Clinical trial NCT03416270
Conditions: Type 2 Diabetes Mellitus Heart Failure
Keywords: SGLT2 inhibtion Ertugliflozin Type 2 Diabetes Heart Failure
Sponsor: University Health Network, Toronto
Start date: 2018-06-28; Completion date: 2021-04-14
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aims to elucidate the mechanisms whereby the SGLT2i "ertugliflozin" modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with type 2 diabetes and heart failure (T2D-HF).

Detailed description:
Newer agents called sodium glucose co-transporter-2 inhibitors (SGLT2i) have been developed to improve glycemic control and lower hemoglobin A1c by increasing glycosuria. SGLT2i also reduce blood pressure and albuminuria in T2D - possibly through natriuresis. Importantly, a landmark trial "EMPA-REG OUTCOME" demonstrated that the SGLT2i "empagliflozin" is the first anti- hyperglycemic agent to reduce mortality and HF risk, and also to decrease the risk of progressive diabetic nephropathy. Similar benefits were also recently reported in the CANVAS Program trial with canagliflozin. Despite the benefits observed in these two pivotal trials, the mechanisms responsible for beneficial effects of SGLT2i in patients with T2D with respect to the development and/or worsening of HF are not currently known.

In light of the results of EMPA-REG OUTCOME, the investigators aim to elucidate the mechanisms whereby the SGLT2i "ertugliflozin" modifies cardiorenal interactions that regulate fluid volume and neurohormonal activation in patients with T2D and HF (T2D-HF). The investigators will test the hypothesis that ertugliflozin increases proximal tubular natriuresis, thereby reducing plasma volume, without inducing significant renal vasoconstriction or activation of the sympathetic nervous system (SNS) (see below, Figure 1). The systematic understanding of the effects of SGLT2i in the setting of HF will enable the design of rational physiology based strategies to decrease the burden of HF, which could have major clinical and research implications internationally.

Arms: arm 1: Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) for 12 weeks arm 2: Placebo Matching Ertugliflozin Tablet for 12 weeks
Interventions: intervention 1: Ertugliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Ertugliflozin Tablets Total Dose 15mg (10mg + 5 mg) once daily for 12 weeks intervention 2: Placebo once daily for 12 weeks

Protocol documents:
Prot_000.pdf: 
Effects of ertugliflozin in heart failure 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ERtugliflozin triAl in DIabetes with preserved or 
reduced ejeCtion FrAcTion mEchanistic evaluation in 
Heart Failure: “ERADICATE-HF” 
 
 
 
 
 
 
 
 
 
 
 
EudraCT 2017-001840-37 


Effects of ertugliflozin in heart failure 
2 
 
 
PROTOCOL TITLE: ERtugliflozin triAl in DIabetes with preserved or reduced ejeCtion FrAcTion mEchanistic evaluation in 
Heart Failure: “ERADICATE-HF” 
 
Protocol ID 
EUDRA-CT 
XXXXXXXXXXX 
2017-001840-37 
Short title 
Effect of ertugliflozin in heart failure 
EudraCT number 
2017-001090-16 
Version 
6.0 
Date 
July 9, 2018 
Coordinating investigator/project 
Prof. D. Cherney 
leader 
Division of Nephrology 
 
University Health Network, University of Toronto 
 
Toronto 
 
Tel: 416 340 4151 
 
E-mail: david.cherney@uhn.ca 
Principal investigator(s) (in Dutch: 
hoofdonderzoeker/ uitvoerder) 
Prof. D. Cherney 
Division of Nephrology 
University Health Network, University of Toronto 
Toronto 
Tel: 416 340 4151 
E-mail: david.cherney@uhn.ca 
 
Prof. H.J. Lambers Heerspink 
Department of Clinical Pharmacology 
University Medical Center Groningen 
Groningen 
Tel: 050-3617859 
E-mail: h.j.lambers.heerspink@umcg.nl 
Sponsor 
University Health Network 
Toronto, Ontario, Canada 
Subsidising party 
Merck (investigator initiated study) 


Effects of ertugliflozin in heart failure 
3 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
[Coordinating Investigator/Project 
leader/Principal Investigator]: 
Dr. David Cherney 
Division of Nephrology 
University Health Network, University of 
Toronto 
Canada 
 
Dr. Hiddo Lambers Heerspink 
Department of Clinical Pharmacology 
UMCG, Groningen, 
Netherlands 
 
 
[Coordinating Investigator/Project 
leader/Principal Investigator]: 
Dr. David Cherney 
Division of Nephrology 
University Health Network, University of 
Toronto 
Canada 
 
Daniel Raalte 
University of Amsterdam 
Amsterdam, Netherlands 
 
 


Effects of ertugliflozin in heart failure 
4 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION AND RATIONALE ................................................................................................. 10 
2. OBJECTIVES .................................................................................................................................... 12 
3. 
STUDY DESIGN .............................................................................................................................. 13 
4. 
STUDY POPULATION ..................................................................................................................... 15 
4.1 
Population (base) .................................................................................................................... 15 
4.2 
Inclusion criteria ..................................................................................................................... 15 
4.3 
Exclusion criteria ..................................................................................................................... 15 
4.4 
Sample size calculation ........................................................................................................... 16 
5. 
TREATMENT OF SUBJECTS ............................................................................................................ 18 
5.1 
Investigational product/treatment ......................................................................................... 18 
5.2 
Use of co-intervention (if applicable) ..................................................................................... 18 
5.3 
Escape medication (if applicable) ........................................................................................... 18 
6. 
INVESTIGATIONAL PRODUCT ........................................................................................................ 19 
6.1 
Name and description of investigational product(s) .............................................................. 19 
6.2 
Summary of findings from non-clinical studies ....................................................................... 19 
6.3 
Summary of findings from clinical studies .............................................................................. 20 
6.4 
Summary of known and potential risks and benefits .............................................................. 20 
6.5 
Description and justification of route of administration and dosage ..................................... 21 
6.6 
Dosages, dosage modifications and method of administration .............................................. 21 
6.7 
Preparation and labelling of Investigational Medicinal Product ............................................. 21 
6.8 
Drug accountability ................................................................................................................. 21 
6.9 Handling and Dispensing ................................................................... 21 
610  Drug ordering ................................................................................. 21 
7. 
NON-INVESTIGATIONAL PRODUCT ............................................................................................... 22 
7.1 
Name and description of non-investigational product(s) ....................................................... 22 
7.2 
Summary of findings from non-clinical studies ....................................................................... 22 
7.3 
Summary of findings from clinical studies .............................................................................. 22 
7.4 
Summary of known and potential risks and benefits .............................................................. 22 
7.5 
Description and justification of route of administration and dosage ..................................... 22 
7.6 
Dosages, dosage modifications and method of administration .............................................. 22 
7.7 
Preparation and labelling of Non Investigational Medicinal Product ..................................... 22 
7.8 
Drug accountability ................................................................................................................. 22 
8. 
METHODS ...................................................................................................................................... 23 
8.1 
Study parameters/endpoints .................................................................................................. 23 
8.1.1 
Main study parameter/endpoint ..................................................................................... 23 
8.1.2 
Secondary study parameters/endpoints (if applicable) .................................................. 23 
8.1.3 
Other study parameters (if applicable) ........................................................................... 23 
8.2 
Randomisation, blinding and treatment allocation ................................................................ 23 
8.3 
Study procedures .................................................................................................................... 23 
8.4 
Withdrawal of individual subjects .......................................................................................... 24 
8.4.1 
Specific criteria for withdrawal (if applicable) ................................................................. 24 
8.5 
Replacement of individual subjects after withdrawal ............................................................ 24 
8.6 
Follow-up of subjects withdrawn from treatment .................................................................. 24 


Effects of ertugliflozin in heart failure 
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8.7 
Premature termination of the study ....................................................................................... 24 
9. 
SAFETY REPORTING ....................................................................................................................... 25 
9.1 
Section 10 WMO event ........................................................................................................... 25 
9.2 
AEs, SAEs and SUSARs ............................................................................................................. 25 
9.2.1 
Adverse events (AEs) ....................................................................................................... 25 
9.2.2 
Serious adverse events (SAEs) ......................................................................................... 25 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ........................................... 26 
9.3 
Annual safety report ............................................................................................................... 27 
9.4 
Follow-up of adverse events ................................................................................................... 28 
9.5 
[Data Safety Monitoring Board (DSMB) / Safety Committee] ................................................ 28 
10. STATISTICAL ANALYSIS .................................................................................................................. 29 
10.1 Primary study parameter(s) .................................................................................................... 29 
10.2 Secondary study parameter(s) ................................................................................................ 29 
10.3 Other study parameters ......................................................................................................... 29 
10.4 Interim analysis (if applicable) ................................................................................................ 29 
11. 
ETHICAL CONSIDERATIONS ......................................................................................................... 30 
11.1 
Regulation statement ........................................................................................................... 30 
11.2 
Recruitment and consent ..................................................................................................... 30 
11.3 
Objection by minors or incapacitated subjects (if applicable) .............................................. 30 
11.4 
Benefits and risks assessment, group relatedness ............................................................... 30 
11.5 
Compensation for injury ....................................................................................................... 30 
11.6 
Incentives (if applicable) ....................................................................................................... 31 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .................................................. 32 
12.1 
Handling and storage of data and documents ...................................................................... 32 
12.2 
Monitoring and Quality Assurance ....................................................................................... 32 
12.3 
Amendments ........................................................................................................................ 32 
12.4 
Annual progress report ......................................................................................................... 33 
12.5 
End of study report ............................................................................................................... 33 
12.6 
Public disclosure and publication policy ............................................................................... 33 
13. 
STRUCTURED RISK ANALYSIS ...................................................................................................... 34 
13.1 
Potential issues of concern ................................................................................................... 35 
13.2 
Synthesis ............................................................................................................................... 35 
14. 
REFERENCES ................................................................................................................................ 37 


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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS 
 
 
ABR 
ABR form, General Assessment and Registration form, is the application form that is 
required for submission to the accredited Ethics Committee (In Dutch, ABR = Algemene 
Beoordeling en Registratie) 
ACEi 
Angiotensin Converting Enzyme Inhibitor 
AE 
Adverse Event 
AR 
Adverse Reaction 
ARB 
Angiotensin Receptor Blocker 
CA 
Competent Authority 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: Centrale Commissie 
Mensgebonden Onderzoek 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
METC 
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC) 
(S)AE 
(Serious) Adverse Event 
SGLT2 
Sodium Glucose Co-Transporter 2 
SGLT2i 
Sodium Glucose Co-Transporter 2 Inhibitor 
SPC 
Summary of Product Characteristics (in Dutch: officiële productinfomatie IB1-tekst) 
Sponsor 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising party. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Wbp 
Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens) 
WMO 
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch- 
wetenschappelijk Onderzoek met Mensen 


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SUMMARY 
Rationale: 
Type 2 diabetes (T2D) is an epidemic that afflicts more than 350 million people world-wide. In 
addition to difficulties managing hyperglycemia, patients with T2D have an increased risk of heart 
failure (HF). Despite the use of existing medical therapies, T2D continues to cause significant 
morbidity and mortality, leading to large societal and financial costs to Canadians. 
Newer agents called sodium glucose co-transporter-2 inhibitors (SGLT2i) have been 
developed to improve glycemic control and lower hemoglobin A1c by increasing glycosuria1. SGLT2i 
also reduce blood pressure2,3 and albuminuria4 in T2D – possibly through natriuresis 4a, 4b. 
Importantly, a landmark trial “EMPA-REG OUTCOME” demonstrated that the SGLT2i “empagliflozin” 
is the first anti- hyperglycemic agent to reduce mortality and HF risk5, and also to decrease the risk of 
progressive diabetic nephropathy. Similar benefits were also recently reported in the CANVAS 
Program trial with canagliflozin6. Despite the benefits observed in these two pivotal trials, the 
mechanisms responsible for beneficial effects of SGLT2i in patients with T2D with respect to the 
development and/or worsening of HF are not currently known. 
In light of the results of EMPA-REG OUTCOME, we aim to elucidate the mechanisms whereby 
the SGLT2i “ertugliflozin” modifies cardiorenal interactions that regulate fluid volume and 
neurohormonal activation in patients with T2D and HF (T2D-HF). We will test the hypothesis that 
ertugliflozin increases proximal tubular natriuresis, thereby reducing plasma volume, without 
inducing significant renal vasoconstriction or activation of the sympathetic nervous system (SNS)7 
(see below, Figure 1). The systematic understanding of the effects of SGLT2i in the setting of HF will 
enable the design of rational physiology based strategies to decrease the burden of HF, which could 
have major clinical and research implications internationally. 
 
Objective: 
Primary: 
1. Our primary goal is to determine if SGLT2i causes a persistent proximal renal tubular 
natriuretic effect (see below). We will capture acute (1 week) and chronic (12 weeks) 
responses, since physiological effects of SGLT2i agents may change over time2,3,8. As an 
extension of our primary aim, we will assess whether ertugliflozin-related effects on proximal 
tubule natriuresis lead to a reduction in plasma volume and extracellular body water (see 
below)7. 
Secondary: 
2. We will determine if volume contraction leads to a decline in hormones that are activated in 
HF patients such as B-type natriuretic peptides (BNP), without activating the SNS7; 
3. We will determine the impact of ertugliflozin on: renal function measured at 1 week2,3,5 
and 12 weeks as a measure of safety; 
4. Blood pressure, echocardiographic measures of cardiac output (and derived systemic 
vascular resistance) arterial stiffness and systemic vascular resistance to better understand 
the blood pressure lowering effect in this patient population; 
5. Heart rate and heart rate variability, to assess effects on SNS activation; 
6. Urinary natriuretic modulators, such as angiotensin converting enzyme-29 and adenosine10; 
7. To characterize the safety of ertugliflozin vs. placebo by determining the number of 
hypoglycemic episodes between groups, and serious adverse events. 


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Study design: 
This study will use a double blind, stratified randomization trial approach involving 36 T2D-HF 
patients taking standard HF therapies. 
 
Study population: Male and female subjects with heart failure and T2D, as described below. 
Intervention: Patients will be randomized to 15 mg tablet PO ertugliflozin daily or a matched 
placebo. Main study parameters/endpoints: Change in natriuresis 
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness: Patients visit the outpatient clinic on a more regular basis than standard patient care - 
i.e. at study inclusion and at each study visit for clinical assessment. Blood work for physiological 
assessments, renal function tests and cardiovascular assessments will be obtained as described in the 
protocol. 24hr urine will be collected one day prior to the hospital visit. No other invasive 
measurements will be executed. Patients receive restitution of all travel costs. Patients receive no 
priority in treatment of other diseases in the clinic during this study. There are no direct benefits for 
the patients to be included and participation is on a voluntary basis. 


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INTRODUCTION AND RATIONALE 
 
Patients with T2D-HF have >50% 5-year mortality, leading to substantial societal and financial 
costs to Canadians. The identification of new therapies is essential to improve the quality of life and 
survival of T2D-HF patients. In EMPA-REG OUTCOME there was a significant decrease in the rate of 
hospitalization for HF after therapy for only 3 months. Despite this beneficial effect, the impact of 
SGLT2i in patients with overt HF remains unknown. The current gap in knowledge around SGLT2i 
effects in patients with existing HF highlights the urgent need for human mechanistic studies in this 
area. The renal and cardiovascular function effects of SGLT2i on natriuresis-related endpoints in 
patients with T2D and HF is not known. Our study will provide needed insights into physiological 
effects of SGLT2i agents on natriuresis, hemodynamic function and neurohormones in HF patients. 
 
Current Management Strategies in Patients with HF: HF is characterized by activation of the SNS and 
renin angiotensin aldosterone system (RAAS) as counter-regulatory responses to maintain blood 
pressure and preserve renal function. Treatment of HF patients with reduced left ventricular ejection 
fraction (HFrEF, ejection fraction <45%) includes b-blockers and RAAS inhibitors, diuretics and digoxin 
to suppress neurohormones, reduce volume overload and improve cardiac contractility11. In HFrEF, 
RAAS inhibitors reduce hospitalizations and mortality11. In contrast, these therapies have failed to 
produce beneficial effects in patients with HF and preserved EF (“HFpEF”, ejection fraction ≥45%), 
which is a common type of HF in T2D11. Accordingly, HFpEF management focuses on the treatment of 
co-morbidities (hypertension, coronary disease, obesity, hyperglycemia) 12. Many of the co- 
morbidities associated with HFpEF can be ameliorated with SGLT2i, making them attractive therapies 
for HFpEF5,13-15. In addition to uncertain benefit, current therapies for HFpEF have clear potential to 
cause side effects, such as hyperkalemia, hypotension and acute kidney injury. In contrast, in EMPA- 
REG OUTCOME, SGLT2i reduced mortality and HF risk without increasing any of these adverse 
events5. Interestingly, SGLT2i with empagliflozin also reduced the need for loop diuretics, which 
could help preserve renal function and avoid side effects16. Empagliflozin also has a surprising neutral 
effect on the SNS, despite an expected contraction of plasma volume17,18. This has been interpreted 
to reflect a possible “suppressive” effect on the SNS17-19. Importantly, although the proportion of 
patients with HFrEF vs. HFpEF in EMPA-REG OUTCOME or the CANVAS Program is not known, based 
on the clinical characteristics of the cohort it is likely that both subtypes had large representation in 
the trial. Based on a strong physiological rationale, the likely proportion of HFpEF patients in EMPA- 
REG OUTCOME and the CANVAS Program and a large unmet clinical need in T2D-HFpEF patients, in 
the current study we will include patients with this physiological profile to examine the effect of 
SGLT2i on natriuresis, renal and systemic hemodynamic and neurohormonal function. In addition, 
due to similar expectations around the high prevalence of HFrEF in EMPA-REG OUTCOME and the 
CANVAS Program, a large unmet clinical need in these patients, and the expectation that individuals 
with HFrEF and volume expansion will respond to SGLT2 inhibition with a significant natriuresis, we 
will also include HFrEF patients with EF ³20% in ERADICATE-HF. We anticipate that that both HFrEF 
and HFpEF will exhibit an expected natriuretic response and similar directional changes in renal and 
systemic hemodynamic parameters. Nevertheless, to maximize homogeneity in the ertugliflozin and 
placebo-treated groups, participants will undergo stratified randomization to assure equal numbers 
of HFrEF and HFpEF phenotypes in the two groups. 


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SGLT2i reduces plasma glucose and HbA1c in patients with T2D by increasing urinary glucose 
excretion. SGLT2i are oral anti-hyperglycemic agents that decrease HbA1c through insulin- 
independent effects via glycosuria. They therefore have negligible hypoglycemic risk as compared to 
other classes of anti-hyperglycemic agents, since the degree of glucose lowering depends on the 
filtered load of glucose, which, in non-diabetic patients, is very low 20,21. Beneficial effects of SGLT2i 
beyond glycemic control in patients with T2D have been suggested by the EMPA-REG OUTCOME and 
CANVAS Program trials, in which SGLT2i treatment added to standard care significantly reduced the 
composite primary endpoint (i.e. death from cardiovascular causes, nonfatal myocardial infarction, or 
nonfatal stroke) and also reduced the risk of being hospitalized for heart failure or developing 
progressive diabetic nephropathy, compared to participants allocated to the placebo group 22,23. In 
these trials, dramatic cardiovascular protective effects were reported, even though HbA1c reductions 
were very modest at the end of the study. The renal outcome data were equally impressive and 
demonstrate that individuals treated with an SGLT2i had >35% reduced risk of new onset of 
nephropathy23,24. In light of modest glucose-lowering effects in the previous cardiovascular endpoint 
trials, renal and cardiovascular benefits have been attributed to natriuretic properties of the class, 
leading to hemodynamic effects in both the renal and systemic vascular circulations. 
 
In the renal microcirculation, SGLT2i “normalizes” tubuloglomerular feedback mechanisms seen in 
the hyperfiltration stage of diabetic nephropathy25. Furthermore, effects of SGLT2i at the afferent 
arteriole likely account for the acute “dip” in eGFR observed in patients with and without impaired 
renal function, which likely reflects a reduction in intraglomerular hypertension at the single nephron 
level across the spectrum of renal function. It is believed that natriuresis leading to increased 
tubuloglomerular feedback at least partially mediates the beneficial effects of SGLT2i via this glucose- 
independent hemodynamic mechanism. 
 
To reduce intraglomerular hypertension, current guidelines recommend the use of RAAS blockers 
as the gold standard therapy for individuals with diabetic nephropathy or in patients with heart 
failure 26. However, despite the use of these agents, renal function continues to decline – a scenario 
that can be worsened in the presence of combined cardiac and renal disease. Therefore, there is a 
need to widen the therapeutic armamentarium for individuals with diabetes and cardiorenal disease 
nephropathy. SGLT2i lowers the threshold of proximal glucose reabsorption resulting in glycosuria, 
and increases distal tubular sodium delivery to macula densa cells. Macula densa cells are specialized 
epithelial cells located at the distal convoluted tubule that sense sodium delivery and mediate 
afferent arteriolar vasoconstriction in response to an increase in tubular sodium. SGLT2 inhibition 
increases the delivery of glucose and sodium in the distal tubule and to the juxtaglomerular 
apparatus, which is sensed as an increase in glomerular perfusion. This leads to a tubuloglomerular 
feedback signal causing afferent arteriolar vasoconstriction, and an acute fall in intraglomerular 
pressure. These effects are clinically manifested as acute reductions in GFR and hence albuminuria, 
followed by renal function preservation in the longer term – as recently reported in EMPA-REG 
OUTCOME and the CANVAS Program. Furthermore, natriuresis diminishes extracellular plasma 
volume and blood pressure. Thus, SGLT2i specifically alters renal hemodynamic function by reducing 
intraglomerular pressure, which could be expected to translate into improved long-term kidney 
outcomes. 


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In light of the results of EMPA-REG OUTCOME and CANVAS Program, we aim to elucidate the 
mechanisms whereby the SGLT2i “ertugliflozin” modifies cardiorenal interactions that regulate fluid 
volume and neurohormonal activation in patients with T2D and HF (T2D-HF). We will test the 
hypothesis that ertugliflozin increases proximal tubular natriuresis, thereby reducing plasma volume, 
without inducing significant renal vasoconstriction or activation of the sympathetic nervous system 
(SNS)7 (see below, Figure 1). The systematic understanding of the effects of SGLT2i in the setting of 
HF will enable the design of rational physiology based strategies to decrease the burden of HF, which 
could have major clinical and research implications internationally. 


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1. OBJECTIVES 
 
Primary: 
1. Our primary goal is to determine if SGLT2i causes a persistent proximal renal tubular natriuretic 
effect (see below). We will capture acute (1 week) and chronic (12 weeks) responses, since 
physiological effects of SGLT2i agents may change over time2,3,8. As an extension of our primary 
aim, we will assess whether ertugliflozin-related effects on proximal tubule natriuresis lead to a 
reduction in plasma volume and extracellular body water (see below)7. FENa and FELi excretion 
were calculated according to FE(electrolyte) = 100 X ([(electrolyte urine) X (creatinine 
plasma)]/[(electrolyte plasma) X (creatinine urine)]). FELi will used as a surrogate to measure 
proximal tubular sodium reabsorption, whereas FENa assesses total overall (proximal and distal) 
tubular sodium handling. Distal sodium handling is calculated by total-proximal sodium 
reabsorption, as described elsewhere8a. As in previous work, plasma and urine lithium levels 
will be measured using inductively with coupled spectroscopy8a. 
 
Secondary: 
1. We will determine if volume contraction leads to a decline in hormones that are activated in HF 
patients such as B-type natriuretic peptides (BNP), without activating the SNS7; 
2. We will determine the impact of ertugliflozin on: renal hemodynamic function measured 
at 1 week2,3,5 and 12 weeks as a measure of safety; 
3. Blood pressure, echocardiographic measures of cardiac output (and derived systemic vascular 
resistance) arterial stiffness and systemic vascular resistance to better understand the blood 
pressure lowering effect in this patient population; 
4. Heart rate and heart rate variability, to assess effects on SNS activation; 
5. Urinary natriuretic modulators, such as angiotensin converting enzyme-29 and adenosine10; 
6. To characterize the safety of ertugliflozin vs. placebo by determining the number of 
hypoglycemic episodes between groups, and serious adverse events. 


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2. STUDY DESIGN 
 
This study will use a double blind, stratified randomization trial approach involving 36 T2D-HF 
patients taking standard HF therapies, who will be allocated to either ertugliflozin or placebo in a 1:1 
ratio (Table 1 – inclusion and exclusion criteria). For feasibility, participants will be recruited from the 
>4000 HF patients followed at UHN-MSH heart failure clinics and from heart failure clinics in 
Groningen, the Netherlands, of whom >40% have T2D. The study will consist of a screening visit, a 4- 
week run-in phase for those subjects not on stable ACEi/ARB treatment, followed by a 12-week 
double blind treatment period. 
 
The target population will be invited for screening. Subjects who meet all entry criteria and who are 
already on a stable dose (no changes in dose or type of drug) of ACEis or ARBs for at least 4 weeks 
proceed directly to randomization. Subjects who had their ACEi or ARB medication changed during 
the preceding 4 weeks of the screening visit proceed to a run-in phase during which the type and 
dose of these drugs are stabilized. Subjects will be randomly assigned to one of the two treatments. 
Subjects will have their study visit in the morning in fasted condition. 
 
Subjects will be instructed to take the study medication once daily, in the morning, except on study 
days; on those days, the study drug will be taken after the patient visit. 
 
Measurements: 
• 
During the double blind treatment period, patients will collect a 24-hour urine collection at each 
visit for measurement of 24-hour protein, albumin, glucose, sodium, potassium, creatinine, and 
urea excretion. Twenty-four hour urine collections will be performed at: Visits 3, 4 and 8. Routine 
biochemistry and safety labs will be drawn at screening, during each physiological assessment and 
at each the specified office safety visits (see visit schedule table below). 
• Office systolic and diastolic blood pressure measurements, heart rate, weight, and waist 
circumference will be performed at screening and at each subsequent physiological testing day 
and at each office visit (see visit schedule table below). 
• Blood will be drawn for measurement of renal function tests, HbA1c, glucose, complete blood 
count, plasma albumin, RAAS biomarkers, natriuretic peptides, and neurohormones on visits 3, 4 
and 8. 
• Blood and urine samples will be stored for future exploratory biomarker analyses to study the 
effect of ertugliflozin in this study population. 


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• Schedule of study procedures and events 
 
 
 
Screening 
 
Baseline 
Post Visit 
1/Start of 
Drug/Placebo 
 
Dosing 
Post Visit 
2 
Follow- 
Up 
Early 
EOS 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
Day 
-14 
-7 
0 
7 
14- 17 
42 
77 
84 
91 
 
Clinic Visit 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Phone/Email Visit 
 
X 
 
 
 
 
X 
 
 
 
Fasting Visit 
 
 
X 
X 
 
 
 
X 
X 
X 
Demographics and 
Medical History 
X  
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
ECG 
X  
 
 
 
 
 
 
X 
X 
Physical Exam 
X  
 
 
X 
X 
 
 
X 
X 
Vital Signs 
X  
X 
X 
X 
X 
 
X 
X 
X 
Weight and Waist 
Measurement 
X  
X 
X 
X 
X 
 
X 
X 
X 
Blood and Urine 
Samples 
X  
X 
X 
X 
X 
 
X 
X 
X 
Renal Function Tests  
 
X 
X 
 
 
 
X 
 
 
Echocardiography 
 
 
X 
X 
 
 
 
X 
 
 
Arterial Stiffness 
 
 
X 
X 
 
 
 
X 
 
 
Plasma Volume 
(Indocyanine Green 
Dilution) 
 
 
 
X 
 
X 
 
 
 
 
X 
 
 
Bioimpedence 
spectroscopy 
 
 
X 
X 
 
 
 
X 
 
 
NICOM 
 
 
X 
X 
 
 
 
X 
 
 
Neurohormones/ 
Biomarkers 
 
 
X 
X 
 
 
 
X 
 
 
Pregnancy Test 
X  
X 
X 
 
 
 
X 
 
 
Start Modified Dietb  
X 
Continue 
until V4 
X 
 
 
X 
 
 
 
Dispense Lithium 
X 
 
 
 
 
 
 
 
 
 
Dispense Study 
Medication 
 
 
X 
X 
 
 
 
 
 
 
24 Hour Urine 
Collection 
 
 
X 
X 
 
 
 
X 
 
 
Dispense 24 hr urine 
bottle 
X 
 
 
 
 
X 
 
 
 
 
Modified 
Euglycaemic clamp 
 
 
X 
X 
 
 
 
X 
 
 
a Informed consent is obtained before any study specific procedure is done. b The diet includes a target of 140 mmol of sodium per day 
to avoid salt depletion and consequence activation of the RAAS which could confound sodium handling and neurohormonal 
assessments. In addition, we target a moderate protein diet of approximately 1.5gram/kg/day to avoid the confounding effect of high 
protein diets on GFR (induces hyperfiltration). This has also been part of previous mechanistic studies in the Cherney Laboratory in 
patients with diabetes.


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Study Periods and Procedures: 
Screening 
Patients with a history of T2D and HF will be eligible for protocol-specific assessment during the 
screening period. Signature of the protocol-specific informed consent form constitutes the first 
procedure of the screening period, followed by the assignment of a unique subject number. Protocol- 
specific assessments and procedures may then be performed, as part of the screening visit, to 
evaluate the subject’s eligibility. During the screening period, subjects will maintain their stable doses 
of commercially available ACEIs or ARBs, and diuretic medication. 
 
At this visit patients will be given a 24 hour urine bottle and will be dispensed lithium pills to be taken 
the night before visits 3, 4 and 8. 
 
When all inclusion and exclusion criteria have been evaluated and the requirements for entry into 
the study have been met, the entry into run-in period or double blind ertugliflozin or placebo period 
will be scheduled. If the patient does not qualify based on the laboratory data, the patient is allowed 
to be re-screened within 4 weeks of the original screening date. The laboratory data based on which 
the patient failed should be repeated. 
 
Run-in Period 
Eligible subjects who complete the screening period will enter the run-in period if they are not using 
a maximum tolerated dose of an ACEi or ARB. During the run-in period, ACEi or ARB will be started or 
up titrated towards the maximum tolerated antihypertensive dose. If a patient does not tolerate the 
maximum dose of an ACEi or ARB, this should be documented in the eCRF and the patient can 
proceed to the double blind treatment period if all other entry criteria are met. 
 
Double-Blind Ertugliflozin/Placebo Period 
Eligible subjects will enter in the randomized, double-blind, ertugliflozin/placebo period if their 
ACEi/ARB and diuretic medication is stable for at least 4 weeks and all entry criteria are met. A 
randomization code stored in each local pharmacy will be used to randomly assign subjects to an 
ertugliflozin/placebo arm. Subjects will continue to maintain their stable doses of commercially 
available ACEi or ARB, and diuretics if applicable, throughout the double blind phase. Patients will be 
counseled to maintain a stable habitual dietary salt intake. 
 
Visit 2 
Visit 2 will be an email visit. Research staff will remind patient to start the modified diet, to 
collect the 24 hour urine one day before visit 3 and to take the Lithium pill the night before 
visit 3. 
 
Visit 3 (Randomization) 
The randomization visit procedures should be completed on a single day under a euglycemic clamp. As part of 
the study procedures, blood glucose will therefore be maintained between 4-6 mmol/L during the long study 
days. From a patient perspective, the procedures involved in the trial involve three intravenous needles (for 
renal function assessments, infusion of insulin and dextrose and finally for blood-letting). The randomization 
visit procedures will include measures of natriuresis, renal and systemic hemodynamic function, 
neurohormonal assessments, echocardiography, arterial stiffness, plasma volume, bioimpedence 
spectroscopy, vital signs, weight and waist circumference, blood and urine samples collection. Cardiac output 
and systemic vascular resistance will also be measured using non-invasive cardiac monitoring (NICOM). This 


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non-invasive technique is a form of bioelectrical impedance (“bioreatance”) to measure thoracic fluid content 
with electrocardiogram electrode stickers. Beat-to-beat changes in fluid content can be used to derive cardiac 
output. Then, using measured mean arterial pressure, systemic vascular resistance can be calculated. This 
entire measurement process takes approximately 15 minutes8a. The first dose of blinded study medication 
should only be administered one day after all randomization visit procedures have been completed. 
 
Visit 4, 5 and 6 
One week after initiation of ertugliflozin/placebo, subjects will return to the renal physiology 
laboratory for the 1-week assessment (Visit 4), with repeated measures of all physiological 
parameters described for Visit 3. They will then continue the same treatment allocation for 
the rest of the trial. A safety visit (vital signs, weight, waist circumference, and physical exam 
and safety laboratory tests) will be conducted approximately 7-10 days later (Visit 5), and 
again 4-5 weeks later (Visit 6). 
 
Additional telephone visits will be scheduled as required to follow weight and home blood pressure, 
in line with usual clinical care. If the patient does not tolerate medication a visit to the out-patient 
clinic will be scheduled. At the end of the treatment period (at visits 3, 4, and 8), the patient will take 
study medication BEFORE physiological procedures are performed. 
 
Visit 7 and 8 
After a total of 12 weeks of dosing with ertugliflozin or placebo, patients will return for a final set of 
physiological assessments as described in Visit 3 (Visit 8). One email/phone visit (visit 7) will be 
conducted. Research staff will remind patient to start the modified diet one week prior to visit 8; 
collect the 24 hour urine one day before visit 8 and to take the lithium pill the night before visit 8. 
 
In subjects who need to discontinue prematurely from the treatment period prior to the final Visit 8 
at 12 weeks, every effort will be made to capture all physiological data on the last day that the 
investigational product is taken. 
 
Visit 9 
One week after the study medication is stopped at visit 8, the patient will return for a follow-up visit. 
ECG, physical exam, vital signs, weight and waist circumference will be measured and blood and 
urine samples will be obtained. 
 
Biomarker analysis 
Aside from planned blood and urine samples, serum, plasma and urine will be collected and stored 
for potential future analyses for exploratory biomarkers to assess relationships with disease activity 
and effects of study drug. After completion of the study, samples will be shipped and stored to a 
central storage facility in Toronto. The results of this biomarker research will be reported either in 
the main publication, or separately in a scientific report or publication. The results of this biomarker 
research may be pooled with biomarker data from other ertugliflozin studies to generate hypotheses 
to be tested in future research. Potential biomarkers to be measured include but are not limited to 
electrolytes, natriuretic peptides, markers of inflammation/fibrosis, metabolomics and urinary 
vesicles. 
3. STUDY POPULATION 


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Population (base) 
The study population will be selected from the outpatient clinics from hospitals based in the 
Netherlands (Groningen) and Canada (Toronto). 
 
Inclusion criteria: 
1. Male or female subjects diagnosed with T2D ≥12 months prior to informed consent; 
2.  eGFR ≥30 ml/min/1.73m2; 
3.    Age >18 years; 
4.    HbA1c 6.5%-10.5%; 
5. Body Mass Index (BMI) 18.5-45.0 kg/m2; 
6. Blood pressure £160/110 and ³90/60 at screening, 
7. Heart failure with New York Heart Association (NYHA) class 2-3 symptoms and ejection 
fraction ³20% 
8. Stable dose of maximally tolerated ACE inhibitor, angiotensin receptor blocker or renin 
inhibitor for at least 30 days 
9. Stable diuretic dose for at least 30 days at the time of baseline physiological assessment 
10. BNP levels at baseline ³100 pg/ml (no atrial fibrillation), ³200 pg/ml if in atrial fibrillation 
 
Exclusion criteria: 
1. Type 1 Diabetes; 
2. Leukocyte and/or nitrite positive urinalysis that is untreated; 
3. Severe hypoglycaemia within 2 months prior to screening; 
4. History of brittle diabetes or hypoglycaemia unawareness based on investigator judgement; 
5. Unstable coronary artery disease with acute coronary syndrome, percutaneous intervention 
or bypass surgery within 3 months; 
6. Clinically significant valvular disease; 
7. Congestive heart failure secondary to an infiltrative cardiomyopathic process (for example 
amyloid) or pericardial constriction; 
8. Uncontrolled systemic hypertension (systolic blood pressure >160 mmHg and/or diastolic 
blood pressure >110) or systemic hypotension (systolic blood pressure < 90/60 mmHg); 
9. Bariatric surgery or other surgeries that induce chronic malabsorption; 
10. Anti-obesity drugs or diet regimen and unstable body weight three months prior to 
screening; 
11. Treatment with systemic corticosteroids; 
12. Blood dyscrasias or any disorders causing hemolysis or unstable red blood cells; 
13. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not 
practicing an acceptable method of birth control; 
14. Participation in another trial with an investigational drug within 30 days of informed consent; 
15. Alcohol or drug abuse within three months prior to informed consent that would interfere 
with trial participation or any ongoing clinical condition that would jeopardize subject safety 
or study compliance based on investigator judgement; 
16. Liver disease, defined by serum levels of alanine transaminase, aspartate transaminase, or 
alkaline phosphatase >3 x upper limit of normal as determined during screening; 
17. Active malignancy at the time of screening; 
18. Allergy to iodine-based substances if receiving iohexol for GFR measures 


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Any disqualifying clinical or biochemical parameter may be repeated, at the discretion of the 
investigator and where there is a clinical reason to do so. The repeat value should be assessed prior 
to the subject recorded as having screen failed. If the repeat value falls within the ranges defined by 
the protocol and the patient meets all other inclusion criteria, the patient is eligible for the study. 


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2.1 
Sample size calculation 
Sample size: The sample size is based on the primary endpoint of proximal fractional sodium excretion 
(FENa), which will be measured using fractional excretion of lithium as a surrogate for proximal sodium 
handling. Based on preclinical studies, and assuming a baseline FENa of 22±7, to be able to detect a 
40% increase in FENa with an 80% power and a two-tailed alpha = 0.05, 18 patients per group are 
required, for a total sample size of n=36. This sample size is similar to those successfully used in 
previous studies2, and sufficient to measure secondary endpoints related to Na+ handling27,28, renal 
function2, arterial stiffness, plasma volume7, systemic vascular resistance 29 and measures of 
neurohormonal function10,17,18. Randomization will be stratified to assure equal numbers of HFrEF and 
HFpEF patients in the ertugliflozin and placebo-treated groups. We anticipate an approximate 50%/50% 
split in the proportion of participants with HFrEF vs. HFpEF, which will be assessed based on the 2D echo 
at the time of the baseline physiological testing. 
 
Data Analysis: The primary outcome is the difference in proximal sodium reabsorption FENa 
(measured using FELi) with ertugliflozin vs. placebo. Secondary outcomes will consist of within and 
between group changes in hemodynamic and tubular function parameters and vasoactive mediators 
in response to combination vs. monotherapy regimens. Within group comparisons will be analyzed 
using repeated measures ANOVA. As in previous work, between group comparisons will also be made 
using a 2-way ANOVA with treatment allocation as the dependent variable. Post-hoc analyses will be 
used to compare means, corrected for multiple comparisons. In pre-specified, exploratory sensitivity 
analyses, the same endpoints will be examined only in those patients who did not have changes in 
RAAS inhibitors and/or diuretic agents during the treatment period. 
 
3. TREATMENT OF SUBJECTS 
3.1 
Investigational product/treatment 
Blinded IP will be provided to the site by Merck. Each bottle will be identified with a unique 
Composite ID in order to maintain the blind. By way of an Unblinding List, Merck will provide 
treatment allocations of each Composite ID sent to the site. The Unblinding List will be maintained 
within a secure location in the Pharmacy. Blinded personnel will not have access to this list. The blind 
must not be broken during the course of the study unless breaking the blind is required to provide 
medical care to the subject in the event of a medical emergency. The decision to break the blind is 
the responsibility of the Investigator. The Investigator may obtain treatment assignment directly from 
the unblinded Pharmacist. The Unblinding List will be used to confirm treatment assignment in the 
event of a medical emergency. The reason for breaking the blind must be clearly recorded by the 
Investigator in the subject’s source documentation. Patients will take 15 mg ertugliflozin tablet once 
daily or matching placebo according to randomised treatment scheme. 
 
Doses of ertugliflozin of up to 25 mg are well tolerated (see Investigator’s Brochure) in patients with 
T2D, with and without CKD. The proposed 15 mg dose is well tolerated and effective for the 
treatment of T2D and in patients with CKD. Ertugliflozin is effective at reducing blood pressure and 
plasma glucose. In addition, in patients with CKD, this dose was found to be well tolerated. 
 
Study medication is received at the study site by a designated person, handled and stored safely and 
properly, and kept in a secured location. The study medication will be stored according to the 
instructions specified on the drug labels. Storage conditions are adequately monitored. Subjects are 


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asked to return all unused study drug and packaging at the end of the study or at the time of study 
drug discontinuation or in every visit to the outpatient clinic. Appropriate documentation of the 
subject specific dispensing process is maintained. Unused drugs are destroyed by the pharmacy 
department at the end of the study. 
3.2 Use of co-intervention (if applicable) 
Use of the following treatments will be strongly discouraged starting 4 weeks before the start of the 
study and during the study as these medications may interfere with the evaluation of safety, 
tolerability and/or efficacy. 
 
Non-steroidal anti-inflammatory drugs (NSAIDS), systemic corticosteroids, and immunosuppressants 
as these medications may interfere with the evaluation of safety, tolerability and/or efficacy. 
 
The dose of diuretics and vitamin-D analogues should be stable at least 4 weeks prior to enrolment. 
Dose adjustments of diuretics or vitamin-D analogues are strongly discouraged during the trial. 
 
In subjects receiving oral medications containing NSAIDs, ephedrine, phenylephrine, 
pseudoephedrine, or phenylpropanolamine, administration of such medications is recommended to 
be discontinued at least 48 hours before physiological assessments. 
 
4. INVESTIGATIONAL PRODUCT 
4.1 Name and description of investigational product(s) 
Ertugliflozin L-pyroglutamic acid: (1S,2S,3S,4R,5S)-5-(4-chloro- 3-(4-ethoxybenzyl)phenyl)-1- 
(hydroxymethyl)-6,8- dioxabicyclo[3.2.1]octane-2,3,4-triol, compound with (2S)-5- oxopyrrolidine-2- 
carboxylic acid 
 
Product Description and 
Dosage Form 
Dosage form and strength 
Manufacturer 
Ertugliflozin Tablets Total 
Dose 15mg  
Green, film coated tablets (orally) 
Merck 
Placebo Matching 
Ertugliflozin Tablet 
Green, plain, film coated tablet. Does not 
contain active ingredient 
Merck 
 
 
4.2 Summary of findings from non-clinical studies 
Available data from non-clinical study in animals is provided in the Investigator’s Brochure. 
4.3 Summary of findings from clinical studies 
Ertugliflozin: 
SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular 
filtrate back into the circulation. Despite the presence of hyperglycaemia in T2D, reabsorption of 
filtered glucose continues. Ertugliflozin improves both fasting and post-prandial plasma glucose levels 
by reducing renal glucose reabsorption leading to urinary glucose excretion. This glucose excretion 
(glycosuric effect) is observed after the first dose, is continuous over the 24-hour dosing interval and 
is sustained for the duration of treatment. The amount of glucose removed by the kidney through 
this mechanism is dependent upon the blood glucose concentration and GFR. In patients with low 
plasma glucose or low eGFR ertugliflozin’s efficacy to lower HbA1c is low and so the risk of 


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hypoglycemia is low as well. Effects on blood pressure, body mass index, albuminuria, hematocrit are 
likely to be independent of GFR (see Investigator’s Brochure). Ertugliflozin acts independently of 
insulin secretion and insulin action rendering the risk of hypoglycemia low. 
 
Increases in the amount of glucose excreted in the urine were observed in healthy subjects and in 
subjects with T2D following the administration of ertugliflozin. Approximately 64 g of glucose was 
excreted in the urine per day (corresponding to 280 kcal/day) at an ertugliflozin dose of 15 mg/day in 
healthy individuals and with urine glucose excretion of 105 g/day in subjects with T2D. The increase 
in urine glucose excretion is sustained over time. 
 
As of May 2016, a total of 29 Phase 1 and 2 Phase 2 studies with ertugliflozin have been completed. 
In addition, analyses from the primary time point in 5 Phase 3 studies were available to support this 
Investigator’s Brochure (IB). Although these Phase 3 studies have not been completed, information 
from these studies is included. Table 5-1 in the Investigator’s Brochure provides an overview of these 
studies. 
4.4 Summary of known and potential risks and benefits 
Potential risks 
The potential risks for the treatment with ertugliflozin and other SGLT2i are described in the IB. Due 
to its mode of action resulting in increased urinary glucose excretion an increased risk of urinary tract 
infections (slightly higher compared to placebo in the phase 3 studies) and genital infections has 
been seen. 
 
Based on the mechanism of action of ertugliflozin there may be a potential risk for this compound to 
cause hypovolaemia or electrolyte imbalance. As a precaution, patients who, in the judgment of the 
Investigator, may be at risk for dehydration or volume depletion due to co-existing conditions or 
concomitant medications, such as loop diuretics, should have careful monitoring of their volume 
status. In patients already receiving ertugliflozin who develop conditions that may cause 
hypovolaemia or electrolyte imbalance, decisions to interrupt or discontinue ertugliflozin therapy 
and management of patients should be based on clinical judgment. 
 
Ertugliflozin treatment led to small increases in serum phosphate, which were of uncertain 
significance. The magnitude and clinical significance of this in patients with CKD is unclear. 
 
After the introduction of other SGLT2i there have been post marketing reports of ketoacidosis, 
including diabetic ketoacidosis (DKA), in patients with type 1 diabetes (T1D) and T2D, although a 
causal relationship has not been established. Patients presenting signs and symptoms consistent 
with ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, 
should be assessed for ketoacidosis, irrespective of blood glucose levels. If ketoacidosis is suspected, 
discontinuation or temporary interruption of ertugliflozin should be considered and the patient 
should be promptly evaluated. 
 
Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from pancreatic 
disorders (e.g., T1D, history of pancreatitis, or pancreatic surgery), insulin dose reduction, reduced 
caloric intake, or increased insulin requirements due to infections, illness or surgery and alcohol 
abuse. Ertugliflozin should be used with caution in these patients. 


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There is no reason to believe that ertugliflozin poses an undue risk of hypoglycemia in diabetic 
patients. The amount of glucose excreted in the urine depends on the total filtered glucose load 
(blood glucose concentration x GFR). Thus, at blood glucose levels in the low normal range, the 
amount of glucose excreted into the urine is not sufficient to induce hypoglycemia (Defronzo et.al 
2013). 
 
Protection against risks 
This study has been designed with appropriate measures in place to monitor and minimize any of the 
potential health risks to participating patients. Safety signal detection will include the integration of 
all available sources of safety information, including clinical study data, adverse events (AE) reports, 
pre-clinical data, epidemiological studies and literature reports, to identify and characterize 
unrecognized safety risks or changes in those which are currently expected Adverse Drug Reactions. 
Any information that may affect the benefit-risk profile of ertugliflozin will be immediately 
communicated to relevant Health Authorities and appropriate actions will be taken regarding the 
clinical study as needed. Thus real-time, active safety surveillance will be conducted during the 
entire duration of this study. 
 
In addition, if deemed necessary by the treating physician, temporary and if necessary permanent 
discontinuation of ertugliflozin in individual patients in whom a potential health risk or a laboratory 
abnormality of clinical concern has been identified. 
 
Potential benefits to patients 
In this study, the dose of ertugliflozin 15 mg was chosen based on previous clinical experience. This 
mechanistic study is non-therapeutic; therefore, it has limited or no direct clinical benefit for the 
subjects. In studies of longer duration ertugliflozin is expected to reduce progression of renal failure 
and reduce CV mortality. Ertugliflozin is known to decrease body weight (or prevent weight gain) as 
well as lower blood pressure and albuminuria in patients with T2D. 
 
Patients are also expected to receive some benefit in the form of increased medical care/attention 
when participating in study procedures. 
 
Informed consent and alternatives to participation 
All prospective participants will be fully informed of the possible risks and benefits associated with 
this study, and their consent will be obtained prior to performing any study-specific activity. Should a 
prospective participant elect to not participate in the study or to withdraw from the study, other 
medications are available to treat their CKD, and other possible concomitant diseases according to 
the discretion of their treating physician. The patient will not be disadvantaged in any way. 
 
Conclusion 
Considering the pre-clinical and clinical experience with ertugliflozin and the precautions included in 
the study protocol, participation in this study presents a minimal and thus acceptable risk to patients 
who meet the inclusion/exclusion criteria and consent to take part in the study. 
4.5 Description and justification of route of administration and dosage 
Ertugliflozin is absorbed from the digestive tract and can therefore be orally administered. 


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4.6 Dosages, dosage modifications and method of administration 
Ertugliflozin will be administered in a dose of 15 mg/day. 
4.7 Preparation and labelling of Investigational Medicinal Product 
Study medication (ertugliflozin and matching placebo) will be provided by Merck. The pharmacy 
department of the University Health Network will be responsible for labelling and distribution of 
study medication to the participating sites. Study medication will be stored by the pharmacy unit of 
each participating centre in accordance with relevant guidelines. 
4.8 Drug accountability 
All study medications will be stored at room temperature at the pharmacy department of each 
participating centre. Study medication will be collected from the pharmacy department by the 
principle investigator at each participating centre. Non-used medication will be returned to the 
pharmacy department where it will be destroyed. 
4.9 Handling and Dispensing 
The investigational product should be stored in a secure area according to local regulations. The 
investigator is responsible for ensuring that it is dispensed only to study subjects and only from 
official study sites by authorized personnel, as dictated by local regulations. The investigator is 
responsible for ensuring that the investigational product is stored under the appropriate 
environmental conditions (temperature, light, and humidity), as described in section 6.1. 
If concerns regarding the quality or appearance of the investigational product arise, the 
investigational product will not be dispensed and Merck will be contacted immediately. 
4.10 Drug Ordering 
Initial Orders 
Contact the protocol manager at the UHN for information. 
Re-Supply 
Contact the protocol manager at the UHN (vesta.lai@uhn.ca) for information. 
 
When assessing need for resupply, institutions should keep in mind that shipments may take 10-15 
business days as of receipt of request. Be sure to check with your pharmacy regarding existing 
investigational stock to assure optimal use of drug on hand. 


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5. NON-INVESTIGATIONAL PRODUCT 
5.1 Name and description of non-investigational product(s) 
Inulin (Inutest) or iohexol (Omnipaque) and paraaminohippurate (PAH), lithium carbonate (300 
mg one day prior to each physiological study day i.e. on three occasions). 
5.2 Summary of findings from non-clinical studies 
Inulin and PAH have very low acute intravenous toxicities in mice and rats. Animal studies have 
shown that these agents have a very low protein binding and are well tolerated by the kidneys. The 
cardiovascular and neurotoxicity are low. Lithium will be administered on three separate occasions to 
measure tubular sodium handling. Plasma volume will be measured using a non-radioactive 
technique (indocyanine green dilution) to assess changes in plasma volume in response to SGLT2 
inhibition 
5.3 Summary of findings from clinical studies 
Close to 100 per cent of the intravenously injected Inulin and PAH are excreted unchanged through 
the kidneys within 24-hours in patients with normal renal function. The elimination half-life is 
approximately 2 hours in patients with normal renal function. The protein binding of these agents is 
so low (<2%) that it has no clinical relevance and can therefore be neglected. In the doses used in this 
set of studies, lithium does not reach steady state and has no known risk. 
5.4 Summary of known and potential risks and benefits 
Measurement of GFR and effective renal plasma flow by plasma clearance of Inulin and PAH has not 
been associated with reports of adverse events, but should be avoided in subjects with known 
intolerances to these agents. Lithium will not be used in patients with a known intolerance to this 
medication. Iohexol will not be administered in patients with known allergic reactions to this 
substance or to iodine based solutions. Iohexol has a very low risk of causing allergic reactions, and 
anyone with an allergy will be treated appropriately by the study team and will not receive it again 
on future study visits. 
5.5 Description and justification of route of administration and dosage 
Inulin (or iohexol) and PAH will be intravenously administered according to established UHN 
protocols through an injection catheter. 
5.6 Drug accountability 
Inulin (or iohexol) and PAH will be stored at room temperature at each site. Inulin (or iohexol) and 
PAH and lithium will be collected from the pharmacy department by the principle investigator at 
each participating center in the morning of the study visit. 


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6. METHODS 
6.1 Study parameters/endpoints 
6.1.1 
Main study parameter/endpoint 
• 
Fractional excretion of sodium, using lithium clearance as a surrogate for proximal tubular 
sodium handling. 
 
6.1.2 
Secondary study parameters/endpoints (if applicable) 
• 
Glomerular Filtration Rate and Renal plasma flow measured with inulin and PAH, 
as well as derived renal hemodynamic parameters as described elsewhere.25 In 
the event that inulin is not available to measure GFR, then iohexol will be used, 
provided that there is no history of allergy to iodine based substances. 
• 
Systolic/diastolic blood pressure, heart rate 
• 
Echocardiography for markers of systolic and diastolic function, cardiac output 
(29) 
• 
Arterial stiffness 
• 
Plasma volume will be measured using a non-radioactive technique (indocyanine green 
dilution) to assess changes in plasma volume in response to SGLT2i (20, 27). 
• 
Extracellular water, will be measured non-invasively using bioimpedence spectroscopy, as 
described elsewhere(28). 
• 
Cardiac output and systemic vascular resistance will also be measured using 
non-invasive cardiac monitoring (NICOM). This non-invasive technique is a 
form of bioelectrical impedance (“bioreatance”) to measure thoracic fluid 
content with electrocardiogram electrode stickers. Beat-to-beat changes in 
fluid content can be used to derive cardiac output. Then, using measured 
mean arterial pressure, systemic vascular resistance can be calculated. This 
entire measurement process takes approximately 15 minutes. 
• 
Neurohormones/biomarkers 
o Hormones of the RAAS (renin, aldosterone in plasma and urine) 
o Natriuretic Peptides 
o Sympathetic nervous system markers 
o Urinary adenosine 
 
6.1.3 
Other study parameters (if applicable) 
• 
Number of hypoglycaemic episodes 
• 
Serious Adverse Events 
• 
Drug related adverse events (causality to investigational product assessed by 
research physician). 
 
6.2 
Randomisation, blinding and treatment allocation 
Treatment ertugliflozin and placebo will be randomized. A computer generated randomized code 
generated by UHN will be used. The pharmacy of each participating centre will store the 
randomization code. 
 
6.3 
Study procedures 
• 
Physical examination 


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Patients will be subjected to physical examination by the principal investigator before 
inclusion. This physical examination entails a routine investigation of heart, lungs and 
abdomen. At each visit patients will be asked for adverse events related to urinary tract 
infections or genital infections. 
• 
24hr urine collection 
Patients are asked to collect 24hr urine at start and end of each treatment period to monitor 
albuminuria. In total, three 24hr urines are collected during the course of this study. 24hr 
urine collection instructions will be provided to each patient. The volume of the urine 
containers is determined when the patient delivers the urine at each visit. Subsequently part 
of the urine is used for clinical chemistry measurement and the other part stored per 
instructions in the laboratory manual. 
• 
Renal hemodynamic function 
GFR and plasma flow measurements will be performed during each of the three physiological 
assessment visits. 
The central laboratory at the UHN will be providing detailed instructions for the renal 
function tests in a separate laboratory manual. The inulin/PAH will be bought by the 
investigational site and should be used in accordance with the approved product label and 
manual instructions. In the event that inulin is not available, then iohexol will be used 
instead according to label and laboratory manual instructions. 
 
Subject preparation: 
After a 10-hr fast, two intravenous (IV) catheters, one in each arm, will be placed in the 
subject’s antecubital vein. One line will be used for the injection of renal function marker 
solutions. The second line will be used for intermittent blood sampling. On each long study 
day (Visits 3, 4 and 8), study medication will be taken between after arrival in the laboratory 
BEFORE physiological measurements are obtained. 
• 
Blood pressure measurements 
Blood pressure will be measured by office blood pressure machine during the outpatient 
visits. Patients will be in a semi-supine position during the blood pressure measurement. The 
average of three readings will be used. 
• 
Venipuncture 
At each of the visits, approximately 20 ml will be taken for routine blood tests (approximately 
20 ml/ 7 visits = 140 ml). At each of the 3 visits to assess kidney function, approximately 24 
ml will be taken (total 72 ml), plus another 20 ml at each kidney function visit for 
measurement of hormones and other factors associated with kidney disease (approximately 
20 ml for each of the 3 kidney visits = 60 ml). At the end of each of the 2 treatment periods 
(Visits 4 and 8), 9 blood samples of 1ml will be taken for ertugliflozin PK analysis (total 18ml). 
A total of approximately 290 ml of blood will be collected over 12 week period. Additional 
blood sampling will be take for plasma volume and lithium/sodium excretion measurements 
as described in the ICF. 
• 
Laboratory measurements 
All routine laboratory measurements of this study will be assessed at the local laboratories of 
participating centres. 
• 
Ertugliflozin plasma/urine concentration measurement 
At the end of the treatment period, during the GFR assessment, a 6 ml blood sample will be 
drawn for ertugliflozin and its metabolite ertugliflozin-3O-glucuronide measurement. 


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6.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
6.5 
Replacement of individual subjects after withdrawal 
Patients that meet inclusion criteria will be invited for participation in the study. When patient 
agrees to participate in the study, informed consent is signed. When patient decides to withdraw 
after start of the treatment period, new patients can be admitted to the study to reach the 
required sample size. 


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6.6 Follow-up of subjects withdrawn from treatment 
Subjects who withdraw from the study will be followed up according to the routine terms of 
patient care at the outpatient clinic or revered back to their general practitioner. 
6.7 Premature termination of the study 
There are no predefined criteria for premature termination of the study. If, however, during the 
conductance of the study information becomes available showing that continuation of the study 
would result in a significant safety risk for the patients, the principal investigator and project 
leader will decide to terminate the study. 
 
7. SAFETY REPORTING 
7.1 Section 10 WMO event 
In accordance to section 10, subsection 1, of the WMO, the investigator will inform the subjects 
and the reviewing accredited medical ethics committee if anything occurs, on the basis of which 
it appears that the disadvantages of participation may be significantly greater than was foreseen 
in the research proposal. The study will be suspended pending further review by the accredited 
medical ethics committee, except insofar as suspension would jeopardize the subjects’ health. 
The investigator will take care that all subjects are kept informed. 
7.2 AEs, SAEs and SUSARs 
 
7.2.1 
Adverse events (AEs) 
An adverse event is any untoward medical occurrence in a patient administered a medicinal 
product and which does not necessarily have to have a causal relationship with this 
treatment. An adverse event can therefore be any unfavourable and unintended sign (for 
example, an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to this medicinal product. 
(ICH E2D) 
 
7.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any dose: 
- 
results in death; 
- 
is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused 
death if it were more severe) ; 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; 
- 
is an important medical event (defined as a medical event [s] that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [eg, medical, surgical] to prevent one of the other serious outcomes listed in 
the definition above.) Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias 
or convulsions that do not result in hospitalization.) 


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AEs will be recorded in the eCRF as: 
• 
AEs 
• 
An SAE 
• 
If the AE is the reason for permanent discontinuation from investigational product 
(DAE), if the AE leading to Investigational Product interruption or dose reduction 
• 
An AE of interest 
• Urinary Tract Infection or Genital Infections 
• Potential DKAs 
• Volume depletion 
• Fractures 
• Major hypoglycaemic events 
• Acute kidney injury 
• Amputation or related events 
 
7.2.3 
Adverse events of interest 
Urinary tract infection or genital infections 
All potential events of urinary tract infection or genital infections will be recorded in the 
eCRF. 
 
Diabetic ketoacidosis (DKA) 
All potential events of DKA will be recorded in the eCRF. 
 
Volume depletion 
Events of volume depletion (eg, dehydration, hypovolemia, or hypotension) will be collected 
on the eCRF as AEs. 
 
Fractures 
All fractures will be recorded in the eCRF as AEs and on a separate eCRF page. 
 
Major hypoglycaemic event 
A major hypoglycaemic event is defined as an event that requires assistance of another 
person to actively administer carbohydrates, glucagon, or take other corrective actions. 
Plasma glucose concentrations may not be available during an event, but neurological 
recovery following the corrective actions is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. Major hypoglycaemic episodes will be 
recorded in the eCRF as an AE and on an additional eCRF page. 
 
Acute Kidney Injury 
Acute kidney injury is defined as an increase of 40% in serum creatinine from the previous 
visit or hospitalization due to acute kidney injury. All acute kidney injury events will be 
recorded on a separate eCRF. 
 
Amputation and related events: 
Amputations and related events will be recorded in the eCRF. Information on the actual 
amputations will be captured on a specific eCRF page. 


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7.3 Recording of Adverse Events 
• Time Period for Collection of Adverse Events 
For this study, AEs, SAEs, DAEs, and AEs of special interest will be collected from the time 
of signing the informed consent and throughout the study, including the run-in and wash-
out periods. 
• Follow-up of Unresolved Adverse Events 
Any AEs, SAEs, DAEs, and AEs of special interest that are unresolved at follow-up are 
followed up by the Investigator for as long as medically indicated, but without further 
recording in the eCRF. 
• Variables 
The following variables will be collected for each SAE/DAE/AE of special interest: 
• 
AE (verbatim). 
• 
The date and time when the AE started and stopped. 
• 
Intensity. 
• 
Whether the AE is serious or not. 
• 
Investigator causality rating against the study drug (yes or no). 
• 
Action taken with regard to study drug. 
• 
AE caused patient’s withdrawal from study (yes or no). 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for a serious AE. 
• 
Date Investigator became aware of the SAE. 
• 
AE is serious due to. 
i. Date of hospitalisation (if applicable). 
ii. Date of discharge (if applicable). 
iii. Probable cause of death (if applicable). 
iv. Date of death (if applicable). 
v. Autopsy performed (if applicable). 
vi. Causality assessment in relation to Study procedure(s). 
vii. Causality assessment in relation to other medication (e.g., concomitant 
medication, background therapy). 
Description of intensity. 
The intensity of the reported AEs/SAEs/DAEs/AE of interest will be assessed according 
to the following scale: 
o Mild (awareness of sign or symptom, but easily tolerated). 
o Moderate (discomfort sufficient to cause interference with normal activities). 
o Severe (incapacitating, with inability to perform normal activities). 
 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 8.2.2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 8.2.2. On the other hand, a stroke that results in only a limited degree of 


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disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 8.2.2. 
• Causality Collection 
The Investigator will assess causal relationship between Investigational Product and each 
SAE/DAE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’ 
• Adverse Events Based on Signs and Symptoms 
All AEs/SAEs/DAEs/AE of special interest spontaneously reported by the patient or reported in 
response to the open question from the study personnel: ‘Have you had any health problems 
since the previous visit/you were last asked?’, or revealed by observation will be collected 
and recorded in the eCRF. When collecting AEs/SAEs/DAEs/AE of special interest, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
• Adverse Events Based on Examinations and Tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values, or vital signs will be reported as AEs if they fulfil any of the AE criteria. If deterioration 
in a laboratory value/vital sign is associated with clinical signs and symptoms, the sign or 
symptom will be reported as an AE and the associated laboratory result/vital sign will be 
considered as additional information. Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). Any new or aggravated clinically relevant abnormal 
medical finding at a physical examination as compared with the baseline assessment will be 
reported as an AE. 
7.4 Serious Adverse Event Collecting and Reporting 
• 
Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs will be collected that occur during the screening 
period and within 30 days of discontinuing dosing. If applicable, SAEs must be collected that 
relate to any later protocol-specific procedure (such as follow-up skin biopsy). 
• 
The investigator should report any SAE occurring after these time periods that is believed to 
be related to study drug or protocol-specified procedure. 
• 
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness. 
• 
If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy, or a complication of a 
study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 


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SAEs that result in death or are life threatening should be reported expedited to the 
competent authorities. The expedited reporting will occur not later than 7 days after the 
responsible investigator has first knowledge of the adverse reaction. This is for a preliminary 
report with another 8 days for completion of the report. Concurrently, the investigator 
(sponsor) will report SAEs accompanied by a cover page mentioning the study code, patient 
number, country, investigator, seriousness to Merck within the same timelines. 
 
7.4.1 
Suspected unexpected serious adverse reactions (SUSARs) 
Adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
Unexpected adverse reactions are SUSARs if the following three conditions are met: 
1. the event must be serious (see chapter 8.2.2); 
2. there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of the 
administered dose; 
3. the adverse reaction must be unexpected, that is to say, the nature and severity of the 
adverse reaction are not in agreement with the product information as recorded in: 
• 
Summary of Product Characteristics (SPC) for an authorised medicinal product; 
• 
Investigator’s Brochure for an unauthorised medicinal product. 
 
Health Authority and METC Reporting 
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC in the Netherlands or accredited ethics committees in other 
countries: 
- SUSARs that have arisen in the clinical trial that was assessed by the METC; 
- SUSARs that have arisen in other clinical trials of the same sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects 
involved in the clinical trial that was assessed by the METC. 
The remaining SUSARs are recorded in an overview list (line-listing) that will be submitted 
once a year to the METC. This line-listing provides an overview of all SUSARs from the study 
medicine, accompanied by a brief report highlighting the main points of concern. 
The expedited reporting of SUSARs through the web portal ToetsingOnline is sufficient as 
notification to the competent authority. 
 
The sponsor will report expedited all SUSARs to the competent authorities in other Member 
States, according to the requirements of the Member States. Concurrently, sponsor will 
report SUSARs to Merck within the same timelines. 
 
Sponsor will report SAE expedited SAR to competent authorities in each member state. The 
expedited reporting will occur not later than 15 days after the sponsor has first knowledge 
of the adverse reactions. For fatal or life threatening cases the term will be maximal 7 days 
for a preliminary report with another 8 days for completion of the report. Concurrently, the 
investigator (sponsor) will report SAEs accompanied by a cover page mentioning the study 
code, patient number, country, investigator, seriousness to Merck within the same 
timelines. 


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There will be two sets of emergency code breaks, one set will be retained by the project leader 
and one set will be forwarded to the pharmacy of each participating center. The blinded 
emergency code break contains the details of drug treatment. In an emergency, de code can be 
unblinded to identify the treatment given to that subject. Unblinding is not to be performed for 
any reason, other than an emergency where unblinding is required. When the Investigator 
removes the scratch-off covering he/she must note the date, time and reason for removing it and 
record this information in the Comments section of the CRF/ on the code-break card (source 
data). He/she must also immediately inform the project leader and the principal investigator that 
the code has been broken. Even though the code is broken, any blood samples for safety or 
pharmacodynamic assessments will continue to be drawn, for at least 24hr following the last 
dose as long as doing so will not compromise subject welfare. 
It is the responsibility of the Investigator to ensure that there is a procedure in place to allow 
access to the code break cards in case of emergency. Study drug must be discontinued after 
unblinding but the subject will be followed until resolution of the adverse event. At the 
conclusion of the study, the occurrence of any emergency code breaks will be determined after 
return of all code break reports. 
7.5 Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor and Merck. 
 
7.5.1 Maternal exposure 
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately. 
 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy should be reported. 
 
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel informs the sponsor’s representatives within 1day of when he/she became 
aware of it. 
7.6 Overdose 
There is no specific antidote for an overdose of ertugliflozin. In the event of an overdose, employ 
usual supportive measures such as removing unabsorbed material from the GI tract, perform clinical 
monitoring, and institute supportive treatment as dictated by the subject’s clinical status. 
 
• An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module. 
• An overdose without associated symptoms is only reported on the Overdose eCRF module. 


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7.7 Annual safety report 
In addition to the expedited reporting of SUSARs, the sponsor will submit, once a year throughout 
the clinical trial, a safety report to the accredited METC, competent authority, and competent 
authorities of the concerned Member States. 
This safety report consists of: 
• 
a list of all suspected (unexpected or expected) serious adverse reactions, along with an 
aggregated summary table of all reported serious adverse reactions, ordered by organ 
system, per study; 
• 
a report concerning the safety of the subjects, consisting of a complete safety analysis and 
an evaluation of the balance between the efficacy and the harmfulness of the medicine 
under investigation. 
All safety reports should be simultaneously communicated to Merck. 
7.8 Data Safety Monitoring / Safety Committee] 
The oversight of safety of ertugliflozin in this trial will be performed by Drs Cherney and 
Heerspink. 
8. STATISTICAL ANALYSIS Primary study parameter(s) 
The primary outcome is the difference in FENa with ertugliflozin vs. placebo. Secondary outcomes 
will consist of within and between group changes hemodynamic and tubular function parameters 
and vasoactive mediators in response to combination vs. monotherapy regimens. Within group 
comparisons will be analyzed using repeated measures ANOVA. As in previous work, between 
group comparisons will also be made using a 2-way ANOVA with treatment allocation as the 
dependent variable. Post-hoc analyses will be used to compare means, corrected for multiple 
comparisons. In pre-specified, exploratory sensitivity analyses, the same endpoints will be 
examined only those patients who did not have changes in RAAS inhibitors and/or diuretic agents 
during the treatment period. 
 
8.2 Other study parameters 
Descriptive statistics will be used to analyse the means and distribution between all the study 
variables. The means of the normal distributed variables will be compared with the student T-test 
and non-parametric tests (Mann-Whitney U-test for continued and Chi-Square test for nominal 
variables) will be used for the variables that do not follow a normal distribution. Missing values 
will be imputed using multiple imputation techniques. Before introducing multiple imputation 
techniques the pattern of missing values will be examined. If the pattern of missing values 
indicates that missing values occur randomly a PROC MI statement in SAS will be implemented to 
impute missing values. 
In case patients require rescue medication this will be recorded in the database. During the data- 
analysis sensitivity analyses will be conducted by adding an additional covariate in the mixed 
model to account for rescue medication required during the study. 
8.3 Interim analysis 
N/A 


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9. ETHICAL CONSIDERATIONS 
9.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (Fortaleza, 
2013) and in accordance with the Medical Research Involving Human Subjects Act (WMO). The 
Medical Ethical Committee of all participating centers will approve the study. 
 
9.2 Recruitment and consent 
Patients will be enrolled to the trial from centers in the Netherlands (1 center) Canada (1 center). 
Prior to their visit to the outpatient clinic, patients will be invited to participate in the study by 
verbal invitation when they attend the clinic or by sending an invitation letter. In this letter, 
patients will find a full explanation of the study, advantages and disadvantages of participating, 
and contact information of the research team members working on this study. Moreover, the 
letter contains contact information of an independent physician, to whom subjects can address 
questions about the research before, during and after a study. The patients will be given 2 weeks 
to consider their decision and will then be asked to sign their written informed consent before 
they take part in the study. 
9.3 Objection by minors or incapacitated subjects (if applicable) 
No minors or incapacitated adults will be included in this study 
9.4 Benefits and risks assessment, group relatedness 
There are no direct benefits for the patients to be included. Participation in the study is on a free- 
will base. Patients will receive restitution of all costs of transportation. Patients will not receive 
priority for treatment of other diseases in the clinic during this study. Participation in the 
proposed study is accompanied with only minor risks. The blood samples will be drawn by means 
of venipuncture that will be performed during the visit to the outpatient clinic. All further 
performed measurements are non-invasive and therefore only minor risks are associated with 
participation. 
9.5 Compensation for injury 
The sponsor University Medical Center Groningen (UMCG) has an insurance which is in 
accordance with the legal requirements in the Netherlands (Article 7 WMO and the Measure 
regarding Compulsory Insurance for Clinical Research in Humans of 23th June 2003). This 
insurance provides cover for damage to research subjects through injury or death caused by the 
study. The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. All patients will receive written information about this insurance. 
The University Health Network also has insurance in accordance with the legal requirements of 
Canada. 
9.6 
Incentives (if applicable) 
Participation of patients in the study is a free-will decision. Patients will receive restitution of all 
costs for transportation and a honorarium for participating. Patients do not receive priority for 
treatment of other diseases in the clinic during this clinical trial. 


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10. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
10.1 Handling and storage of data and documents 
A subject identification code list will be made to link the data to the subject in order to be able to 
trace data to an individual subject. This code will not be based on the patient initials and birth- 
date. The key to the code will be safeguarded by the investigator since the data will be kept for a 
period of 15 years. The handling of personal data will comply with privacy laws, legislation, codes 
and/or guidelines that apply in the applicable jurisdictions the study is conducted. 
10.2 Amendments 
A ‘substantial amendment’ is defined as an amendment to the protocol or any other supporting 
documentation, that is likely to affect to a significant degree: 
• 
the safety or physical or mental integrity of the subjects of the trial; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 
• 
the quality or safety of any intervention used in the trial. 
All substantial amendments will be notified to the local competent authority.  
Non-substantial amendments will be reported to Health Canada as a CTA-Notification, or to the local  
competent health authority as appropriate as per the jurisdiction. 
 
Non-substantial amendments will not be notified to the competent authority, but will be 
recorded and filed by the sponsor. 
10.3 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the REB as part of 
the annual renewal process. Information will be provided on the date of inclusion of the first 
subject, numbers of subjects included and numbers of subjects that have completed the trial, 
serious adverse events/ serious adverse reactions, other problems, and amendments. 
10.4 End of study report 
The sponsor will notify the competent authority of the end of the study within a period of 90 
days. The end of the study is defined as the last patient’s last visit. In case the study is ended 
prematurely, the sponsor will notify the accredited METC and the competent authority within 15 
days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
Competent Authority. 
10.5 Public disclosure and publication policy 
The study will be registered at clinicaltrials.gov or equivalent trial registries. Publication policy is in 
agreement with international regulations. Nor the sponsors, nor the principal investigator has a 
right of veto regarding the way of publishing the results. 
 
11. STRUCTURED RISK ANALYSIS 
11.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
• 
The Sodium glucose co-transporter 2 (SGLT2), located in the proximal tubule of the 


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kidney, is an effective transporter system which is responsible for the nearly complete 
reabsorption of glucose in order to maintain appropriate glucose levels. Each glucose 
molecule that is reabsorbed is accompanied by reabsorption of a sodium molecule in a 
1:2 ratio. SGLT2i reversely inhibit the SGLT-2 transporter, which leads to enhanced 
glucose and sodium excretion and a reduction in plasma glucose and HbA1c. The effects 
of ertugliflozin on the SGLT2 transporter are well characterized and sufficient knowledge 
is available about the mechanisms of action.30,31 
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar 
biological mechanism 
 
• 
Twelve phase 3 randomized controlled clinical trials were conducted involving more than 
6000 patients with T2D of whom ~4000 were treated with ertugliflozin. Eleven studies 
were 24-weeks in duration with extension in 6 studies up to 78 weeks. One study was 52 
weeks in duration with extension of another 52 weeks. 
• 
As of the data cut for the most recent edition of the Investigator’s Brochure, a total of 
8446 human subjects, including 7852 (93.0%) with T2DM, have been exposed to 
ertugliflozin. Oral doses as high as 300 mg (single dose), 100 mg q.d. for up to 14 days, 
and 25 mg q.d. for up to 12 weeks have been found to be safe and well tolerated. The 
maximum tolerated dose in the clinical setting has not been identified. 
• 
Other SGLT2 inhibitors canagliflozin and empagliflozin are registered in the US and 
Europe. In addition, a number of other SGLT-2 inhibitors are in various stages of clinical 
development. 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human 
cell material? 
• 
Various animal models and cell lines are available to study the effect of SGLT2 inhibitors in 
more detail at a tissue/cell level. 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
SGLT2 is highly localized to the kidney and major effects are expected to be related to 
glycosuria and natriuresis. 
 
e. Analysis of potential effect 
In placebo controlled clinical trials the following adverse reactions have been identified: 
• Infections and infestations: vulvovaginitis, balanitis and genital infections, urinary 
tract infections (Common) 
• Metabolism and nutrition disorders: Hypoglycemia; volume depletion 
(uncommon) 
• Gastrointestinal disorders: Constipation (uncommon) 
• Musculoskeletal: Back pain (Common) 
• Renal and urinary disorders: Dysuria; Polyuria (Common); Nocturia (uncommon) 
Common (>1/100 to <1/10) and uncommon (>1/1000 to <1/100) 
 
Few adverse events led to discontinuation of treatment and adverse events were balanced across 
study groups. The most commonly reported events leading to discontinuation in patients treated 


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(0.3%), nausea (0.2%), and rash (0.2%). It should be noted that the transient rise in serum 
creatinine may reflect a reduction in intra-glomerular pressure which may be associated with 
long-term structural renal protection. 
 
f. Pharmacokinetic considerations 
The potential for clinically significant drug-drug interactions (DDIs) resulting from ertugliflozin- 
mediated inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A activity, or 
induction of CYP1A2 or CYP3A4, is low. Hence, clinically meaningful DDIs between ertugliflozin 
and other oral antidiabetic drugs that are oxidatively metabolized by CYP2C9 and CYP2C8 are not 
anticipated. Furthermore, clinically meaningful drug interactions with concomitant medications 
that are substrates of breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), human 
organic cation transporter (hOCT)2 (e.g. metformin), human organic anion transporter (hOAT)1, 
hOAT3 (e.g. sitagliptin), hOATP1B1 (statins), or hOATP1B3 are not anticipated. 
 
In vitro studies with Caco-2, MDR1-MDCK, and BCRP-MDCK cells suggest that ertugliflozin may be 
a substrate for P-gp and BCRP-mediated efflux. However, ertugliflozin has high aqueous solubility 
and moderate permeability, and, following a 25-mg oral dose of [14C]ertugliflozin, more than 50% 
of the dose was absorbed in humans. These data, along with the dose-proportional increases in 
exposure observed in humans over the dose range of 0.5 to 300 mg, indicate that neither P-gp nor 
BCRP is likely to be a limiting factor for oral absorption of ertugliflozin. 
 
Co-administration of multiple doses of rifampin resulted in a 38.8% reduction in AUC for 
ertugliflozin. There were no clinically meaningful DDIs between ertugliflozin and sitagliptin, 
metformin, glimepiride, or simvastatin. Dose adjustment for ertugliflozin is not required in 
patients with renal impairment, or when ertugliflozin is coadministered with rifampin, sitagliptin, 
metformin, glimepiride, or simvastatin. 
 
In healthy subjects, a supratherapeutic dose of ertugliflozin was not associated with QTc interval 
prolongation at Cmax values >6× the mean Cmax,ss for q.d. administration of 15 mg. 
 
g. Study population 
The enrolled population is in a stable condition and no unexpected serious adverse events are 
foreseen. 
 
h. Interaction with other products 
See section f above. 
 
i. Predictability of effect 
Efficacy is monitored by measuring albuminuria / blood pressure / Hba1c which are accepted and 
accurate surrogates to evaluate efficacy. 
 
j. Can effects be managed? 
Patients are regularly monitored and asked about adverse effects of urinary tract infections or 
infestations. As reported above, ertugliflozin administration is associated with an increased risk of 
infections which can be managed with standard antimicrobial treatment. 32 


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11.2 Synthesis 
The available data show that ertugliflozin decreases HbA1c, blood pressure and body weight in 
patients with T2D and increases incidence of urinary tract infections. This adverse effect led in 
rare instances to treatment discontinuation and is manageable with standard antimicrobial 
treatment. 


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12. REFERENCES 
 
1. Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 
diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of 
randomized trials. Ann Med 2012;44:375-93. 
2. Cherney DZI, Perkins BA, Soleymanlou N, et al. The Renal Hemodynamic Effect of SGLT2 Inhibition 
in Patients with Type 1 Diabetes. Circulation 2014;129:587-97. 
3. Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat 
Rev Endocrinol 2012;8:495-502. 
4. Cherney DZI, Lund SS, Perkins BA, et al. Empagliflozin Reduces Microalbuminuria and 
Macroalbuminuria in Patients with Type 2 Diabetes ASN poster, Philadelphia 2015;SA-PO-1109. 
 4a. David Cherney, Bernard Zinman, Silvio E. Inzucchi, Audrey Koitka-Weber, Maximilian von Eynatten, 
  Christoph Wanner. Effect of Empagliflozin on Albuminuria in Patients with Type 2 Diabetes and High    
  Cardiovascular Risk. Lancet Diabetes Endocrinology 2017;5:610-621 
4b. David Cherney, Maximilian von Eynatten, Soeren S. Lund, Stefan Kaspers, Susanne Crowe, 
Hans J. Woerle, Maximilian von Eynatten. The Effect of Sodium Glucose Cotransport 2 (SGLT2) 
Inhibition with Empagliflozin on Microalbuminuria and Macroalbuminuria in Patients with Type 
2 Diabetes. Diabetologia. 2016;59:1860-70. 
5. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in 
Type 2 Diabetes. N Engl J Med 2015;373:2117-28. 
6. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 
2 Diabetes. N Engl J Med 2017. 
7. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug 
with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013;15:853-62. 
8. Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal 
protection in diabetic nephropathy. Curr Opin Nephrol Hypertens 2015;24:96-103. 
8a. Lovshin, JA, Rajasekeran, H, Lytvyn, Y, Lovblom, E, Khan, S, Alemu, R, Perkins, B, Wang, W, Drucker, DJ, DZ 
  Cherney. Dipeptidyl Peptidase-4 Inhibition in Patients with Type 2 Diabetes Stimulates Distal Tubular   
  Natriuresis and Increases in SDF-1α1-67. Diabetes Care 2017:40;1073-1081 
9. Cherney DZ, Perkins BA, Soleymanlou N, et al. Sodium glucose cotransport-2 inhibition and 
intrarenal RAS activity in people with type 1 diabetes. Kidney Int 2014;86:1057-8. 
10. Rajasekeran H, Lytvyn Y, Bozovic A, et al. The Effect of SGLT2 Inhibition on Adenosine Excretion in 
Patients with Type 1 Diabetes. Poster No: X Presented at the American Diabetes Association (ADA) 
76rd Scientific Sessions 2016. 
11. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart 
failure: a report of the American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239. 
12. Mentz RJ, Broderick S, Shaw LK, Fiuzat M, O'Connor CM. Heart failure with preserved ejection 
fraction: comparison of patients with and without angina pectoris (from the Duke Databank for 
Cardiovascular Disease). J Am Coll Cardiol 2014;63:251-8. 
13. Wanner C. Empagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and 
Chronic Kidney Disease American Society of Nephrology 2015;High Impact Late Breaking Clinical 
Trials session. 
14. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin Reduces Blood Pressure in Patients With Type 2 
Diabetes and Hypertension. Diabetes Care 2014;38:420-8. 
15. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with 


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type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 
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;37:1526-34. 
17. Jordan J, Tank J, Heusser K, et al. Empagliflozin has no discernible effect on muscle sympathetic 
nerve activity in patients with type 2 diabetes despite reductions in blood pressure and weight. 
Diabetes 2014;63:A265 [1030-P]. 


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18. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and 
heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 
2014;13:28. 
19. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 
Inhibitors in the Treatment of Diabetes: Cardiovascular and Kidney Effects, Potential Mechanisms and 
Clinical Applications. Circulation 2016;134:752-72. 
20. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 
2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary 
glucose excretion in healthy subjects. Diabetes Obes Metab 2011;13:669-72. 
21. Sarashina A, Koiwai K, Seman LJ, et al. Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) 
inhibitor, in healthy Japanese subjects. Drug Metab Pharmacokinet 2013;28:213-9. 
22. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in 
Type 2 Diabetes. N Engl J Med 2015;373:2117-28. 
23. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 
2 Diabetes. N Engl J Med. 
24. Christoph Wanner JML, David H. Fitchett, Silvio E. Inzucchi, Maximilian von Eynatten, Michaela 
Mattheus, Odd Erik Johansen, Hans-Jürgen Woerle, Uli Christian Brödl, Bernard Zinman. Würzburg, 
Germany. Empagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Chronic 
Kidney Disease. ASN renal week High Impact Clinical trial 2015. 
25. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose 
cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587-97. 
26.group Kcpgw. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int 2012;2. 
27. Montanari A, Pela G, Musiari L, et al. Nitric oxide-angiotensin II interactions and renal 
hemodynamic function in patients with uncomplicated type 1 diabetes. Am J Physiol Renal Physiol 
2013;305:F42-51. 
28. Montanari A, Biggi A, Cabassi A, et al. Renal hemodynamic response to L-arginine in 
uncomplicated, type 1 diabetes mellitus: the role of buffering anions and tubuloglomerular feedback. 
Am J Physiol Renal Physiol;303:F648-58. 
29. Valvo E, Bedogna V, Casagrande P, et al. Captopril in patients with type II diabetes and renal 
insufficiency: systemic and renal hemodynamic alterations. Am J Med 1988;85:344-8. 
30. Obermeier M, Yao M, Khanna A, et al. In vitro characterization and pharmacokinetics of 
dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and 
humans. Drug Metab Dispos 2010;38:405-14. 
31. Defronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of Renal Glucose Reabsorption 
in Response to Dapagliflozin in Healthy Subjects and Subjects With Type 2 Diabetes. Diabetes Care 
2013. 
32. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ, List JF. Urinary tract infections in patients 
with diabetes treated with dapagliflozin. J Diabetes Complications 2013;27:473-8. 


Effects of ertugliflozin in heart failure 
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APPENDIX A – Lab samples/visit – ERADICATE-HF 
Sample Analysis performed at UHN 
BLOOD: 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
-14 
-7 
0 
7 
14-17 
42 
77 
84 
91 
Screening 
Baseline 
Start of 
Drug/placebo 
Dosing 
Post Visit 
2 
Follow Up 
Sodium 
 
Sodium 
Sodium 
Sodium 
Sodium 
 
Sodium 
Sodium 
Potassium 
 
Potassium 
Potassium 
Potassium 
Potassium 
 
Potassium 
Potassium 
Urea 
 
Urea 
Urea 
Urea 
Urea 
 
Urea 
Urea 
Creatinine 
 
Creatinine 
Creatinine 
Creatinine 
Creatinine 
 
Creatinine 
Creatinine 
CBC & Diff 
 
CBC & Diff 
CBC & Diff 
CBC & Diff 
CBC & Diff 
 
CBC & Diff 
CBC & Diff 
AST 
 
AST 
 
AST 
AST 
 
 
AST 
ALT 
 
ALT 
 
ALT 
ALT 
 
 
ALT 
Total 
Bilirubin 
 
Total Bilirubin 
Total Bilirubin Total 
Bilirubin 
Total 
Bilirubin 
 
Total 
Bilirubin 
Total 
Bilirubin 
Phosphate 
 
Phosphate 
Phosphate 
Phosphate 
Phosphate 
 
Phosphate 
Phosphate 
Calcium 
 
Calcium 
Calcium 
Calcium 
Calcium 
 
Calcium 
Calcium 
BNP 
 
BNP 
BNP 
BNP 
BNP 
 
BNP 
BNP 
HbA1c 
 
HbA1c 
 
HbA1c 
HbA1c 
 
 
HbA1c 
Glucose 
 
Glucose 
Glucose 
Glucose 
Glucose 
 
Glucose 
Glucose 
Total 
Protein 
 
Total Protein 
Total protein 
Total 
Protein 
Total 
Protein 
 
Total 
protein 
Total 
Protein 
Lipid Profile  
Lipid Profile 
Lipid Profile 
Lipid Profile 
Lipid Profile  
Lipid 
Profile 
Lipid Profile 
Bicarbonate  
Bicarbonate 
 
Bicarbonate Bicarbonate  
 
Bicarbonate 
Chloride 
 
Chloride 
 
Chloride 
Chloride 
 
 
Chloride 
beta hCG 
 
 
 
 
 
 
 


Effects of ertugliflozin in heart failure 
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URINE Analysis at UHN: (24 hour urine) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
-14 
-7 
0 
7 
14-17 
42 
77 
84 
91 
Screening 
Baseline 
Start of 
Drug/placebo 
Dosing 
Post Visit 2 
Follow Up 
 
 
Sodium 
Sodium 
 
 
 
Sodium 
 
 
 
Potassium 
Potassium 
 
 
 
Potassium 
 
 
 
Urea 
Urea 
 
 
 
Urea 
 
 
 
Creatinine 
Creatinine 
 
 
 
Creatinine 
 
 
 
Albumin 
Albumin 
 
 
 
Albumin 
 
 
 
Protein 
Protein 
 
 
 
Protein 
 
 
Spot Urine (done at each visit) 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
-14 
-7 
0 
7 
14-17 
42 
77 
84 
91 
Screening 
Baseline 
Start of 
Drug/placebo 
Dosing 
Post Visit 2 
Follow Up 
Sodium 
 
Sodium 
Sodium 
Sodium 
Sodium 
 
Sodium 
Sodium 
Potassium 
 
Potassium 
Potassium 
Potassium 
Potassium 
 
Potassium 
Potassium 
Urea 
 
Urea 
Urea 
Urea 
Urea 
 
Urea 
Urea 
Creatinine 
 
Creatinine 
Creatinine 
Creatinine 
Creatinine 
 
Creatinine 
Creatinine 
Albumin 
 
Albumin 
Albumin 
Albumin 
Albumin 
 
Albumin 
Albumin 
Protein 
 
Protein 
Protein 
Protein 
Protein 
 
Protein 
Protein 
 
 
1. 
Lovshin JA, Rajasekeran H, Lytvyn Y, Lovblom LE, Khan S, Alemu R, Locke A, Lai V, He H, Hittle L, Wang W, Drucker DJ, Cherney DZI. 
Dipeptidyl Peptidase-4 Inhibition Stimulates Distal Tubular Natriuresis and Increases in Circulating SDF-1alpha1-67 in Patients 
With Type 2 Diabetes. Diabetes Care. 2017. 
 
 

SAP_001.pdf: 
ERADICATE Data Analysis Plan  
 
1 
ERtugliflozin triAl in DIabetes with preserved or reduced ejeCtion FrAcTion mEchanistic 
evaluation in Heart Failure: “ERADICATE-HF” 
 
Clinicaltrialgov: NCT03416270 
 
Principal investigator(s):  
Prof. D. Cherney 
Division of Nephrology 
University Health Network, University of Toronto Toronto 
Tel: 416 340 4151 
E-mail: david.cherney@uhn.ca   
Prof. H.J. Lambers Heerspink  
Department of Clinical Pharmacology  
University Medical Center Groningen Groningen 
Tel: 050-3617859 
E-mail: h.j.lambers.heerspink@umcg.nl  
Sponsor: University Health Network Toronto, Ontario, Canada 
Subsidising party: Merck (investigator initiated study) 
 
 
 
 
 


ERADICATE Data Analysis Plan  
 
2 
Objectives 
1. Primary objective:  
The primary objective is to determine if acute and chronic ertugliflozin use causes a persistent 
proximal renal tubular natriuretic effect compared to placebo. Acute means changes from 
baseline to Visit 4 (1 week), and chronic means changes from baseline to Visit 8 (12 weeks). 
 
2. Secondary objectives: 
2.1. We will assess whether the proximal renal tubular natriuretic effect of ertugliflozin leads 
to volume contraction compared to placebo. To this end, we will determine the 
association between acute and chronic changes to fractional sodium handling and acute 
and chronic changes in volume.  
2.2. We will assess whether volume contraction with ertugliflozin leads to a decline in 
hormones that are activated in heart failure (HF) patients, without activating the 
sympathetic nervous system (SNS) compared to placebo. To this end, we will determine 
the association between acute and chronic changes to volume and acute and chronic 
changes in hormone levels.  
2.3. We will determine the impact of ertugliflozin on renal function. Specifically, the acute 
and chronic change in markers of renal hemodynamic function will be measured and 
compared between ertugliflozin and placebo. 
2.4. We will determine if ertugliflozin causes a blood pressure lowering effect. Specifically, 
we will evaluate the acute and chronic change in cardiovascular hemodynamic 
assessments with ertugliflozin compared to placebo.   
2.5. We will assess the acute and chronic changes to SNS activation with ertugliflozin use 
compared to placebo.  
2.6. We will assess the acute and chronic effects of ertugliflozin on the level of urinary 
natriuretic modulators normalized to creatinine compared to placebo. 
2.7. We will characterize the safety of ertugliflozin use compared to placebo. 
 
 
3. Exploratory objectives: 
3.1. We will assess whether ertugliflozin causes acute and chronic changes in measures of 
system volume compared to placebo. 
3.2. We will assess whether ertugliflozin causes acute and chronic changes in measures of 
systemic water and fluid balance compared to placebo. 
3.3. We will assess the acute and chronic change of all blood and urine biomarker levels with 
ertugliflozin compared to placebo.  
3.4. We will determine whether changes in neurohormones are associated with changes in 
renal function. To this end, we will determine the association between acute and chronic 
changes in absolute measures of renal function and the acute and chronic changes in 
neurohormones with ertugliflozin compared to placebo.  


ERADICATE Data Analysis Plan  
 
3 
3.5. We will determine whether changes in neuro-hemodynamic markers associated with HF 
patients are associated with changes in arterial stiffness. To this end, we will determine 
the association between acute and chronic changes in arterial stiffness and the 
corresponding acute and chronic changes in neuro-hemodynamic markers with 
ertugliflozin compared to placebo.  
3.6. We will determine whether changes in neurohormones that are activated in HF patients 
are associated with changes in blood pressure. To this end, we will determine the 
association between acute and chronic changes in blood pressure and the acute chronic 
changes in neurohormones with ertugliflozin compared to placebo. 
3.7. We will assess the acute and chronic effects of ertugliflozin on the level of oxidative 
stress markers compared to placebo. 
3.8. We will assess the acute and chronic changes with ertugliflozin on urine and plasma 
chemistry marker levels and metabolic parameters compared to placebo. 
 
Outcomes 
1. Outcomes for the primary objective: 
1.1. The primary outcome is measured by the acute and chronic change in lithium clearance 
from baseline with ertugliflozin vs placebo. 
FE(Li+) = 100 X ([(urine Li+) X (creatinine plasma)]/[(plasma Li+) X (creatinine urine)] 
1.2. We will also measure the primary objective on these secondary outcomes: 
a. Total overall (proximal and distal) tubular sodium handling  
FE(Na+) = 100 X ([(urine Na+) X (creatinine plasma)]/[(plasma Na+) X (creatinine urine)] 
b. Distal sodium handling: FE(Na+) – FE(Li+) 
 
 
2. Outcomes for the secondary objectives:  
2.1. Relationship between proximal renal tubular natriuretic effects and volume reduction: 
proximal renal tubular natriuretic effects will be evaluated by lithium clearance FE(Li+); 
volume change will be measured using the following two outcomes: 
a. Plasma volume (PV) 
i. Measured by indocyanine green (for site 2 and 3) 
ii. Estimated percent change by Strauss estimation 
([{Hbbaseline/Hbend}×{(100−Htend)/(100−Htbaseline)}]−1)×100 
b. Extracellular fluid (ECF) 
i. Measured by bioimpedance spectroscopy 
2.2. Relationship between volume and hormones: Volume will be measured by PV and ECF. 
Hormones will be measured by:  
a. Hormones activated in HF patients (NT-proANP, BNP) 
b. Renin-angiotensin-aldosterone system (RAAS) markers (serum aldosterone, 
renin, PRA, ANGII, AGT, ACE2, ACE) 


ERADICATE Data Analysis Plan  
 
4 
c. SNS markers (norepinephrine, epinephrine, heart rate, heart rate variability 
(SDNN and RMSSD) 
2.3. Renal hemodynamic function will be measured using the following groups of outcomes: 
a. Absolute measured values 
i. 
mGFR 
ii. 
ERPF (for site 1 and 2) 
iii. 
Hematocrit 
b. Creatinine-derived values 
i. 
24-hour Crt (mmol/day) 
ii. 
Creatinine clearance (ml/min) 
c. Gomez-derived values (for site 1 and 2) 
i. 
RBF = RPF/(1-HCT) 
ii. 
RVR = MAP/RBF [Mean arterial pressure = MAP] 
iii. 
Filtration fraction = GFR/RPF 
iv. 
PGLO=(GFR/𝐾FG)+10mmHg+[5×(TP/FF×ln(1/1−FF)−2)] 
v. 
RA=[(MAP−PGLO)/RBF]×1,328 
vi. 
RE=[GFR/(𝐾FG×(RBF−GFR))]×1,328 
2.4. Blood-pressure lowering effect will be measured using the following group of outcomes:  
a. blood pressure (systolic [SBP] and diastolic [DBP]) 
b. NICOM parameters 
c. echocardiographic measures  
d. systemic vascular resistance  
e. arterial stiffness  
i. 
radial, aortic and carotid augmentation index (AIx) 
ii. 
carotid-radial pulse-wave velocity (PWV) 
iii. 
carotid-femoral PWV 
2.5. SNS activation will be measured by norepinephrine, epinephrine, heart rate and heart 
rate variability (RMSSD and SDNN).  
2.6. Changes to urinary natriuretic modulators will be assessed by the level of ACE-2, 
adenosine, ACE activity, NT-proANP and ANGII, normalized to urine creatinine. 
2.7. Safety will be assessed by the number of hypoglycemic episodes and serious adverse 
events. 
 
 
3. Outcomes for the exploratory objectives: 
3.1. Volume contraction will be assessed by: 
a. Plasma volume measured by ICG (site 2 and 3) 
b. Plasma volume measured by Strauss estimation 
c. Extracellular body of water measured by bioimpedance spectroscopy  
3.2. Water and fluid levels will be assessed by: 
a. Absolute (L) and relative (%) total body water (TBW) 
b. Absolute (L) and relative (%) intracellular fluid (ICF) 
c. Absolute (kg) and relative (%) fat-free mass (FFM) 
d. Absolute (kg) and relative (%) fat mass (FM) 
e. BMI 


ERADICATE Data Analysis Plan  
 
5 
3.3. The blood and urine biomarkers are: 
a. Blood: Hemoglobin, hematocrit, creatinine, total bilirubin, albumin, bicarbonate, 
NT-proANP, BNP, PGF2a, cGMP, nitric oxide (nitrite, nitrate, total nitrite) 
b. Urine: NT-proANP, sodium, RAAS markers – normalized to urine creatinine 
i. 
24-hour urine clearance markers (protein, creatinine, UACR, urea, 
potassium, sodium) 
3.4. Relationship between neurohormones and renal function. Hormones will be measured by 
NT-proANP, BNP, and RAAS markers (serum aldosterone, renin, PRA, ANGII, AGT, 
ACE2, ACE). Absolute measure of renal function outcomes is measured by: 
a. mGFR 
b. ERPF 
c. hematocrit 
3.5. Relationship between arterial stiffness and neuro-hemodynamic markers. Markers will 
be measured by SBP, DBP, MAP, NT-proANP, BNP, SNS markers (epinephrine, 
norepinephrine) and RAAS markers (serum aldosterone, renin, PRA, ANGII, AGT, 
ACE2, ACE). Arterial stiffness outcomes will be measured by:  
a. Radial, aortic and carotid AIx 
b. Carotid-radial PWV 
c. Carotid-femoral PWV 
3.6. Relationship between neurohormones and blood pressure. Hormones will be measured 
by NT-proANP, BNP, and RAAS markers (serum aldosterone, renin, PRA, ANGII, 
AGT, ACE2, ACE). SBP, DBP, and MAP will be the outcome. 
3.7. Urine oxidative stress markers normalized to urine creatinine, including 8-isoprostane, 
8-OHdG, cGMP, nitric oxide (endogenous nitrite, nitrate, total nitrite), PGF2a, as well as 
plasma oxidative stress markers, such as cGMP, nitric oxide, and PGF2a.  
3.8. Plasma/urine chemistry markers and metabolic parameters are:   
a. Metabolic (weight, waist measurement, HbA1c) 
b. Urine chemistry (UACR, urea, protein, potassium) 
c. Plasma chemistry: 
i. 
Sodium, potassium, urea, urate, magnesium, phosphate, chloride, calcium 
ii. 
AST, ALT, ALP, LDL, HDL, cholesterol, triglyceride 
iii. 
Glucose, total protein  
 
Statistical Analysis Plan (SAP) 
0. Summary of baseline demographic and clinical characteristics separated by ertugliflozin 
group and placebo group will be generated. Significance testing between-group will be 
performed. The following variables will be included: 
- 
Age, sex, weight, waist circumference, BMI, HbA1c, hemoglobin, fasting 
blood glucose 
- 
race (white/black/Hispanic/Asian/other) 
- 
SBP, DBP, HR 
- 
Mean eGFR 
- 
UACR (median and IQR) 
- 
Concomitant medication (ACEi, ARB, Diuretic, statin) 


ERADICATE Data Analysis Plan  
 
6 
 
1. Analysis for the primary objective: 
1.1. To assess ertugliflozin-related acute and chronic changes in the primary outcome 
FE(Li+) compared to placebo, linear mixed-effects models will be used. Two separate 
models will be fit. For acute change, the vector of outcomes will include the baseline and 
1-week values (i.e. Visit 3 and Visit 4 values). For chronic changes, the vector of 
outcomes will include the baseline and 12-week values (i.e. Visit 3 and Visit 8 values). 
The covariates will include the visit and treatment-by-visit interaction; due to 
randomization, a covariate for the main effect of treatment will not be included. The 
treatment-by-time coefficient, its 95% confidence interval, and its p-value will be used 
to assess the effect of treatment. 
1.2. We will repeat this analysis with:  
a. FE(Na+) as an outcome 
b. FE(Na+) – FE(Li+) as an outcome 
1.3. In exploratory analysis to determine the overall effect of ertugliflozin across all time-
points, we will repeat the above analysis with one model where the vector of outcomes 
will include all data collected at baseline, 1-week, and 12-week values. 
 
2. Analysis for secondary objective: 
2.1. Linear regression will be performed with change in volume as the dependent variable 
and change in FE(Li+) as the independent variable, with treatment as a covariate. Two 
separate models will be fit for acute and chronic changes. Acute changes will use the 
baseline and 1-week values for both the dependent and independent variable values; 
chronic changes will use baseline and 12-week values.  
2.2. The same models described in the analysis of secondary objective 2.1 will be completed, 
with changes in PV or ECF as independent predictors, for neurohormones as the 
dependent variables/outcomes.  
2.3. – 2.6. The same models described in the analysis of primary objective 1.1 and 1.3 will be 
completed for each of the different outcomes. 
2.7.The numbers of hypoglycemic events and serious adverse events will be reported for both 
the placebo group and ertugliflozin group. No statistical comparisons will be performed. 
 
3. Analysis for exploratory objective: 
3.1.– 3.3. The same models described in the analysis of primary objective 1.1 and 1.3 will be 
performed for each of the different outcomes. 
3.4. The same models described in the analysis of secondary objective 2.1 will be completed, 
with changes in neurohormones as independent predictors, for changes in absolute 
measure of renal function as the dependent variables/outcomes.  
3.5.The same models described in the analysis of secondary objective 2.1 will be completed, 
with changes in neuro-hemodynamic markers as independent predictors and changes in 
arterial stiffness as the different dependent variables/outcomes. 


ERADICATE Data Analysis Plan  
 
7 
3.6.The same models described in the analysis of secondary objective 2.1 will be completed, 
with changes in neurohormones as independent predictors and changes to blood pressure 
as dependent variable/outcome.  
3.7.– 3.8. The same models described in the analysis of primary objective 1.1 and 1.3 will be 
completed for each of the different outcomes. 
 
 
Analysis population: The intention to treat population will be used for all analyses. There are no 
planned subgroup analyses for the primary outcome.  
Hypothesis testing: For hypothesis testing, a 5% significance level will be used (two-sided). No 
interim analyses will be performed. For secondary objectives, nominal p-values will be reported. 
General model assumptions and model diagnostic procedures: For the linear mixed-effects 
models with visit and treatment-by-visit interaction as covariates, a participant-level random 
intercept will be included. Restricted-maximum-likelihood will be used for estimation and the 
missing-at-random framework will be assumed. Plots of marginal and conditional residuals will 
be used for model diagnostics and assessment. Similar diagnostic procedures will be used for the 
linear regression models.