studies. Diabetes and Vascular Disease 
Research. 2013;10:302-314. 
10. 
Eurich DT, McAlister FA, Blackburn DF, Majumdar SR, Tsuyuki RT, Varney J and 
Johnson JA. Benefits and harms of antidiabetic agents in patients with diabetes and heart 
failure: systematic review. BMJ. 2007;335:497. 
11. 
Smooke S, Horwich TB and Fonarow GC. Insulin-treated diabetes is associated with a 
marked increase in mortality in patients with advanced heart failure Am Heart J United States; 
2005(149): 168-74. 
12. 
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, 
Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mozenson O, McGuire 
DK, Ray KK, Leiter LA and Raz I. Saxagliptin and Cardiovascular Outcomes in Patients with Type 
2 Diabetes Mellitus. N Engl J Med. 2013. 
13. 
Thomas L, Grempler R, Eckhardt M, Himmelsbach F, Sauer A, Klein T, Eickelmann P 
and Mark M. Long-term treatment with empagliflozin, a novel, potent and selective SGLT-2 
inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats. 
Diabetes, Obesity and Metabolism. 2012;14:94-96. 


                             
                         
     
 
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14. 
Mudaliar S, Henry RR, Boden G, Smith S, Chalamandaris AG, Duchesne D, Iqbal N and 
List J. Changes in insulin sensitivity and insulin secretion with the sodium glucose 
cotransporter 2 inhibitor dapagliflozin. Diabetes Technol Ther. 2014;16:137-44. 
15. 
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins 
T, Johansen OE, Woerle HJ, Broedl UC and Inzucchi SE. Empagliflozin, Cardiovascular 
Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117-28. 
16. 
Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in 
patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG 
OUTCOME(R) trial. Eur Heart J. 2016;37(19):1526-1534. doi:10.1093/eurheartj/ehv728. 
17. 
Ravnan SL, Ravnan MC and Deedwania PC. Pharmacotherapy in congestive heart 
failure: diuretic resistance and strategies to overcome resistance in patients with congestive 
heart failure. Congest Heart Fail. 2002;8:80-5. 
18. 
Neuberg GW, Miller AB, O'Connor CM, Belkin RN, Carson PE, Cropp AB, Frid DJ, Nye 
RG, Pressler ML, Wertheimer JH and Packer M. Diuretic resistance predicts mortality in 
patients with advanced heart failure. Am Heart J. 2002;144:31-8. 
19. 
Cox ZL and Lenihan DJ. Loop diuretic resistance in heart failure: resistance etiology-
based strategies to restoring diuretic efficacy. J Card Fail. 2014;20:611-22. 
20. 
Jentzer JC, DeWald TA and Hernandez AF. Combination of loop diuretics with thiazide-
type diuretics in heart failure. J Am Coll Cardiol. 2010;56:1527-34. 
21. 
De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G and Minutolo R. 
Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting 
the renal tubule in diabetes. Am J Kidney Dis. 2014;64:16-24. 
22. 
Thomas MC. Renal effects of dapagliflozin in patients with type 2 diabetes. 
Therapeutic Advances in Endocrinology and Metabolism. 2014. 
23. 
Škrtic M and Cherney DZI. Sodium–glucose cotransporter-2 inhibition and the 
potential for renal protection in diabetic nephropathy. Current Opinion in Nephrology and 
Hypertension. 2015;24:96-103. 
24. 
Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle 
HJ, Johansen OE, Broedl UC and von Eynatten M. Renal Hemodynamic Effect of Sodium-
Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus. Circulation. 
2014;129:587-597. 
25. 
Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B and List J. Dapagliflozin a glucose-
regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes 
Metab. 2013;15:853-62. 
26. 
Majewski C and Bakris GL. Blood pressure reduction: an added benefit of sodium-
glucose cotransporter 2 inhibitors in patients with type 2 diabetes. Diabetes Care. 
2015;38:429-30. 
27. 
Heise T, Seewaldt-Becker E, Macha S, Hantel S, Pinnetti S, Seman L and Woerle HJ. 
Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment 
with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 
2013;15:613-21. 
28. 
Bebawy JF, Ramaiah VK, Zeeni C, Hemmer LB, Koht A and Gupta DK. The effect of 
furosemide on intravascular volume status and electrolytes in patients receiving mannitol: an 
intraoperative safety analysis. J Neurosurg Anesthesiol. 2013;25:51-4. 
29. 
Sirivella S, Gielchinsky I and Parsonnet V. Mannitol, furosemide, and dopamine 
infusion in postoperative renal failure complicating cardiac surgery. Ann Thorac Surg. 
2000;69:501-6. 


                             
                         
     
 
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30. 
Turagam MK, Velagapudi P, Kalra AS, Ramalingam VS, Sinnakirouchenan R and Holley 
JL. Outcomes of furosemide-mannitol infusion in hospitalized patients with heart failure: 
An observational single-center cohort study of 122 patients. International Journal of 
Cardiology. 151:232-234. 
31. 
Ptaszynska A CA, Sugg JE, Johnsson KM, Parikh S, List JL. Effect of 
dapagliflozin on renal function. 2012. 
32. 
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):323-334. 
doi:10.1056/NEJMoa1515920. 
33. 
McMurray J. EMPA-REG - the "diuretic hypothesis". J Diabetes Complications. 
2015. 
34. 
Sairaku A, Nakano Y and Kihara Y. Increased urine output by ipragliflozin in a non-
diabetic patient with a diuretic-resistant heart failure. Int J Cardiol. 2015;180:42-3. 
35. 
Macha S, Sennewald R, Rose P, Schoene K, Pinnetti S, Woerle HJ and Broedl UC. Lack 
of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose 
cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers. Clin Ther. 
2013;35:226-35. 
36. 
Nguyen MK and Kurtz I. Derivation of a new formula for calculating urinary electrolyte-
free water clearance based on the Edelman equation. American Journal of Physiology - Renal 
Physiology. 2004;288:F1-F7. 
37. 
Lang CC, Choy AM, Rahman AR and Struthers AD. Renal effects of low dose prazosin 
in patients with congestive heart failure. Eur Heart J. 1993;14:1245-52. 
38. 
Lang CC, Rahman AR, Balfour DJ and Struthers AD. Prazosin blunts the antinatriuretic 
effect of circulating angiotensin II in man. J Hypertens. 1992;10:1387-95. 
39. 
Lang CC, Choy AM, Balfour DJ and Struthers AD. Prazosin attenuates the natriuretic 
response to atrial natriuretic factor in man. Kidney Int. 1992;42:433-41. 
40. 
Sturrock ND, Lang CC, Baylis PH and Struthers AD. Sequential effects of cyclosporine 
therapy on blood pressure, renal function and neurohormones. Kidney Int. 1994;45:1203-10. 
41. 
Goldsmith SR, Gilbertson DT, Mackedanz SA and Swan SK. Renal effects of conivaptan, 
furosemide, and the combination in patients with chronic heart failure. J Card Fail. 
2011;17:982-9. 
42. 
List JF, Woo V, Morales E, Tang W and Fiedorek FT. Sodium-Glucose Cotransport 
Inhibition With Dapagliflozin in Type 2 Diabetes. Diabetes Care. 2009;32:650-657. 


                                                                  
                                                                     
 
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 51 of 55 
17 APPENDIX 1: TRIAL SCHEDULE 
Visit 
Visit 1* 
Screening 
Visit 2* 
Baseline/ 
Randomisation 
Visit 3 Visit 4 
(Tele 
Visit) 
Visit 5 
Two week 
wash-out 
period 
Visit 6 
Visit 7 
Visit 8 
(Tele 
Visit) 
Visit 9 
**** 
Visit 10 
(Final 
visit) 
 
Up to 4 
weeks pre 
visit 2 
Day 0 
Day 3  
(+/-2 
days) 
Week 3 
(+/- 3 
days) 
Week 6 
(+/- 3 
days) 
 
Week 9 
(+/- 3 
days) 
Week 9 + 3 
days (+/- 2 
days) 
Week 12 
(+/- 3 
days) 
Week 15 
(+/- 3 
days) 
Week 
19 (+/- 
7 days) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inc./Exc. Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
PMH 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Clinical examination 
X 
 
 
 
 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Vital Signs – blood pressure 
& pulse 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Safety Bloods 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
HbA1c 
X 
 
 
 
X 
 
X 
 
 
X 
 
Research Bloods 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
Genetic Blood Sample 
 
X 
 
 
 
 
 
 
 
 
 
Additional blood sample 
 
X 
 
 
X 
 
X 
 
 
X 
 
Urine sample 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 


                                                                  
                                                                     
 
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 52 of 55 
Urine 
Pregnancy 
Test 
(WoCBP) 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Ask 
if 
participant 
is 
pregnant (WoCBP) 
 
 
 
X 
 
 
 
 
X 
 
 
24 hour urinary collection  
 
 
X 
 
X 
 
 
X 
 
X 
 
Renal Physiology Test 
 
 
X 
 
X 
 
 
X 
 
X 
 
Drug Dispensing 
 
X 
 
 
 
 
X 
 
 
 
 
AE assessment 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Record/Review Con Meds 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Drug Compliance Check 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
*Visits 1 and Visits 2 combined into one visit where participant is able to stay for results of safety blood tests. 
Clinical examination: This will include examination for dehydration via examination of the cardiovascular system including capillary refill, jugular 
venous pressure and the presence/absence of oedema 
Safety Blood sample:   U&Es including bicarbonate, LFTs, Glucose, Magnesium, Calcium and Phosphate, Cholesterol, Urate and FBC 
Research blood Sample: NT-proBNP, Cystatin C 
Genetic Blood Sample: only to be taken if participant consent given. 
Additional blood sample: for research purposes, will be stored anonymously for future research use for up to 10 years at the University 
of Dundee, only to be taken if participant consent given. 
Urine sample: for protein/creatinine ration and albumin/creatinine ratio 


                                                                  
                                                                     
 
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 53 of 55 
24 hour urinary collection: Participant will complete this in the 24 hours before visit and bring to visit. 
Renal Physiological test: described in Appendix 2 
Visit 9**** - if the participant wishes to withdraw prematurely or at the PI’s discretion, all trial procedures will be conducted as though the final 
visit, if participant agrees.  
 
 
 
 
 
 
 
 


                                                                  
                                                                     
 
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 54 of 55 
18 APPENDIX 2: TRIAL DAY TIMELINE 
- 2 days pre-trial day: 2gram sodium and 2L/day controlled diet (food diary) 
- 1 day: 24 urinary collection 
 
Interval 
(minutes) 
Urine 
 
Blood 
 
- 
30 
 
 
 
Arrives fasted. 2 x cannula sited 
- 
15 
 
 
 
15mls/kg oral water load over 15 minutes 
0 
 
 
 
 
+ 30 
Void urine. Water intake equal to urine 
volume.  
 
 
 
+ 60 
Void urine. Water intake equal to urine 
volume 
 
 
 
+ 90 
Void urine. Water intake equal to urine 
volume.  
 
 
 
+ 105 
 
 
 
Bloods (serum B1) for 
U&Es & osmolality 
 
+ 120 
Void urine. Water intake equal to urine 
volume. Collect urine (urine B1) for 
volume, 
sodium, 
creatinine 
& 
osmolality.  
B1  
(90-120 mins) 
 
 
+ 135 
 
 
Bloods (serum B2) for 
U&Es & osmolality 
 
+ 150 
Void urine. Water intake equal to urine 
volume. Collect urine (urine B2) for 
volume, sodium, creatinine & osmolality 
B2 
(120-150 mins) 
 
IMP 
administered: 
Oral 
tablet 
(empagliflozin 25mg or placebo) 


                                                                  
                                                                     
 
 
RECEDE-CHF Trial Protocol Version 4.0 22/01/2018                                           Page 55 of 55 
+ 165 
 
D1 
(150-180 mins) 
Bloods (serum D1) for 
U&Es & osmolality 
 
+ 180 
Void urine. Water intake equal to urine 
volume. Collect urine for volume, 
sodium, creatinine & osmolality 
 
 
 
+ 195 
 
D2 
(180-210 mins) 
Bloods (serum D2) for 
U&Es & osmolality 
 
+ 210 
Void urine. Water intake equal to urine 
volume. Collect urine for volume, 
sodium, creatinine & osmolality 
 
 
IV 
Frusemide 
administered: 
half 
participant’s screening dose 
+ 225 
 
F1 
(210 – 240 mins) 
Bloods (serum F1) for 
U&Es & osmolality 
 
+ 240 
Void urine. Water intake equal to urine 
volume. Collect urine for volume, 
sodium, creatinine & osmolality 
 
 
 
+ 255 
 
F2 
(240-270 mins) 
Bloods (serum F2) for 
U&Es & osmolality 
 
+ 270 
Collect urine for volume, sodium, 
creatinine & osmolality.  
 
 
END OF STUDY PERIOD 
 
 

SAP_001.pdf: 
REnal and Cardiovascular Effects of SGLT2 inhibition in 
combination with loop DiurEtics in diabetic participants with 
Chronic Heart Failure 
CCTU/TPL007V1 Approved 06/09/2011 
 
Statistical Analysis Plan 
 
 
 
 
 
 
TRIAL FULL TITLE 
REnal and Cardiovascular Effects of SGLT2 inhibition in 
combination with loop DiurEtics in diabetic participants with 
Chronic Heart Failure: RECEDE-CHF trial 
EUDRACT NUMBER 
2016-003968-39 
SAP VERSION 
1.0 
SAP VERSION DATE 
November 2018 
TRIAL STATISTICIAN 
Dr Natalie A. Mordi 
TRIAL CHIEF INVESTIGATOR 
Prof. Chim C. Lang 
SAP AUTHOR 
Dr Natalie A. Mordi  
 
 
 
 


Statistical Analysis Plan: RECEDE-CHF trial   
SAP version 1.0: RECEDE-CHF 
November 2018 
Page 2 of 20 
 
1 Table of Contents 
 
1 
Table of Contents ............................................................................................. 2 
2 
Abbreviations and Definitions ........................................................................... 3 
3 
Introduction ...................................................................................................... 5 
3.1 
Preface ....................................................................................................... 5 
3.2 
Purpose of the analyses .............................................................................. 5 
4 
Study Objectives and Endpoints ........................................................................ 6 
4.1 
Study Objectives ......................................................................................... 6 
4.2 
Endpoints ................................................................................................... 6 
5 
Study Methods .................................................................................................. 7 
5.1 
General Study Design and Plan ................................................................... 7 
5.2 
Inclusion-Exclusion Criteria and General Study Population ......................... 7 
5.3 
Randomisation and Blinding ....................................................................... 7 
5.4 
Study Variables ........................................................................................... 9 
6 
Sample Size .................................................................................................... 11 
7 
General Considerations ................................................................................... 11 
7.1 
Timing of Analyses ................................................................................... 11 
7.2 
Analysis Populations ................................................................................. 12 
7.3 
Covariates and Subgroups ........................................................................ 12 
7.4 
Missing Data ............................................................................................ 12 
8 
Summary of Study Data ................................................................................... 13 
8.1 
Subject Disposition ................................................................................... 13 
8.2 
Protocol Deviations .................................................................................. 14 
8.3 
Demographic and Baseline Variables ........................................................ 15 
8.4 
Concurrent Illnesses and Medical Conditions ............................................ 16 
8.5 
Prior and Concurrent Medications ............................................................. 16 
8.6 
Treatment Compliance ............................................................................. 16 
9 
Efficacy Analyses ......................................................................................... 16 


Statistical Analysis Plan: RECEDE-CHF trial   
SAP version 1.0: RECEDE-CHF 
November 2018 
Page 3 of 20 
 
9.1 
Primary Efficacy Analysis .......................................................................... 17 
9.2 
Secondary Efficacy Analyses ..................................................................... 17 
10 
Safety Analyses ............................................................................................ 18 
10.1 Adverse Events ......................................................................................... 18 
10.2 Deaths, Serious Adverse Events and other Significant Adverse Events ....... 18 
10.3 Pregnancies .............................................................................................. 18 
10.4 Clinical Laboratory Evaluations ................................................................. 19 
10.5 Other Safety Measures .............................................................................. 19 
11 
Reporting Conventions ................................................................................ 19 
12 
Technical Details ......................................................................................... 19 
13 
References ................................................................................................... 19 
 
2 Abbreviations and Definitions 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AR 
Adverse Reaction 
BNP 
Brain Natriuretic Peptide 
BP 
Blood Pressure 
CHF 
Chronic Heart Failure 
CI 
Chief Investigator 
CRC 
Clinical Research Centre 
CRF 
Case Report Form 
CTIMP 
Clinical Trials of Investigational Medicinal Product 
DM 
Diabetes Mellitus 
ECG 
Electrocardiogram 
eGFR 
Estimated Glomerular Filtration Rate 


Statistical Analysis Plan: RECEDE-CHF trial   
SAP version 1.0: RECEDE-CHF 
November 2018 
Page 4 of 20 
 
FBC 
Full Blood Count 
GCP 
Good Clinical Practice 
GP 
General Practitioner  
HbA1c 
Glycated Haemoglobin 
HF 
Heart Failure 
HIC 
Health Informatics Centre 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ISF 
Investigator Site File 
LFTs 
Liver Function Tests 
LPLV 
Last Participant Last Visit 
LVSD 
Left Ventricular Systolic Dysfunction 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
NYHA 
New York Heart Association 
PI 
Principal Investigator 
PSF 
Pharmacy Site File 
QC 
Quality Control 
R&D 
Research & Development 
REC 
Research Ethics Committee 
RPT 
Renal Physiological Test 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Standard Deviation 


Statistical Analysis Plan: RECEDE-CHF trial   
SAP version 1.0: RECEDE-CHF 
November 2018 
Page 5 of 20 
 
SDRN 
Scottish Diabetes Research Network 
SGLT2 
Sodium-Glucose co-Transporter-2 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T2D 
Type 2 Diabetes 
TASC 
Tayside Medical Sciences Centre 
TCTU 
Tayside Clinical Trials Unit 
TG 
Tubulo-glomerular 
TMF 
Trial Master File 
U&Es 
Urea & Electrolytes 
UAR 
Unexpected Adverse Reaction 
UoD 
University of Dundee 
 
3 Introduction 
3.1 Preface 
Sodium-Glucose co-Transporter-2 (SGLT2) inhibitors, the newest class of anti-
diabetic drugs, may have additional beneficial cardio-renal effects in participants 
with concomitant Type 2 Diabetes Mellitus (DM) and Chronic Heart Failure (CHF). 
SGLT2 inhibitors have an osmotic diuretic effect by reducing sodium and glucose 
absorption in the proximal tubules of the nephrons. We hypothesize that these effects 
could potentially be beneficial in treatment of participants with HF who are prone to 
sodium and fluid retention. 
3.2 Purpose of the analyses 
The purpose of these analyses were to assess the efficacy and safety of empagliflozin 
25 mg in comparison with the placebo and were included in the clinical study report. 


Statistical Analysis Plan: RECEDE-CHF trial   
SAP version 1.0: RECEDE-CHF 
November 2018 
Page 6 of 20 
 
4 Study Objectives and Endpoints 
4.1 Study Objectives 
The primary aim/objective was to assess whether empagliflozin (SGLT2 Inhibitor) can 
augment the diuretic effect of loop diuretics in diabetic participants with mild CHF 
with left ventricular systolic dysfunction (LVSD), as measured by urinary volume, when 
compared to placebo. 
The secondary aims/objectives were to assess the effect of empagliflozin (SGLT2 
inhibitor) on natriuresis when used with loop diuretics in diabetic patients with mild 
CHF with LVSD as measured by urinary sodium excretion, to measure the safety of 
add-on SGLT2 inhibitor therapy versus placebo on top of loop diuretics as measured 
by serum creatinine and estimated glomerular filtration rate (eGFR), to assess effects 
of empagliflozin on protein/creatinine ratio, albumin/creatinine ratio and on the 
renal biomarker, cystatin C.  
4.2 Endpoints 
The primary outcome for this trial was: 
• 
To assess the effect of empagliflozin versus placebo on urine output  
The secondary outcomes for this trial were: 
• 
To assess the effect of empagliflozin versus placebo on urinary sodium 
excretion 
• 
To assess the change in glomerular filtration rate (safety endpoint) 
• 
To assess the change in creatinine (safety endpoint) 
• 
To assess the effect of empagliflozin on protein/creatinine ratio  
• 
To assess the effect of empagliflozin on albumin/creatinine ratio 
• 
To assess the effect of empagliflozin on the renal biomarker, cystatin C. 


Statistical Analysis Plan: RECEDE-CHF trial   
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November 2018 
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5 Study Methods 
5.1 General Study Design and Plan 
The RECEDE-CHF Trial is a single centre randomised, double-blind, placebo-
controlled, crossover trial conducted in NHS Tayside to compare the SGLT2 inhibitor 
empagliflozin 25 mg, to placebo. Participants were randomised to treatment 1, 
empagliflozin 25 mg/placebo at week 1 for 6 weeks. Then following a two week 
washout period were randomised to treatment 2, placebo/empagliflzoin 25 mg for a 
further 6 weeks. Renal physiology test days (RPTs) were performed in the first week 
and the last week of both treatment arms.  
 
 
5.2 Inclusion-Exclusion Criteria and General Study Population 
Participants were eligible if they were: 
• 
Aged 18 to 80 years with previously diagnosed Type 2 Diabetes Mellitus 
• 
Diagnosed with NYHA Functional class II-III HF with prior echocardiographic 
evidence of LVSD 
• 
On stable doses of furosemide, or alternative loop diuretic for at least one 
month. 
• 
eGFR ≥ 45 ml/min 
• 
Had stable HF symptoms for at least three months prior to consent 


Statistical Analysis Plan: RECEDE-CHF trial   
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November 2018 
Page 8 of 20 
 
• 
Had stable HF therapy for at least three months prior to consent 
• 
Had not been hospitalised for HF for at least three months prior to consent  
• 
Women of childbearing potential* (WoCBP) must agree to take precautions to 
avoid pregnancy throughout the trial and for 4 weeks after intake of the last 
dose. 
Participants were excluded if they: 
• 
Had a diagnosis of chronic liver disease and/or liver enzymes that are twice 
the upper limit of normal 
• 
Systolic BP of <95mmHg at screening visit 
• 
HbA1c < 6.0% 
• 
were on thiazide diuretics 
• 
were receiving renal dialysis 
• 
had previously had an episode of diabetic ketoacidosis 
• 
had type 1 diabetes mellitus 
• 
had malignancy (receiving active treatment) or other life threatening disease  
• 
were pregnant or lactating women 
• 
had difficulty in micturition e.g. severe prostate enlargement 
• 
had allergy to any SGLT2 inhibitor or lactose or galactose intolerance 
• 
had any past or current treatment with any SGLT2 inhibitor 
• 
had participated in any other clinical interventional trial of an investigational 
medicinal product within 30 days 
• 
were unable to give informed consent 
• 
Any other reason considered by the physician to be inappropriate for inclusion 


Statistical Analysis Plan: RECEDE-CHF trial   
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5.3 Randomisation and Blinding 
Participants 
were 
randomised 
to 
either 
empagliflozin 
25mg/placebo 
or 
placebo/empagliflozin 25 mg in a double blind fashion in this crossover study. 
The double blind medication (empagliflozin or placebo) was prepared, packaged and 
labelled by Tayside Pharmaceuticals. Randomisation was carried out by Tayside 
Pharmaceuticals, using block randomisation using a validated randomisation 
programme, and will securely backup both the randomisation seed and the 
randomisation 
allocation. 
Tayside 
Pharmaceuticals 
use 
www.Randomization.com to generate the randomisation lists which they then apply 
when labelling and packing IMP. This is not specifically named in the Protocol or the 
Technical Agreement, however it is mentioned in TASC SOP 40 as an example of 
sources for Randomisation lists. The Clinical Trials Pharmacy, Ninewells Hospital was 
provided with a copy of the randomisation allocation for the purposes of 24h 
emergency unblinding. 
5.4 Study Variables 
The primary end point was analysed as the total volume of urine from the 24 hour 
urine collection at the end of treatment.  
 


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Visit 
Visit 1* 
Screening 
Visit 2* 
Baseline/ 
Randomisation 
Visit 3 
Visit 4 
(Tele 
Visit) 
Visit 5 
Two week 
wash-out 
period 
Visit 6 
Visit 7 
Visit 8 
(Tele 
Visit) 
Visit 9 
**** 
Visit 10 
(Final 
visit) 
 
Up to 4 
weeks pre 
visit 2 
Day 0 
Day 3  
(+/-2 
days) 
Week 3 
(+/- 3 
days) 
Week 6 
(+/- 3 
days) 
 
Week 9 
(+/- 3 
days) 
Week 9 + 3 
days (+/- 2 
days) 
Week 12 
(+/- 3 
days) 
Week 15 
(+/- 3 
days) 
Week 
19 (+/- 7 
days) 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
Vital Signs – blood pressure & 
pulse 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Safety Bloods 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
HbA1c 
X 
 
 
 
X 
 
X 
 
 
X 
 
Research Bloods 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
Urine sample 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
24 hour urinary collection  
 
 
X 
 
X 
 
 
X 
 
X 
 
Renal Physiology Test 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
Table 1: Trial schedule for RECEDE-CHF


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6 Sample Size  
Power calculations were based on our previous data in participants with CHF1-5 as 
well as more contemporary data.6 The sample size was based on the mean 
furosemide-induced urinary volume (SD=250). A 20% increase is expected in this 
parameter following SGLT2 inhibition. This increase in urinary volume is based on 
published percentage increases in urinary volume in T2D patients that range from 
11%-33% depending on the dose of the SGLT2 inhibitor as shown by List and 
colleagues7 in the available data with dapagliflozin (dapagliflozin 2.5 mg: 11% 
increase in 24-hr urine volume; dapagliflozin 5 mg: 22% 11% increase in 24-hr urine 
volume; dapagliflozin 10 mg: 24% 11% increase in 24-hr urine volume; dapagliflozin 
20 mg: 27% 11% increase in 24-hr urine volume and dapagliflozin 50 mg: 33% 11% 
increase in 24-hr urine volume). There is no data of SGLT2 inhibition together with 
loop diuretics apart from a case report of a diuretic resistant HF patient in whom the 
fluid overload was successfully treated with the SGLT2 inhibitor, ipragliflozin. The 
authors reported a striking 50% increase in urinary volume (following treatment with 
50 mg daily of oral ipragliflozin for 5 days).8 Based on the above, it was determined 
that a 20% increase in furosemide induced increase in urinary volume was reasonable. 
With an alpha 0.05 and power of 90%, 22 participants per arm are required, assuming 
35% drop out. Since this trial is using an AB/BA crossover design, a total of 34 
participants was required, as each participant was exposed to both arms of the trial. 
The rationale for the high dropout rate, was due to the high intensity renal 
physiological tests that will occur on 4 occasions for the participants, from 0830 to 
1330 we feel that anything less than a 35% drop out rate would be conservative. 
7 General Considerations 
7.1 Timing of Analyses 


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The final analysis was performed when all the randomised subjects had completed 
visit 10 or dropped out prior to visit 10. The final analysis was performed on data 
transferred to the file RECEDE Master Spreadsheet having been documented as 
meeting the cleaning and approval requirements of SOP32 and after the finalisation 
and approval of this SAP document.  
7.2 Analysis Populations 
The full analysis population was an intention to treat analysis, including all subjects 
who were randomised and received any study drug after consent.  
The safety population was all subjects who received any study treatment (including 
control) but excluding subjects who drop out prior to receiving any treatment. 
Prior to breaking the blind, each subject’s inclusion or exclusion status with regard 
to each analysis population was established. The exact process for assigning the 
statuses was defined and documented prior to breaking the blind along with any 
predefined reasons for eliminating a subject from a particular population. 
7.3 Covariates and Subgroups 
Covariates that may have an influence on the end points listed include gender, BMI, 
age 
and 
treatment 
order 
received 
i.e. 
placebo/empagliflozin 
versus 
empagliflozin/placebo. As the study is a crossover in design, the treatment order was 
included in the initial analysis as a covariate to ascertain if the intervention being 
investigated has a sustained effect on the primary outcome despite the 2 week 
washout period. These demographic subgroups were analysed for different 
treatments effects (for example comparison of effects by age, gender, BMI and 
treatment order). Where possible forest plot figures were used to communicate the 
relevant information about possible subgroup effects and interactions.  
7.4 Missing Data 


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Missing values represent a potential source of bias in a clinical trial. Therefore every 
effort should be undertaken to fulfil all requirements of the protocol concerning the 
collection and management of data. The extent of the missing data was examined 
and the reason for drop-out ascertained. Multiple imputation was used to impute 
missing values where necessary and where assumptions for missing at random (MAR) 
data were met.  
8 Summary of Study Data 
All continuous variables were summarised using the following descriptive 
statistics: n (non-missing sample size), mean, standard deviation, median, 
maximum and minimum. The frequency and percentages (based on the non-
missing sample size) of observed levels were reported for all categorical 
measures. In general, all data were listed, sorted by site, treatment and subject, 
and when appropriate by visit number within subject. All summary tables were 
structured with a column for each treatment in the order (Intervention, Control) 
and was annotated with the total population size relevant to that table/treatment, 
including any missing observations. 
Baseline characteristics for patients are: age, gender, past medical history, BMI, 
smoking history, blood pressure, HbA1c, eGFR, medication classes, severity of heart 
failure as identified by the ejection fraction (mild, moderate or severe), and 
medication classes.  
Concurrent illnesses and medical conditions were recorded and listed but not 
analysed.  
Patient medication was recorded at baseline and at each study visit. Anti-diabetic, 
diuretic and anti-hypertensive drug classes were reported.  
8.1 Subject Disposition 


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From the CRF it was established how many subjects reached what stage of the trial, 
how many dropped out and for what reasons (death, toxicity, treatment failure, 
withdrew consent). It was therefore identified the number screened, randomised, 
completed treatment 1, completed treatment 2, and ultimately how many completed 
the study. 
8.2 Protocol Deviations 


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Specific protocol deviations that could impact the analysis of the trial include those 
entered into the study even though the subject did not satisfy the entry criteria, the 
development of withdrawal criteria during the study but were not withdrawn, or those 
who received the wrong treatment or incorrect dose.  
8.3 Demographic and Baseline Variables 
Demographic variables that were recorded at the screening visit prior to 
randomisation were: 
• 
Age 
• 
Gender 
• 
Concurrent Illnesses and Medical Conditions 
• 
BMI 
• 
Smoking history  
• 
Alcohol intake (units/week) 
• 
Severity of heart failure as identified by the ejection fraction (mild, moderate 
or severe) on echocardiogram 
• 
Medication classes 
All baseline variables that were recorded at the screening visit prior to randomisation 
include: 
• 
blood pressure 
• 
pulse 
• 
weight 
• 
BMI  


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• 
HbA1c 
• 
eGFR 
• 
Serum creatinine 
• 
Urine Protein/Creatinine Ratio 
• 
Urine Albumin/Creatinine Ratio 
8.4 Prior and Concurrent Medications 
Patient medication was recorded at baseline and at each study visit. Anti-diabetic, 
diuretic and anti-hypertensive drug classes were reported.  
8.5 Treatment Compliance 
The calculation of adherence was performed and reported as a percentage, were the 
number of tablets issued minus the number of drugs returned, was then divided by 
the number of drugs that should have been taken. This was performed by the PI at 
visit 3 and visit 7, and by the Pharmacy department at visit 5 and visit 9. 
Adherence of 80-120% will be deemed as being compliant. Where an issue of non-
compliance was evident, a sensitivity analysis was performed and adherence was 
included as a covariant.  
9 Efficacy Analyses 
Efficacy analysis was performed on the intention to treat population as defined in 
section 7.2.  
Data for continuous outcome measures were assessed for normality prior to analysis. 
Transformation of the outcome variables was used where necessary were these were 
not normally distributed. Outcome measures were assessed by 2 way Analysis of 
Variance (ANOVA). Initial comparison was between treatment groups (empagliflozin 


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vs placebo) at the final visit of each treatment arms (visit 5 and visit 9) adjusted for 
baseline measures (visit 2 and visit 6) of the outcomes. 
Where data was not normally distributed and could not be transformed into a normal 
distribution, data were analysed using non-parametric methods. Data for categorical 
outcomes measures were assessed by logistic regression in the same way as 
described for continuous outcome measures.  
All efficacy variables were listed by subject within study centre. Data were 
summarised by treatment group. Number, Mean, Standard Deviation, Minimum and 
Maximum will summarise continuous efficacy variables, whereas number and percent 
will summarise categorical efficacy variables. 
9.1 Primary Efficacy Analysis 
The primary outcome measure was analysed in the same manner as described above 
and presented as the between treatment group difference in change in urine volume 
between the baseline and final visits.  
9.2  Secondary Efficacy Analyses 
All secondary outcomes were analysed in the same manner as the primary 
outcomes. Results were presented as:  
• 
between treatment group difference in urinary sodium excretion, from the 24 
hour urinary collection 
• 
between treatment group difference in estimated glomerular filtration rate 
(safety endpoint) 
• 
between treatment group difference in serum creatinine (safety endpoint) 
• 
between treatment group difference on protein/creatinine ratio  
• 
between treatment group difference on albumin/creatinine ratio 


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• 
between treatment group difference on the renal biomarker, cystatin C. 
In analysing the results from the Renal Physiology test days, these will be analysed 
via a 2 way repeated measures ANOVA for both urinary volume and urinary sodium.  
10 Safety Analyses 
An all patient group analysis was performed for safety variables (glomerular filtration 
rate and serum creatinine).  
10.1 Adverse Events 
When calculating the incidence of adverse events, or any sub-classification thereof 
by treatment, time period, severity, etc., each subject will only be counted once and 
any repetitions of adverse events was ignored; the denominator was the total 
population size. The adverse events will be coded using the MedDRA coding system, 
version 21.1 dated September 2018.  
Treatment emergent adverse events are those events that occur after the baseline 
assessment. Those subjects with adverse events that worsen post-treatment will also 
be included.  The incidence of AEs that are judged to be related to the treatment was 
reported.  
10.2 Deaths, Serious Adverse Events and other Significant Adverse 
Events 
Serious Adverse Events (SAE) was reported with all other AEs. However, they were 
reviewed for the trial report on a case by case basis by the PI.  
10.3 Pregnancies 
The study did not perform any pregnancy tests on the subjects randomised as all 
female randomised subjects signed in their informed consent form that they were not 
of child bearing potential i.e. post-menopausal.  


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10.4 Clinical Laboratory Evaluations 
Laboratory tests was summarised using descriptive statistics, which will show the 
change in laboratory values from baseline to each subsequent visit.  
10.5 Other Safety Measures 
Vital signs was summarised using descriptive statistics and will show the change in 
vital signs from baseline to each subsequent visit.  
11 Reporting Conventions 
P-values ≥0.001 was reported to 3 decimal places; p-values less than 0.001 was 
reported as “<0.001”. The mean, standard deviation, and any other statistics other 
than quantiles, was reported to one decimal place greater than the original data. 
Quantiles, such as median, or minimum and maximum will use the same number 
of decimal places as the original data. Estimated parameters, not on the same 
scale as raw observations (e.g. regression coefficients) was reported to 3 
significant figures.  
12 Technical Details 
All analysis was performed using IBM SPSS Statistics 22 for Windows or R Ver 3.4.1 
for Windows. All data, analysis programs and output was kept on the University server 
and backed up according to the internal IT SOPs. Analysis programs was required to 
run without errors or warnings.  
13 References 
1. 
Nguyen MK and Kurtz I. Derivation of a new formula for calculating urinary 
electrolyte-free water clearance based on the Edelman equation. American Journal of 
Physiology - Renal Physiology. 2004;288:F1-F7. 


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2. 
Lang CC, Choy AM, Rahman AR and Struthers AD. Renal effects of low dose 
prazosin in patients with congestive heart failure. Eur Heart J. 1993;14:1245-52. 
3. 
Lang CC, Rahman AR, Balfour DJ and Struthers AD. Prazosin blunts the 
antinatriuretic effect of circulating angiotensin II in man. J Hypertens. 1992;10:1387-
95. 
4. 
Lang CC, Choy AM, Balfour DJ and Struthers AD. Prazosin attenuates the 
natriuretic response to atrial natriuretic factor in man. Kidney Int. 1992;42:433-41. 
5. 
Sturrock ND, Lang CC, Baylis PH and Struthers AD. Sequential effects of 
cyclosporine therapy on blood pressure, renal function and neurohormones. Kidney 
Int. 1994;45:1203-10. 
6. 
Goldsmith SR, Gilbertson DT, Mackedanz SA and Swan SK. Renal effects of 
conivaptan, furosemide, and the combination in patients with chronic heart failure. J 
Card Fail. 2011;17:982-9. 
7. 
List JF, Woo V, Morales E, Tang W and Fiedorek FT. Sodium-Glucose 
Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes. Diabetes Care. 
2009;32:650-657. 
8. 
Sairaku A, Nakano Y and Kihara Y. Increased urine output by ipragliflozin in a 
non-diabetic patient with a diuretic-resistant heart failure. Int J Cardiol. 
2015;180:42-3.