Efficacy, Mechanisms and Safety of SGLT2 Inhibitors in Kidney Transplant Recipients: The INFINITI Study
Phase: PHASE3
Conditions: Kidney Transplant Recipients, Post-transplant Diabetes Mellitus, Type 2 Diabetes
Sponsor: University Health Network, Toronto

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
The INFINITI study 
March 18, 2022 
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Investigator Initiated Study Protocol (version March 18, 2022) 
Unique Protocol Identifier #INFINITI2019 
Principal Investigator: 
Sunita K. Singh, MD, MSc, FRCPC (Department of Medicine, Division of Nephrology, Toronto 
General Hospital, University of Toronto, Toronto, Ontario, Canada) 
 
Co-Principal Investigator: 
David Z. I. Cherney, MD CM, PhD, FRCPC (Department of Medicine, Division of Nephrology, 
Toronto General Hospital, Department of Physiology, Banting and Best Diabetes Centre, 
University of Toronto, Toronto, Ontario, Canada) 
 
Co-investigators: 
S. Joseph Kim, MD, PhD, FRCPC (Department of Medicine, Division of Nephrology, Toronto 
General Hospital, University of Toronto, Toronto, Ontario, Canada) 
 
Bruce Perkins, MD, MPH, FRCPC (Department of Medicine, Division of Endocrinology, 
Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada) 
Jacob Udell, MD, MPH, FRCPC (Department of Medicine, Division of Cardiology, Women’s 
College Hospital, University of Toronto, Toronto, Ontario, Canada) 
Yuen Darren, MD, PhD, FRCPC (Department of Medicine, Division of Nephrology, St 
Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada) 
Yuliya Lytvyn, PhD (Department of Medicine, Division of Nephrology, Toronto General 
Hospital, University of Toronto, Toronto, Ontario, Canada) 
 
Vikas S. Sridhar, MD, FRCPC (Department of Medicine, Division of Nephrology, Toronto 
General Hospital, University of Toronto, Toronto, Ontario, Canada) 
 
 
Version Number: INFINITY 3.0 
Sponsors: Dr. Sunita K. Singh and Dr. David Z.I. Cherney 
 
 

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1. TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ....................................................................................................... 2 
2. 
INTRODUCTION AND RATIONALE .................................................................................... 4 
2.1 
Kidney transplantation: Treatment of choice for end-stage renal disease ............................. 4 
2.2 
Challenges in kidney transplantation: Mortality, cardiovascular disease and graft loss ........ 4 
2.3 
SGLT2 inhibitors in the general (non-transplant) population ................................................ 5 
2.4 
SGLT2 inhibitors in kidney transplant recipients: Special considerations .............................. 8 
2.5 
SGLT2i in kidney transplant recipients: Current state of knowledge ..................................... 8 
3. 
OBJECTIVES ..................................................................................................................... 9 
3.1 
Primary ................................................................................................................................ 9 
3.2 
Secondary ............................................................................................................................ 9 
3.3 
Anticipated Outcomes ....................................................................................................... 10 
4. 
STUDY DESIGN ............................................................................................................... 10 
5. 
STUDY POPULATION ...................................................................................................... 11 
5.1 
Inclusion Criteria ................................................................................................................ 11 
5.2 
Exclusion Criteria ............................................................................................................... 11 
5.3 
Sample Size ........................................................................................................................ 12 
6. 
TREATMENT OF SUBJECTS ............................................................................................. 13 
7. 
INVESTIGATIONAL PRODUCT ......................................................................................... 15 
8. 
NON-INVESTIGATIONAL PRODUCT ................................................................................. 20 
9. 
METHODS ...................................................................................................................... 21 
9.1 
Study parameters/endpoints ............................................................................................. 21 
9.1.1 
Main study parameter/endpoint ......................................................................................................... 21 
9.1.2 
Secondary study parameters/endpoints .............................................................................................. 22 
9.2 
Randomization, blinding and treatment allocation ............................................................. 24 
9.3 
Study procedures ............................................................................................................... 24 
9.4 
Withdrawal of individual subjects ...................................................................................... 25 
9.5 
Reasons for possible drug discontinuation ......................................................................... 25 
9.6 
Replacement of individual subjects after withdrawal ......................................................... 25 
9.7 
Follow-up of subjects withdrawn from treatment .............................................................. 25 
9.8 
Premature termination of the study ................................................................................... 26 
10. 
SAFETY REPORTING ................................................................................................... 26 
10.1 
Section 10 WMO event ...................................................................................................... 26 

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10.2 
AEs and SAEs ...................................................................................................................... 26 
10.2.1 
Adverse events (AEs) ..................................................................................................................... 26 
10.2.2 
Serious adverse events (SAEs) ...................................................................................................... 26 
10.2.3 
Adverse events of interest .............................................................................................................. 27 
10.3 
Recording of Adverse Events .............................................................................................. 27 
10.4 
Serious Adverse Event Collecting and Reporting .............................................................................. 29 
10.5 
Suspected unexpected serious adverse reactions (SUSARs) ................................................ 30 
10.6 
Pregnancy ........................................................................................................................................... 31 
10.7 
Overdose ............................................................................................................................................. 31 
10.8 
Annual safety report ........................................................................................................................... 31 
11. 
STATISTICAL ANALYSIS ............................................................................................... 32 
12. 
ETHICAL CONSIDERATIONS ........................................................................................ 32 
12.1 
Regulation statement .......................................................................................................................... 32 
12.2 
Recruitment and consent .................................................................................................................... 32 
12.3 
Objection by minors or inanticipated subjects (if applicable) ........................................................... 33 
12.4 
Benefits and risks assessment, group relatedness ............................................................................. 33 
12.5 
Compensation for injury .................................................................................................................... 33 
12.6 
Incentives (if applicable) .................................................................................................................... 33 
13. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ................................... 33 
13.1 
Handling and storage of data and documents ................................................................................... 33 
13.2 
Monitoring and Quality Assurance ................................................................................................... 34 
13.3 
Amendments ....................................................................................................................................... 34 
13.4 
Annual progress report ...................................................................................................................... 34 
13.5 
Public disclosure and publication policy ........................................................................................... 34 
13.6 
Data Safety Monitoring Board (DSMB)/Safety Committee .............................................................. 35 
14. 
REFERENCES ...................................................................... Error! Bookmark not defined. 
 
 
 
 

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2. INTRODUCTION AND RATIONALE 
 
2.1 Kidney transplantation: Treatment of choice for end-stage renal disease 
 
Over 40,000 Canadians are currently living with end-stage renal disease (ESRD), and the 
prevalence continues to rise in Canada and worldwide1. The impact of ESRD on mortality is 
substantial, with an estimated 5-year survival of approximately 50% for patients on dialysis 
therapy1. Kidney transplantation is the renal replacement therapy of choice for patients with ESRD. 
It has been well established that kidney transplantation improves patient survival and quality of 
life, and results in significant savings to the health care system2, 3.  Wolfe et al. demonstrated in a 
landmark study that kidney transplant recipients (KTR) gained an additional 10 years of life as 
compared to eligible transplant candidates who remained on chronic dialysis therapy2. These life-
years gained were notable for all subgroups of the ESRD population, with even greater benefits 
for those with ESRD due to diabetic kidney disease (DKD), with up to 17 life-years gained in this 
subgroup2.  
 
DKD is the most common cause of ESRD in Canada, accounting for 36% of all incident cases of 
ESRD1. This group also comprises over a quarter of the 14,500 Canadians living with a functioning 
kidney transplant1. Furthermore, KTR without diabetes at the time of transplantation are at risk for 
developing post-transplant diabetes mellitus (PTDM). In addition to traditional risk factors, there 
are a number of transplant-specific risk factors such as the use of diabetogenic immunosuppressive 
medications, hypomagnesemia and post-transplant weight gain that predispose KTR to PTDM. 
The incidence of PTDM is variable based on the definition used and the transplant era, however a 
large US cohort study of 11,659 KTR demonstrated that the cumulative incidence of PTDM was 
9.1% at 3 months, 16% at 12 months and 24% at 36 months post-transplantation4. 
 
2.2 Challenges in kidney transplantation: Mortality, cardiovascular disease and graft loss 
 
Despite the survival benefit conferred by transplantation, KTR still face a number of challenges, 
especially in patients with diabetes. First, KTR still have a higher risk of mortality than their age-
matched counterparts without kidney disease5. This mortality risk is even greater amongst KTR 
with diabetes. Ojo et al. showed that the risk of death with a functioning kidney transplant is 
increased by almost two-fold in those with diabetes as compared to those without6.  Furthermore, 
mortality from cardiovascular disease (CVD) continues to be an important problem after 
transplantation. Large registry analyses from the Canada, the US and Europe have demonstrated 
that death accounts for up to 50% of graft losses, with CVD as the leading cause of death in KTR6-
8. This is likely due to the high burden of cardiovascular risk factors in KTR such as 
hypercholesteremia and hypertension9, 10. Hypertension is reported to occur in up to 92% of KTR10-
12, and is often suboptimally controlled9, 10. An analysis of the Folic Acid for Vascular Outcome 
Reduction in Transplantation (FAVORIT) study found that 69% of KTR did not meet blood 
pressure targets9, 10. The cause of hypertension in KTR is multifactorial, and includes transplant-

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specific risk factors. For example, calcineurin inhibitors (CNIs) are used in virtually all KTR to 
decrease the risk of acute rejection and increase patient and graft survival13, 14. However, CNIs 
induce endothelial dysfunction, increase vascular and sympathetic tone and promote sodium 
reabsorption by activation of the renin-angiotensin-aldosterone system, thereby increasing the risk 
of hypertension10, 15, 16. The risk of hypertension in KTR is also increased by the use of 
glucocorticoids, by post-transplant weight gain and via the impact of ambient hyperglycemia in 
patients with diabetes.   
 
Another major challenge faced by KTR is the continuing risk of developing graft failure over time.  
Although there has been substantial improvement in short-term graft survival over the last few 
decades, late graft failure (i.e., graft loss beyond 1 year after transplantation) continues to be an 
important problem in KTR. When graft failure occurs, the survival benefit offered by kidney 
transplantation is lost, and the transitional period between graft failure and re-initiation of dialysis 
is associated with a three-fold increase in the risk of death17,18. Furthermore, only 10 to 15% of 
those who experience graft failure eventually undergo re-transplantation1, 19. Unfortunately, in the 
subgroup of KTR with diabetes, the incidence of graft failure is 50% higher than the general kidney 
transplant recipient population, and recurrent DKD occurs in almost half of allografts after 
transplantation20, 21. The development of chronic kidney disease (CKD), a common precursor to 
graft failure, occurs due to a number of immunologic and non-immunologic risk factors. Examples 
of the latter include hypertension, dyslipidemia, obesity, recurrent disease (i.e., DKD) in the graft, 
and albuminuria22. CKD in KTR is common, affecting up to 90% of the population23, 24, 25, and 
significantly increases the risk of death and graft loss23, 25. However, to date, effective strategies to 
mitigate the risk of graft dysfunction and slow the progression to graft failure are lacking. In light 
of the beneficial effects of angiotensin converting enzyme inhibitors (ACEi) and angiotensin 
receptor blockers (ARB) in reducing the risk of death and progression to ESRD in the non-
transplant population with proteinuric CKD, a multi-centre randomized controlled trial comparing 
ramipril to placebo in KTR was conducted. Unfortunately, this trial showed that ramipril was not 
effective in reducing the risk of graft failure or cardiovascular death in KTR26, albeit the study may 
have been underpowered. Current strategies in the management of graft dysfunction and CKD are 
therefore focused on optimizing immunosuppression and control of hypertension and 
dyslipidemia. Accordingly, there is an important unmet need for cardio- and renoprotective 
strategies to address premature death and graft loss in the KTR population.  
 
2.3 SGLT2 inhibitors in the general (non-transplant) population 
 
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are glucose lowering agents that are effective 
in the treatment of T2D, resulting not only in improved glycemic control, but also weight loss, 
blood pressure and albuminuria reduction27, 28.  SGLT2i agents block glucose reabsorption in the 
proximal tubule epithelial cell of the kidney and increase urinary glucose excretion28, 29. This 
insulin-independent mechanism reduces blood glucose levels, without the risk of hypoglycaemia. 
Several clinical trials have shown significant benefits of SGLT2i on cardiovascular and renal 

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outcomes. The EMPA-REG OUTCOME study randomized patients with type 2 diabetes with 
established cardiovascular disease to empagliflozin vs. placebo30. This study showed significant 
reductions in major adverse cardiac events, cardiovascular mortality, all-cause mortality and 
hospitalization for heart failure with empagliflozin30. The CANVAS trial randomized patients with 
type 2 diabetes at high cardiovascular risk with and without established CVD and demonstrated a 
22% reduction in cardiovascular death or hospitalization for heart failure with canagliflozin31. 
From a renal perspective, the CANVAS-R study showed a reduction in albuminuria progression, 
as well as a 40% reduction in ESRD, death and sustained eGFR reduction31. Similarly, a pre-
specified analysis of the EMPA-REG OUTCOME trial also showed that empagliflozin was 
associated with slower progression of kidney disease and lower rates of renal events as compared 
to placebo32. CREDENCE was the first dedicated renal clinical trial, which aimed to randomize 
over 4000 patients with type 2 diabetes, stage 2 or 3 CKD and microalbuminuria treated with an 
ACEi/ARB, to canagliflozin vs. placebo33. The primary outcome of interest was a composite of 
ESRD, doubling of serum creatinine and renal or cardiovascular death. This trial was recently 
stopped early as it achieved the prespecified efficacy criteria for the primary composite endpoint34.  
Hence, in non-transplant patients with T2D, the use of SGLT2i is changing the way clinicians 
attenuate the progression of cardiorenal complications. Further evidence supporting the glycemic-
independent benefits of SGLT2 inhibition has emerged from recent heart failure trials. The 
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) and 
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure (EMPEROR-Reduced) 
trials were the first large trials to study SGLT2 inhibition in participants with heart failure and 
reduced ejection fraction (HFrEF) with and without T2D35, 36. The application of SGLT2i as 
dedicated kidney-protective agents continued to evolve with the publication of the DAPA-CKD 
trial, which extends their cardiorenal protection to patients with non-diabetic CKD37. DAPA-CKD 
enrolled 4304 participants with CKD, eGFR of 25-75 ml/min/1.73m2 and UACR of 200 to 
5000mg/g. About two-thirds of participants had T2D and almost all patients were on stable doses 
of ACE inhibitors/ARBs. Other than DKD, the cause of CKD was almost equally distributed 
between ischemic/hypertensive nephropathy and chronic GN with about 16% for each subgroup. 
The chronic GN subgroup was further divided into IgA nephropathy (IgAN) (6.3%), FSGS (2.7%) 
and membranous nephropathy (1%). Patients with kidney transplants, type 1 diabetes (T1D), 
polycystic kidney disease, lupus nephritis and ANCA vasculitis were excluded. Dapagliflozin was 
safe and significantly reduced the risk of the primary composite end point (≥50% eGFR decline, 
onset of ESKD, renal or CV death) by 39% versus placebo, with a number needed to treat of 19 to 
prevent one primary outcome event. Like DAPA-HF and EMPEROR-Reduced, this effect was 
consistent among patients with and without diabetes, with no evidence of hypoglycemia. 
 
SGLT2i exert a number of glucose-independent effects, which have been linked to the beneficial 
cardiovascular and renoprotective effects observed in clinical trials. In the setting of diabetes, 
hyperglycemia results in increased tubular reabsorption of glucose and sodium, which activates 
tubuloglomerular feedback (TGF). This leads to a decrease in sodium delivery to the macula densa, 

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which in turn leads to vasodilation of the afferent arteriole and hyperfiltration38. SGLT2i increases 
delivery of sodium to the macula densa, restores TGF and results in vasoconstriction of the afferent 
arteriole, leading to reductions in intraglomerular hypertension, glomerular filtration rate (GFR) 
and albuminuria39. These mechanisms appear to be intact in non-DM populations as well. Bay and 
colleagues determined the effect of canagliflozin versus placebo on 376 non-diabetic obese 
subjects for 12 weeks 40. Canagliflozin reduced weight and blood pressure over the study period. 
A decrease in eGFR over the 12-week period was observed with canagliflozin, consistent with 
SGLT2 inhibition-mediated reductions in glomerular pressure. Our group also published results of 
the DIAMOND trial where fifty-three participants with non-diabetic CKD, eGFR 
≥25ml/min/1.73m2, and proteinuria >500 to ≤3500mg/day were treated with dapagliflozin and 
placebo in a randomized, double-blind 6-week crossover trial. Dapagliflozin resulted in an acute 
and reversible decline in measured GFR while decreasing body weight and increasing markers of 
hemoconcentration, suggesting mechanisms of kidney function are intact irrespective of glycemic 
effects41. These mechanisms are shown in Figure 1. The natriuresis induced by SGLT2i is also 
one of the postulated mechanisms underlying reductions in the systolic and diastolic blood pressure 
and arterial stiffness observed with SGLT2i42, 43, 28, 44. Decreases in systemic and intraglomerular 
hypertension with SGLT2i may in turn be responsible for decreases in albuminuria and CKD 
progression in clinical trials of patients with and without T2D28, 45. Interestingly, although there is 
an attenuation of the glucose lowering effects of SGLT2i as GFR declines due to reduced 
glucosuria, natriuresis-related reductions in blood pressure and reductions in albuminuria persist 
even in the setting of reduced kidney function46. From a cardiac perspective, it is hypothesized that 
the natriuresis-induced decrease in intravascular volume and reduction in arterial stiffness that 
occurs with SGLT2i leads to an unloading of the myocardium and an improvement in cardiac 
function, although other factors may also play a role39, 47.  
 
A number of experimental studies have also uncovered other potential renoprotective effects of 
SGLT2i. In the setting of hyperglycemia, there is an increase in the reabsorption of sodium and 
glucose due to upregulation of the sodium-glucose cotransporter 2 in the proximal tubule48. These 
increases in metabolic demands predispose the proximal tubule epithelial cells (PTECs) to 
hypoxia, which in turn, stimulates a cascade of mediators leading to fibrosis and apoptosis49-52. 
The increase in glucose reabsorption that occurs in PTECs in the setting of diabetes also results in 
the generation of advanced glycosylation end-products. Advanced glycosylation end-products and 
the high glucose milieu have been shown trigger the generation reactive oxygen species as well as 
pro-fibrotic and pro-inflammatory pathways, ultimately leading to progressive DKD53, 54. 
Similarly, increased albumin reabsorption by the proximal tubule in the setting of diabetes is also 
toxic to the PTECs, promoting a similar cascade of cytokines and pro-inflammatory mediators 
contributing to tubulointerstitial injury53-55.  In light of these known changes in DKD, SGLT2i 
have the potential to decrease the release of reactive oxygen species and attenuate pro-fibrotic and 
pro-inflammatory pathways by decreasing the metabolic demands of the PTECs. Although the 
results are conflicting, some experimental studies in mice have demonstrated a reduction in pro-

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fibrotic and pro-inflammatory mediators, although this has yet to be shown in humans56,39. The 
various effects and mechanisms of SGLT2i are shown in Figure 2.  
 
2.4 SGLT2 inhibitors in kidney transplant recipients: Special considerations 
 
Given the glucose-dependent and independent effects of SGLT2i, as well as the accumulating 
evidence demonstrating cardiorenal protection in non-KTR, the use of these agents in KTR is 
attractive – especially since traditional renin-angiotensin-aldosterone system inhibitors are not 
effective. Moreover, the use of SGLT2i as a cardiorenal protective therapy may be of particular 
value in KTR given the high burden of comorbidities such as diabetes, CVD and hypertension, as 
well as the ongoing challenges of premature death and graft loss in this population. However, there 
are several unique aspects of KTR that are important to consider when using SGLT2i, including 
the immunosuppressed state of KTR, the impact of SGLT2i on denervated kidneys as well as the 
effectiveness of SGLT2i with concomitant use of CNIs. Given the susceptibility of KTR to 
infectious complications due to immunosuppression, there is the potential for concern regarding 
safety of these agents in this population. For example, urinary and mycotic infections are well 
described with SGLT2i use57, 58, and urinary tract infections are one of the most common infectious 
complications in KTR59, 60.  In addition, transplanted kidneys are denervated and therefore the 
autoregulation of renal blood flow that occurs in the setting of sympathetic nervous system activity, 
particularly when hypotension occurs, is attenuated61. SGLT2i can cause volume depletion and 
acute kidney injury (AKI), and it is unclear whether these adverse effects are magnified in KTR 
with denervated kidneys. Finally, CNIs are commonly used in almost all KTR, and are well known 
to affect the kidney62. In particular, CNIs can result in tubular toxicity through a variety of 
mechanisms including hypoxia of the tubulointersitium, apoptosis of tubular cells and alterations 
in tubular transport, as manifested by well-described electrolyte disturbances15, 62. In non-KTR, 
SGLT2i therapies are very safe over a wide range of kidney function and have even been shown 
to reduce the risk of AKI. Thus, an important aim of our study is to capture potential safety signals, 
including infectious complications and changes in renal function in the KTR population.  
 
2.5 SGLT2i in kidney transplant recipients: Current state of knowledge 
 
Currently, there are few published experiences on the use of SGLT2i in transplant recipients63 
(Table 1). To our knowledge, the use of SGLT2i has also been described in a few other 
immunosuppressed populations including heart transplant recipients. We studied 10 KTR and 
simultaneous pancreas-kidney transplant recipients and showed that the use of use of the SGLT2 
inhibitor canagliflozin was associated with improvements in glycemic control (hemoglobin A1c 
(HbA1c) -0.84 ± 1.2 %), weight     (-2.14 ± 2.8kg) and blood pressure (systolic -6.5 ± 10.8 mmHg 
and diastolic -4.8± 12 mmHg), which were similar in magnitude to effects reported in non-
transplant cohorts. Furthermore, we did not observe any episodes of ketoacidosis, AKI, acute 
rejection or urinary/mycotic infections during treatment. One patient experienced hypoglycemia, 
and one patient developed cellulitis. Finally, there were no clinically significant changes in CNI 

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levels. However, this was a small cohort of patients with excellent kidney function (eGFR 
>60ml/min/1.73m2) where canagliflozin was initiated several years after transplantation, with a 
limited follow-up of 80.5 person-months. In order to better understand the efficacy, safety and 
potential mechanisms of SGLT2i in this unique population with variable degrees of renal 
impairment, further comparative studies are needed in larger cohorts of KTR.  
 
There are currently two clinical trials evaluating SGLT2i in KTR64, 65, both of which do not include 
patients with pre-existing T2D, or patients without diabetes. These are summarized in Table 1. 
The first is a single-arm non-inferiority study of 16 patients with PTDM on insulin therapy, 
comparing the efficacy of empagliflozin to pre-existing insulin therapy, on glycemic control. The 
second is a randomized controlled trial of empagliflozin vs. placebo in a cohort of 50 KTR with 
PTDM. The primary outcome of this study is also glycemic control, as measured by a weighted 
mean glucose before and after SGLT2i therapy. However, based on the glucose-independent 
benefits of SGLT2i in the non-transplant cohorts with and without diabetes described above, we 
strongly believe that in KTR, the glucose-independent effects of SGLT2i are likely to be of greatest 
benefit given the high prevalence of CKD in the KTR population23, 24. In addition, in the setting of 
deceased donation, kidney transplant candidates with diabetes frequently receive kidneys from 
more ‘marginal’ donors given their high mortality on the transplant waiting list1.  Although this 
strategy may be beneficial from a patient survival perspective (vs. chronic dialysis), KTR with 
diabetes are more likely to have kidney transplants with reduced kidney function66. It is known 
that HbA1c lowering is attenuated as the eGFR decreases, however, the glucose-independent 
effects, such as blood pressure reduction, persist across the range of eGFR irrespective of diabetes 
status46. In KTR, we believe that the most clinically important effect is likely the natriuresis 
induced by SGLT2i, resulting in a reduction in blood pressure as well as enhancement of other 
cardiovascular and renoprotective mechanisms beyond glycemic control.  
 
3. OBJECTIVES 
 
3.1 Primary 
 
To evaluate the effect of 12 weeks of 10 mg daily oral dapagliflozin vs. placebo on systolic 
blood pressure in KTR with or without T2D or PTDM. 
 
3.2 Secondary 
 
1. To determine the safety of 12 weeks of 10 mg daily oral dapagliflozin therapy vs. placebo 
in 52 KTR with or without T2D or PTDM.    
 
2. To elucidate the potential mechanisms responsible for blood pressure lowering, as well as 
the potential cardio- and renoprotective effects of 12 weeks of 10 mg daily oral 
dapagliflozin therapy vs. placebo in 52 KTR with or without T2D or PTDM.  In order to 

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elucidate the mechanisms underpinning the potential blood pressure lowering and 
cardiovascular effects of SGLT2i in KTR, we have incorporated comprehensive 
measurements of natriuresis, arterial stiffness and sympathetic nervous system activity, as 
well as changes in weight and lipid profile. Furthermore, to elucidate potential 
renoprotective effects, we have incorporated detailed study of renal function, 
neurohormone biomarker measurements, as well as markers of oxidative stress and 
changes in allograft hypoxia using novel photoacoustic ultrasonography, as a measure of 
renal metabolic demands. 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. 
 
3. To determine the glucose lowering effects of 12 weeks of 10 mg daily oral dapagliflozin 
therapy vs. placebo in 52 KTR with or without T2D or PTDM.    
 
3.3 Anticipated Outcomes 
 
1. We hypothesize that dapagliflozin will result in a significant reduction in systolic and 
diastolic blood pressure in a cohort of KTR with or without T2D and PTDM.  
 
2. We hypothesize that dapagliflozin will be well tolerated in KTR with or without T2D and 
PTDM, with adverse events similar to that of non-transplant populations. We also 
hypothesize that there will be no clinically significant changes in CNI levels or episodes of 
acute rejection in KTR treated with dapagliflozin vs. placebo during the study. 
 
3. We hypothesize that dapagliflozin will result in a significant natriuresis, as well as 
reductions in arterial stiffness, albuminuria, allograft hypoxia and markers of oxidative 
stress, while having neutral effects on cardiac and renal function over the course of the 12-
week study period.  
 
4. We hypothesize that the glucose-lowering effects of dapagliflozin will be modest in KTR 
with T2D or PTDM due the high prevalence of CKD in this population. In participants 
without T2D or PTDM, we do not expect any glucose lowering. 
 
4. STUDY DESIGN 
 
This study will be a randomized, double-blind, placebo-controlled clinical trial comparing the 
SGLT2 inhibitor dapagliflozin to placebo in 52 KTR with or without pre-existing T2D or PTDM. 
The primary outcome of the trial is to determine if dapagliflozin is superior to placebo in reduction 
of blood pressure in KTR. 
 

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We will include incident and prevalent KTR at least 6 months after their transplant date We 
selected a period of at least 6 months after kidney transplantation prior to study enrolment for 
safety reasons. The risk of infection as well as acute rejection is highest in the early post-transplant 
period67, 
68. Furthermore, fluctuations in kidney function as well as adjustments to 
immunosuppressive medications are also common. Thus, a period of 6 months was selected to 
capture stable KTR for study inclusion.  
 
We have selected patients with and without diabetes (including T2D and PTDM) to be included in 
the study for the following reasons: 1) As described in detail in the sections above, the mechanisms 
hypothesized to confer cardiorenal benefit are independent of improvements in glycemic control 
and are intact in patients with and without diabetes. Furthermore, recent large clinical trials such 
DAPA-HF, EMPEROR-Reduced and DAPA-CKD demonstrate that SGLT2 inhibition is safe and 
highly effective in non-transplant populations without diabetes, leading to approval for clinical use 
in multiple health jurisdictions; 2) It is still important to include KTR with T2D and PTDM as both  
conditions are common in the KTR population, with T2D as the cause of ESRD in approximately 
30 to 40% of KTR, and PTDM occurring in approximately 25% of KTR4. Additionally, both 
conditions are associated with a high prevalence of hypertension in KTR, as well as an increased 
risk of cardiovascular disease, death and graft loss69 with existing preliminary data from our centre 
suggesting the potential efficacy and safety of SGLT2i in a selected group of KTR with both T2D 
and PTDM63.  
 
In patients with diabetes, we have imposed an upper limit on  HbA1c of <12.0% to avoid starting 
the drug in participants with poorly controlled diabetes who may be pre-disposed to ketoacidosis 
due to relative hypoinsulinemia. There is minimal experience with SGLT2 inhibition  in patients 
with stage 4 or 5 CKD; therefore an eGFR of ≥30 ml/min/1.73m2 is required for inclusion. The 
BMI criteria is reflective of the current experience to date using SGLT2i in non-transplant 
populations.  
 
5. STUDY POPULATION 
 
5.1 Inclusion Criteria 
 
1. Male or females >18 years old ≥ 6months after kidney transplantation;  
2. In patients with T2D or PTDM, HbA1c <12.0%;  
3. eGFR ≥30 ml/min/1.73m2 (as per the CKD-EPI equation70);  
4. BMI £45kg/m2;  
5. Blood pressure £160/90 and ≥90/60 at screening.  
 
5.2 Exclusion Criteria 
 
1. Diagnosis of type 1 diabetes;  

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2. Presence of severe peripheral vascular disease (i.e. prior amputation, gangrene, non-
healing ulcer or ischemic rest pain);  
3. Presence of acute coronary syndrome, stroke or transient ischemic attack in the 3 months 
prior to screening;  
4. Prior episode of graft pyelonephritis in the 1 month prior to screening;  
5. Episode of acute graft rejection in the 3 months prior to screening;  
6. Initiation of a new immunosuppressive agent or discontinuation of an 
immunosuppressive agent in the 1 month prior to screening;  
7. Untreated urinary or genital tract infection;  
8. Severe hypoglycemia within 3 months of screening, or hypoglycemia unawareness;  
9. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not 
practicing an acceptable method of birth control;  
10. Participation in another trial with an investigational drug within 30 days of informed 
consent;  
11. Alcohol or drug abuse within 3 months prior to informed consent that would interfere 
with trial participation;  
12. Any ongoing clinical condition that would jeopardize subject safety or study compliance 
based on investigator judgement.  
13. Patients currently using antipsychotic medications. 
14. Use of SGLT2 inhibitors within 1 month of starting the study. 
 
5.3 Sample Size  
 
The sample size is based on the primary endpoint of blood pressure. Currently, there is only one 
publication from our group with information available on the effect of SGLT2i on blood pressure 
reduction in KTR with diabetes. In this observational study of 10 KTR and simultaneous pancreas-
kidney transplant recipients treated with canagliflozin, we reported a SBP decrease of 6.5 ± 10 
mmHg63. Given the small sample size in our observational study, we believe the standard deviation 
would be smaller in a larger cohort. Blood pressure reduction with SGLT2 inhibition appear to be 
similar between patients with and without diabetes in non-transplant studies. We, therefore, 
estimated the sample size based on a SBP change of 6.5 mmHg with a standard deviation of 8 
mmHg. Under the hypothesis that SGLT2i decreases SBP by 6.5 ± 8 mmHg compared to placebo 
with a two-sided alpha of 0.05 and 80% power, we calculate a sample size of n=48, with 24 
randomized to dapagliflozin and 24 randomized to placebo. Assuming a 10% attrition rate, the 
final sample size required is 52 participants. This sample size is similar to those successfully used 
in previous studies71, and sufficient to measure secondary renal endpoints related to renal 
hemodynamic function71, natriuresis and arterial stiffness72-74. Based on previous studies, we 
anticipate an even sex distribution in each group.  
 

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6. TREATMENT OF SUBJECTS 
 
6.1 Investigational Product/Treatment 
 
Dapagliflozin and matching placebo will be provided in 35 cc bottles, and the sponsor will be 
responsible for labelling. Each bottle of IP will be identified with a unique Composite ID in order 
to maintain the blind. By way of an Unblinding List, Pharmacy will provide treatment allocations 
of each Composite ID. 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 10 mg dapagliflozin (1 tablet 10mg once 
daily) or matching placebo according to randomised treatment scheme. 
 
Study participants will be allocated to receive either 10 mg daily of dapagliflozin or a matching 
placebo for 12 weeks in a 1:1 ratio. Participants with diabetes will continue on existing medical 
therapy for glycemic control as recommended by Diabetes Canada75. The study design is shown 
in Figure 3. The study investigator can titrate dapagliflozin down to 5 mg in the event that 
dapagliflozin 10 mg dose is not well tolerated by the participant. However, in the event of 
hypoglycemia, a decrease in dose of other glucose lowering therapies (including insulin), will be 
first initiated, if applicable, by the study investigator prior to down-titration of dapagliflozin. Every 
effort will be made to keep the dose of dapagliflozin constant at 10mg daily.  
 
There are no known or reported drug interactions with dapagliflozin and immunosuppressive 
therapies commonly used in KTR including CNIs (tacrolimus, cyclosporine), mammalian target 
of rapamycin inhibitors (sirolimus, everolimus), antiproliferative medications (mycophenolic acid, 
mycophenolate mofetil, azathioprine) and prednisone.  SGLT2i are primarily metabolized via 
UDP-glucoronosyltransferase, with minimal effects on cytochrome P450 enzymes. CNIs are 
substrates of these enzymes, however the interaction does not appear to be clinically relevant63. 
CNI levels will be monitored for the duration of this trial and will be reported to the participants’ 
primary transplant nephrologist within 24 hours for CNI dose adjustments, as needed. There will 
be no change required to the general management of KTR as a result of participation in the study. 
 
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 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 

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the subject specific dispensing process is maintained. Unused drugs are destroyed by the pharmacy 
department at the end of the study. 
 
 
6.2 Use of co-interventions (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)  
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 iohexol injection and should not be resumed until 
completion of the GFR measurement procedure. 
 
Drugs which lower seizure threshold, especially phenothiazide derivatives including those used 
for their antihistaminic properties, are not recommended for use with iohexol. Others include 
monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, CNS stimulants, psychoactive 
drugs described as analeptics, major tranquilizers, or antiphychotic drugs. The dose of such 
medications, if applicable, are recommended to be discontinued at least 48 hours before iohexol 
injection. 
 
KTR are typically treated with multiple medications including immunosuppression, anti-
hypertensive and glucose-lowering therapies. This may predispose participants to side effects of 
SGLT2i given their known blood pressure and glucose lowering properties. To mitigate this, we 
will implement the following strategies:  
 
1.  At the time of study drug initiation, if participants are on a loop diuretic, the dose will be 
reduced by 50% by the study investigators to avoid volume contraction given the natriuretic 
effect of SGLT2i. The loop diuretic dose will be titrated back to the full dose by study 
investigators as needed, over a period of 7 days after drug initiation;  
2. Our study endocrinologist, Dr. Bruce Perkins will be responsible for glycemic management 
in participants with diabetes during the study through study and telephone visits71. All anti-
diabetes medications will be allowed including insulin, sulfonylureas, DPP4 inhibitors, and 
GLP-1 receptor agonists. SGLT2 inhibitors may not be used within 1 month of starting the 
study. No minimum time on anti-diabetes medications will be required prior to 
randomization. Adjustment of insulin and other glucose-lowering medications will be 

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made as necessary by Dr. Perkins utilizing an individualized approach based on the 
patients’ specific risk of hypoglycemia and/or DKA. Changes in glycemic management 
will always made in conjunction with the patients’ own endocrinologist/family doctor. 
Major hypoglycemic events will be captured as an adverse event of interest.  
3. Given the lack of definitive data supporting the use of ACEi/ARB as a renoprotective 
strategy, the use of an ACEi/ARB is variable in KTR. However, these drugs are prescribed 
to KTR based on physician preference, and due to non-renal indications such as post-
transplant erythrocytosis, hypertension or cardioprotection.  The use of ACEi/ARB with 
SGLT2i will be permitted during the entre duration of the trial and we have incorporated 
frequent safety monitoring in our study to allow for the early detection of any potential 
adverse events that may occur with concomitant renin-angiotensin-aldosterone system 
blockade and SGLT2i.  
 
7. INVESTIGATIONAL PRODUCT 
 
7.1 Name and description of investigational product(s) 
 
Drug name: dapagliflozin (Forxiga, AstraZeneca, RPF-EU-12-MB102-016);  
 
Chemical structure: (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6 
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; 
 
Product Description and 
Dosage Form 
Dosage form and strength 
Manufacturer 
Dapagliflozin 10mg Tablets  
10 mg Yellow, biconvex, 
round, film coated tablets 
with “10” engraved on 
one side and “1428” engraved 
on the other side (orally) 
Astra Zeneca 
Dapagliflozin 5mg Tablets  
5 mg Yellow, biconvex, 
round, film coated tablets 
with “5” engraved on 
one side and “1427” engraved 
on the other side (orally) 
Astra Zeneca 
Placebo Matching 
Dapagliflozin Tablet 
Yellow, plain, film coated 
tablet. Does not contain 
active ingredient 
Astra Zeneca 
 
7.2 Summary of findings from non-clinical studies 
 
Available data from non-clinical study in animals is provided in the Investigator’s Brochure. 
 

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7.3 Summary of findings from clinical studies 
 
SGLT2 is the predominant transporter responsible for reabsorption of glucose from the glomerular 
filtrate back into the circulation. Despite the presence of hyperglycaemia in type 2 diabetes, 
reabsorption of filtered glucose continues. Dapagliflozin 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 dapagliflozin's efficacy to lower 
HbA1c is low and so the risk of hypoglycemia is low as well. Effects on blood pressure, body mass 
index, albuminuria, hematocrit appear to be independent of GFR. 
 
Dapagliflozin does not impair normal endogenous glucose production in response to 
hypoglycaemia. Dapagliflozin 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 type 2 diabetes mellitus following the 
administration of dapagliflozin. Approximately 70 g of glucose was excreted in the urine per day 
(corresponding to 280 kcal/day) at a dapagliflozin dose of 10 mg/day in subjects with type 2 
diabetes for 12 weeks. Evidence of sustained glucose excretion was seen in subjects with type 2 
diabetes given dapagliflozin 10 mg/day for up to 2 years. 
 
Twelve double-blind, randomised, controlled clinical trials were conducted with 6,144 subjects 
with type 2 diabetes to evaluate the efficacy and safety of Forxiga; 4,164 subjects in these studies 
were treated with dapagliflozin. Two double-blind, randomized, controlled clinical trials were 
conducted in 9,048 with and without T2D to evaluate the efficacy and safety of Forxiga; 4,520 
subjects in these studies were treated with dapagliflozin. In DAPA CKD study, dapagliflozin was 
safe and significantly reduced the risk of the primary composite end point (≥50% eGFR decline, 
onset of ESKD, renal or CV death) by 39% versus placebo, with a number needed to treat of 19 to 
prevent one primary outcome event. Moreover, all the secondary end points including the 
composite kidney outcome (sustained 50% eGFR decline, ESKD or renal death), the composite 
CV outcome (hospitalization for heart failure or CV death) or all-cause mortality were significantly 
lower in the dapagliflozin group. Examining the hazard ratios of primary and secondary outcomes 
across subgroups of CKD etiology, it is apparent that the long-term kidney benefits of 
dapagliflozin in non-diabetic participants are similar to those with T2D. 
 
7.4 Monotherapy 
 
A double-blind, placebo-controlled study of 24-week duration (with an additional extension 
period) was conducted to evaluate the safety and efficacy of monotherapy with dapagliflozin in 

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subjects with inadequately controlled type 2 diabetes. Once-daily treatment with dapagliflozin 
resulted in statistically significant (p<0.0001) reductions in HbA1c compared to placebo. 
 
7.5 Combination Therapy 
 
In a 52-week, active-controlled non-inferiority study (with a 52-week extension period), 
dapagliflozin was evaluated as add-on therapy to metformin compared with a sulphonylurea 
(glipizide) as add-on therapy to metformin in subjects with inadequate glycaemic control (HbA1c 
> 6.5% and ≤ 10%). The results showed a similar mean reduction in HbA1c from baseline to Week 
52, compared to glipizide, thus demonstrating non-inferiority. At Week 104, adjusted mean change 
from baseline in HbA1c was -0.32% or dapagliflozin and -0.14% for glipizide. At 52 and 104 
weeks, a significantly lower proportion of subjects in the group treated with dapagliflozin (3.5% 
and 4.3%, respectively) experienced at least one event of hypoglycaemia compared to the group 
reated with glipizide (40.8% and 47.0%, respectively). In a study of 808 patients with type 2 
diabetes who had inadequate glycemic control and received on average 30 units insulin, 
dapagliflozin 10 mg/day caused a 0.57% reduction in HbA1c relative to placebo. Dapagliflozin 
did not increase insulin requirements but these requirements increased progressively in the placebo 
group.76 
 
7.6 Summary of known potential risks and benefits 
 
Dapagliflozin has global market approval and based on global cumulative sale figures is 
estimated that dapagliflozin has been administered during >1000000 patient years. Details 
regarding potential risks associated with administration of dapagliflozin once daily are 
provided in the Investigator's Brochure (IB). 
 
7.6.1 Potential risks 
The potential risks for the treatment with dapagliflozin and other SGLT2 inhibitors 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 
Ill studies) and genital infections has been seen. 
Based on the mechanism of action of dapagliflozin 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 dapagliflozin who 
develop conditions that may cause hypovolaemia or electrolyte imbalance, decisions to 
interrupt or discontinue dapagliflozin therapy and management of patients should be based 
on clinical judgment. 

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Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia 
were reported in dapagliflozin vs placebo. The magnitude and clinical significance of this in 
patients with CKD is unclear. 
After the introduction of dapagliflozin and other SGLT2 inhibitors 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 dapagliflozin 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.   Dapagliflozin should be used with caution in these patients. 
There is no reason to believe that dapagliflozin poses an undue risk of hypoglycemia in non- 
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 77. In Clinical Pharmacology studies in healthy subjects’ single doses up to 
500 mg and multiple oral doses of 2.5 to 100 mg up to 14 days have been evaluated and have 
shown that dapagliflozin does not induce even a single case of hypoglycemia in non-diabetic 
subjects. Additionally, in a recent clinical trial in 50 non- diabetes obese individuals treated 
with the combination of dapagliflozin and exenetide, none of the patients experienced a 
hypoglycemic event 78. 
 
7.6.2 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 dapagliflozin 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 dapagliflozin in individual patients in whom a potential health 
risk or a laboratory abnormality of clinical concern has been identified. 

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7.6.3 Potential benefits to patients 
In this study, the dose of dapagliflozin 10 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, patients randomized to active 
drug, dapagliflozin is expected to reduce progression of renal failure and reduce CV mortality. 
Dapagliflozin is known to decrease body weight (or prevent weight gain) as well as lower 
blood pressure and albuminuria in patients with and without type 2 diabetes.  
Patients are also expected to receive some benefit in the form of increased medical 
care/attention when participating in study procedures. 
 
7.6.4 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, and the patient 
will not be disadvantaged in any way. 
 
7.6.5 Conclusion 
Considering the pre-clinical and clinical experience with dapagliflozin 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. 
 
7.7 Description and justification of route of administration and dosage 
Dapagliflozin is absorbed from the digestive tract and can therefore be orally administered. 
 
7.8 Dosages, dosage modifications and method of administration 
Dapagliflozin will be administered in a dose of 10 mg/day. 
 
7.9 Preparation and labelling of Investigational Medicinal Product 
Study medication (dapagliflozin and matching placebos) will be provided by AstraZeneca. 
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 in accordance with relevant guidelines. 
 
7.10 Drug Accountability 

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All study medications will be stored at room temperature (<30°C) in a secure location. Study 
medication will be collected from the pharmacy department by the principle investigator. Unused 
and partially used study drug will be returned by the subject to the site for drug accountability.  
Returned and unused study drug will be returned to the pharmacy department where it will be 
destroyed. 
 
7.11 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). If concerns regarding the 
quality or appearance of the investigational product arise, the investigational product will not be 
dispensed and AstraZeneca will be contacted immediately. 
 
7.12 Drug Ordering 
Initial Orders and 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 existing investigational stock to assure 
optimal use of drug on hand. 
 
8. NON-INVESTIGATIONAL PRODUCT 
 
8.1 Name and description of non-investigational product(s) 
Iohexol (Omnipaque), lithium carbonate (300 mg one day prior to each physiological study day 
i.e. on three occasions). 
 
8.2 Summary of findings from non-clinical studies 
Iohexol has 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.  
 
8.3 Summary of findings from clinical studies 
Close to 100 per cent of the intravenously injected Iohexol is excreted unchanged through the 
kidneys within 24-hours in patients with normal renal function. The elimination half-life is 

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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. 
 
8.4 Summary of known potential risks and benefits 
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. 
 
8.5 Description and justification of route of administration and dosage 
Iohexol will be intravenously administered according to established UHN protocols through an 
injection catheter. Lithium will be administered orally on three separate occasions to measure 
tubular sodium handling. 
 
8.6 Drug accountability 
Iohexol will be stored at room temperature at each site, and will be collected along with lithium 
from the pharmacy department by the study nurse at each participating center in the morning of 
the study visit. 
 
9. METHODS 
 
9.1 Study parameters/endpoints 
9.1.1 Main study parameter/endpoint 
The primary outcome of this study is blood pressure (SBP) reduction. Blood pressure will be 
measured using a calibrated automated office oscillometric device with a proper sized cuff, as per 
the Hypertension Canada Guidelines79. Patients will be seated comfortably for 5 minutes. After 
this period of rest, blood pressure will be obtained on 3 occasions with at least 1 minute between 
measurements. The first measurement will be discarded, and an average of the subsequent two 
measurements will be recorded. Similar methodology for blood pressure measurement has been 
used in previous clinical trials in KTR26.  Furthermore, patients with CKD have a higher prevalence 
of peripheral vascular disease and increased arterial stiffness as compared to the general 
population. As a result, the first SBP measurement may be less accurate as compared to subsequent 
measurements in patients with CKD80. Blood pressure will be measured at the following time 
points during the study: Day 0 (baseline), day 7 (1 week), day 42 (6 weeks), day 84 (12 weeks) 
and day 91 (13 weeks).  
 

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9.1.2 Secondary study parameters/endpoints 
 
The secondary outcomes of this study include metabolic, vascular, renal and transplant-specific 
measures. These outcomes have been included to elucidate the potential mechanisms responsible 
for blood pressure lowering, and putative cardio- and renoprotective effects in KTR. Safety 
outcomes (described further below) will also be assessed. The time points and specific 
measurements of secondary outcomes are shown in Table 2.  
 
Metabolic outcomes: Glycemic control will be measured using the following methods: Fasting 
blood glucose, HbA1c and home glucose monitoring. Home glucose monitoring will be performed 
in patients with T2D/PTDM during 2 discrete 14 day periods during the study using the 
participants’ usual glucose monitoring device. These two discrete 14 day periods are as follows: 
1) Starting 7 days prior to drug administration and stopping 7 days after drug administration (week 
-1 to 1); and 2) Starting 7 days prior to drug discontinuation, and stopping 7 days after during drug 
discontinuation (week 11 to 13). The rationale for home glucose monitoring is to study the impact 
of SGLT2i on blood glucose dynamics in this unique population with variable degrees of renal 
impairment, concomitantly treated with diabetogenic immunosuppressive medications such as 
glucocorticoids and CNIs. Although the impact of CNIs on the expression of SGLT2 in human 
kidney allografts is not known, changes to the proximal tubular epithelial cell have been well 
documented with use of CNIs in KTR62. Urinary glucose excretion will also be measured using a 
24-hour urine collection for glucose. Lastly, height, weight, waist circumference and fasting lipid 
profile will also be measured.  
 
Vascular outcomes:  Arterial stiffness will be assessed by measuring right radial artery 
waveforms by high-fidelity micromanometer (SPC-301; Millar Instruments) and central aortic 
pressure waveforms (SphygmoCor, AtCor Medical Systems, Sydney, Australia) after a 
euglycemic clamp. Systemic arterial stiffness will be determined by the augmentation index (AIx), 
which is calculated as the difference between the second systolic peak and inflection point, 
expressed as a percentage of the central pulse pressure and corrected to an average heart rate of 75 
beats/min. Aortic pulse wave velocity will be measured by sequentially recording ECG-gated right 
carotid and radial artery waveforms. Our group has extensively used this methodology in prior 
studies of participants with diabetes81. Sympathetic nervous system activity will be measured by 
heart rate variability using methods previously described by our group (SphygmoCor, Atcor 
Medical Systems Inc., Sydney, Australia). Cardiac output, stroke volume and total peripheral 
resistance will measured using the Non-Invasive Cardiac Output Monitoring (NICOM® system 
Cheetah Medical Inc.). 
 
Renal outcomes: Renal function will be assessed using serum creatinine in order to calculate the 
estimated GFR (CKD-EPI equation). GFR will also be measured in the supine position using the 
gold-standard iohexol clearance technique, standardized per 1.73m2 body surface area. Both eGFR 
and measured GFR are included in this study as the eGFR is the renal parameter that is utilized in 

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clinical practice, and provides information on what eGFR change could be expected with 
dapagliflozin therapy clinically. In addition, the eGFR is also a safety measure that is followed in 
clinical practice.  
 
Markers of oxidative stress, including 8-hydroxydeoxyguanosine and 8-isoprostane will be 
measured in plasma and urine using an ELISA assay (Eve technologies, Calgary, Alberta). 
Albuminuria will be assessed by measuring urine albumin excretion from a 24-hour urine 
collection. Natriuresis will be assessed with a 24-hour urine collection for sodium excretion. In 
addition, fractional lithium excretion (FELi), fractional sodium excretion (FENa) and renal 
segmental tubular Na+/Li+ clearances will also be measured to study the SGLT2i-related 
natriuresis mechanisms and localization of sodium excretion in the renal tubule. This methodology 
has been described in detail elsewhere in our previous work82, 83. 
 
Transplant-specific outcomes: CNI levels will be measured during the trial. All results of CNI 
monitoring will be communicated within 24 hours to the primary transplant nephrologist, in the 
event that dose adjustments to CNIs are required. In light of the data in native kidneys suggesting 
that tubulointerstitial hypoxia plays an important role in the development of DKD50, all 
participants will be offered the opportunity to undergo a renal ultrasound (photoacoustic 
ultrasonography) at baseline (between day -7 and 0) prior to drug administration, and at the end of 
the study (between day 77 and 84) prior to drug discontinuation. This novel methodology uses 
spectroscopic photoacoustics to assess kidney ischemic damage using non-invasive 
ultrasonography (Vevo System, FujiFilm, VisualSonics Inc., Toronto). This tool determines the 
degree of tissue hypoxia, as measured by oxygen saturation, and has been shown to correlate with 
areas of renal tissue ischemia84, 85, 86. In addition, the use of this methodology is ideal in KTR due 
to the anatomic proximity of the transplanted kidney, which is traditionally placed in the anterior 
abdomen (iliac fossa). This methodology has been previously used by Dr. Darren Yuen (co-
applicant). Photoacoustic renal ultrasounds will be performed at SMH and incorporated into a 
study visit when possible, given the short distance (~ 2 kilometers) between TGH and SMH. This 
is an optional ultrasound for participants of the study.  
 
Safety outcomes: The side effects of SGLT2i have been well described and will be assessed at 
each study visit. Adverse events include AKI, volume depletion, hyperkalemia, urinary and 
mycotic infections, ketoacidosis, amputations and allergic reactions. Episodes of biopsy-proven 
acute rejection (as defined by the Banff criteria), death-censored graft failure (defined as the need 
for initiation of chronic dialysis or re-transplantation) or death with graft function (defined as death 
with a functioning allograft) will also be collected. Kidney transplantation assures complete 
denervation of the transplanted kidney and the renal vasoconstrictive response in the setting of 
intravascular volume depletion is diminished in KTR. Therefore, frequent monitoring for adverse 
events has been integrated in our study design, occurring on 7 separate occasions, to capture these 
adverse events should they occur. Adverse event monitoring is shown in Table 2 and will occur 

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in person on study day 7 (1 week), day 42 (6 weeks), day 77 (11 weeks), day 84 (12 weeks) and 
day 91 (1 week after drug discontinuation) and by telephone/e-mail on study day 21 (3 weeks) and 
day 63 (9 weeks).  All adverse events will be recorded on case report forms.  
 
9.2 Randomization, blinding and treatment allocation 
 
The randomization scheme will be computer-generated by an independent biostatistician. To 
achieve a balance of participants in each arm, permuted block randomization will be used with 
variable blocks of 4 and 6. Randomization will be stratified based on T2D and PTDM status, as 
the effects of dapagliflozin may differ between these two groups. Participants will be randomized 
only after screening and informed consent has been obtained. All participants, nurses, physicians, 
study coordinators and investigators will be blinded to the treatment allocation. In addition, all 
participants, study personnel and study sponsor will be blinded until the end of the trial to all the 
laboratory and test results obtained during the trial. Dapagliflozin and placebo tablets, as well as 
drug packaging will be identical in appearance. Adherence to the intervention will be determined 
using pill counts and questioning of participants at each study visit87. Reasons for non-adherence 
and drug discontinuation will be ascertained.  
 
9.3 Study procedures 
 
Leading up to week 0, 1 and 12, participants will be placed on a 7-day diet targeting 150 mmol/day 
Na+ and £1.5 g/kg/day protein, verified with a 24-hour urine sample to measure Na+ and urea 
excretion prior to all experiments. This moderate, fixed dose Na+ and moderate protein diet avoids 
the confounding effect of circulating volume contraction and renin-angiotensin-aldosterone 
system activation due to low Na+ diets, and the renal hyperfiltration effect of high protein intake88. 
An electrocardiogram will also be performed at the screening visit. At 22:00 on the night prior to 
the study day, all participants will take 300 mg of lithium carbonate (Li+CO3) to derive renal 
segmental tubular Na+/Li+ clearances the following day, as described previously82, 83. Week 0, 1 
and 12 studies will start at 0745 hours, and participants will fast for the duration of the day. All 
studies will be performed under clamped euglycemic conditions (capillary blood glucose 4 to 6 
mmol/L) to avoid confounding effects of hyperglycemia on blood pressure and renal function. 
After clamped euglycemia is achieved for approximately 2-4 hours, blood samples will be 
collected for makers of oxidative stress (8-isoprostane and 8-hydroxydeoxyguanosine). 
Sympathetic nervous system activation will be assessed using heart rate variability89, 90. Following 
blood and urine tests, blood pressure will be assessed using an automated vital signs monitor 
(Connex Vital Signs Monitor, Welch Allyn ) at  60-minute intervals. Baseline arterial stiffness 
(SphygmoCor, Atcor Medical Systems Inc., Sydney, Australia) will be measured non-invasively 
using applanation tonometry using standard techniques that we have used previously72, 73. Cardiac 
output, stroke volume and total peripheral resistance will be derived from stroke volume and heart 
rate that is measured using the Non-Invasive Cardiac Output Monitoring (NICOM® system 
Cheetah Medical Inc.) that we have also used previously91. GFR (per 1.73 m2) will be measured in 

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the supine position using iohexol clearance71. Participants will then be randomized to dapagliflozin 
10 mg PO daily or a placebo. Identical studies will be performed at study weeks 0, 1 and 12, with 
the exception of NICOM, which will be performed on study weeks 0 and 12 only. All procedures 
will be supervised by a study physician.  
 
Serum, plasma and urine will be collected and stored on study weeks 0,1, and 12 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 stored into a secure central storage 
facility at Toronto General Hospital. Those results may be pooled with biomarker data from other 
similar 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. 
 
9.4 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. 
9.5 Reasons for possible drug discontinuation 
 
1. Serious adverse events or an intolerable adverse effect such as a persistent allergy or rash; 
2. Clinically significant persistent changes from baseline based on laboratory safety 
assessments;  
3. Pregnancy or breastfeeding; 
4. Withdrawal of consent; 
5. Participant unable to adequately complete study visits or procedures. 
 
9.6 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. 
 
9.7 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. Subjects will be followed up until resolution of the inciting adverse 
event responsible for drug withdrawal. If withdrawal was unrelated to an AE, then subjects will 
be followed up approximately 10 days after drug discontinuation for an end of treatment visit with 

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repeat bloodwork from the time of screening. In case of withdrawal of consent, participants will 
not be contacted nor followed by the study team. 
 
9.8 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. 
 
10. SAFETY REPORTING 
 
10.1 
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. 
10.2 
AEs and SAEs  
 
10.2.1 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 unfavorable 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). 
 
10.2.2  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; 

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- 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.) 
 
AEs will be recorded in the electronic case report form (eCRF).  
 
10.2.3 Adverse events of interest 
 
Urinary tract infections  
 
Genital infections 
 
Diabetic ketoacidosis (DKA) 
 
Volume depletion 
(Eg, dehydration, hypovolemia, or hypotension) 
 
Fractures 
 
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. 
 
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.  
 
Amputation:  
Amputations will be recorded in the eCRF. We will report the underlying cause of amputation as 
the AE and include the information regarding the actual amputation in the AE description rather 
than reporting the amputation procedure as a separate AE. 
 
10.3 
Recording of Adverse Events 
 

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• Time Period for Collection of Adverse Events 
For this study, SAEs, discontinuations due to AEs (DAEs), AEs of special interest and other AEs 
will be collected from the time of signing the informed consent and throughout the study, including 
the run-in and wash-out periods. Information about all adverse events (serious or not) will be 
recorded in source documents according to good clinical practice, and retained at the 
investigative sites. 
 
• Follow-up of Unresolved Adverse Events 
Any SAEs, DAEs, AE of special interest, or other AEs will be followed by the investigator until 
resolution or until a clinically stable outcome is reached, or until further follow-up is no longer 
considered by the investigator to provide clinically meaningful information.   
 
• Variables  
The following variables will be collected for each SAE/DAE/AE: 
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. 
SAE Variables to be collected: 
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 SAEs/DAEs/AE 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 above. An AE of severe intensity need not necessarily 
be considered serious. For example, nausea that persists for several hours may be considered 

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severe nausea, but not a SAE unless it meets the criteria shown in above. On the other hand, a 
stroke that results in only a limited degree of disability may be considered a mild stroke but would 
be a SAE when it satisfies the above criteria. 
 
• 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 SAEs/DAEs/AE 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 SAEs/DAEs/AEs, 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 should therefore only be reported as AEs if they fulfil any of the SAE criteria, 
are the reason for discontinuation of study treatment, or fulfil criteria of AEs of special interest. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, the 
sign or symptom will be reported as an SAE/DAE or 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. 
 
10.4 
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). 
 

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If an SAE occurs after the 30 days of drug discontinuation, it should be reported. If an SAE occurs 
after the occurrence of a protocol-specific procedure, it should also be reported. 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. 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 sponsor’s principal investigator and project leader will 
report SAEs accompanied by a cover page mentioning the study code, patient number, country, 
investigator, 
seriousness 
to 
AstraZeneca 
via 
the 
product 
safety 
e-mail 
box 
AEMailboxClinicalTrialTCS@AstraZeneca.com within the same timelines.  
 
10.5 
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; 
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 
 
SUSARs will be reported to the accredited ethics committee and recorded in an overview list. 
When needed, they will be also reported expedited to the appropriate health authority (Health 
Canada). 
 
In an emergency, unblinding can be performed 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 unblinds the subject he/she must note the date, time and reason 
for removing it and record this information in the Comments section of the CRF and in the source 
data. He/she must also immediately inform the project leader/principal investigator about the 
unblinding of the subject treatment. Even though the subject has been unblinded, 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 Principal Investigator to ensure the investigator site staff are appropriately 

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trained on the unblinding procedure in case of emergency. Study drug must be discontinued after 
unblinding but the subject will be followed until resolution of the adverse event.  It is the intent 
that subjects who discontinue treatment with the study drug will continue in the study according 
to the visit schedule.  At the conclusion of the study, the occurrence of any unblinding can be 
reported.   
 
10.6 
Pregnancy 
 
All pregnancies and outcomes of pregnancy will be reported to the sponsor and AstraZeneca, after 
obtaining separate consent from the study participant/participant partner. 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 1 day of when he/she became aware of it. 
 
10.7 
Overdose 
 
Dapagliflozin has been well tolerated at doses of up to 500 mg/day in single dose testing in healthy 
volunteers and up to 100 mg/day in repeat dose testing for 14 days in healthy volunteers and 
patients with T2D.  Overdose defined as at least twice the intended dose within the therapeutic 
interval, whether accidental or intentional, suspected by the Investigator or spontaneously notified 
by the patient, will be recorded in the eCRF overdose module. If the overdose is symptomatic, it 
will also be recorded as an adverse event.  If an overdose is suspected, monitoring of vital functions 
as well as treatment should be performed as appropriate.  
 
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. 
 
10.8 
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) adverse reactions and serious adverse 
reactions, along with an aggregated summary table of all reported serious adverse 
reactions, ordered by organ system, per study; 

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• 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 Astra 
Zeneca. 
11. STATISTICAL ANALYSIS 
 
The analytical plan mirrors that operationalized in previous work92, 93. Data will be analyzed using 
Stata/SE 15. The primary outcome is the difference in blood pressure reduction in dapagliflozin 
vs. placebo treated participants at 12 weeks. Secondary outcomes will consist of within and 
between group changes metabolic, vascular, renal and transplant outcomes. Frequency of adverse 
events, non-adherence and drug discontinuation will be tabulated (no comparisons will be made). 
Within group comparisons will be analyzed using repeated measures ANOVA (baseline value will 
be included in these ANOVA models). As in previous work, between group comparisons will also 
be made using a 2-way ANOVA with treatment as the dependent variable71, 92, 94-96. This clinical 
trial is not sufficiently powered to detect sex- or gender-based differences. However, data analyses 
will be stratified by sex and gender to detect any similarities or differences. These will be 
exploratory analyses and hypothesis generating, which may be informative in the design of future 
studies. Other exploratory analyses will include stratification by GFR (measured iohexol GFR of 
<45 ml/min/1.73m2 vs. >45 ml/min/1.73m2), as well as diabetes type (T2D and PTDM).  An 
intention-to-treat (ITT) approach will be used. Adherence will be measured (see ‘Randomization’ 
in the proposal), and non-adherent patients will also be included in the ITT analysis. 
 
12. ETHICAL CONSIDERATIONS 
 
12.1 
Regulation statement 
The trial will be carried out in compliance with the protocol, the ethical principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for GCP, 
relevant Standard Operating Procedures (SOPs), and relevant regulations. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient. 
 
12.2 
Recruitment and consent 
Patients will be enrolled to the trial from our center in Canada. Identification of patients eligible 
for trial participation will occur at two sites, Toronto General Hospital (TGH) and St. Michael’s 
Hospital (SMH) in Toronto, Ontario. Both sites have large, well-established kidney transplant 
programs (total of 300 to 350 kidney transplants per year and 4000 to 5000 prevalent KTR across 
both centres). After identification of a patient potentially eligible for the trial, all screening 
activities and informed consent will take place at TGH.  Prior to their visit to the outpatient clinic, 

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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 provided with as much time as required to consider their 
decision and will also be provided with an informed consent form. Participants will be required to 
sign their written informed consent before they take part in the study. 
 
12.3 
Objection by minors or inanticipated subjects (if applicable) 
No minors or incapacitated adults will be included in this study. 
 
12.4 
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. 
 
12.5 
Compensation for injury 
The sponsor has an insurance which is in accordance with the legal requirements in Canada. This 
insurance provides cover for damage to research subjects through injury or death caused by the 
study.  
 
12.6 
Incentives (if applicable) 
Participation of patients in the study is a free-will decision. Patients will receive restitution of all 
costs for transportation for participating. Patients do not receive priority for treatment of other 
diseases in the clinic during this clinical trial. 
 
13. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
13.1 
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- 

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date. The key to the code will be safeguarded by the investigator since the data will be kept for a 
period of 25 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. 
 
13.2 
Monitoring and Quality Assurance 
 
The investigator will permit trial-related monitoring, audits, IRB/IEC review, and regulator 
inspection(s), providing direct access to source data/documents.  
 
13.3 
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. 
 
13.4 
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. 
 
13.5 
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. 
 

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13.6 
Data Safety Monitoring Board (DSMB)/Safety Committee 
The institution of a DSMB is not a prerequisite to improve the safety of the patients as the safety 
profile of dapagliflozin has been well characterized and investigated in completed clinical trials 
that involved >6000 patients with type 2 diabetes. Dapagliflozin is registered for clinical use in 
Europe. 
 

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14. References 
1. 
Canadian Organ Replacement Register, Canadian Institute for Health Information. April 
2015. 
2. 
Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ and Port 
FK. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting 
transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725-30. 
3. 
Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C and Muirhead N. A study 
of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996;50:235-42. 
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43 
15. Tables and Figures. 
 
Figure 1: Effects of SGLT2 inhibition on the nephron.  
Figure reproduced from: van Bommel EJ. Et al. SGLT2 Inhibition in the Diabetic Kidney-From 
Mechanisms to Clinical Outcome. Clin J Am Soc Nephrol. 2017;12:700-710. 
 
 
 
 
 
 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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44 
Figure 2: Potential cardio- and renoprotective mechanisms of SGLT2 inhibition. 
Figure reproduced from: Heerspink HJ. et al. Sodium Glucose Cotransporter 2 Inhibitors in the 
Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and 
Clinical Applications. Circulation. 2016;134:752-72. 
 
 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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Figure 3: Study design 
 
 
 
 
 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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Table 1: Summary of studies of SGLT2i in kidney transplant recipients. 
Observational studies 
Author, Year Participants 
Design 
Treatment 
Results 
Rajasekeran 
et al. Diabetes 
Care 20171 
N=10 KTR & 
SPKTR with 
PTDM or T2D 
 
 
Observational 
cohort study,  
80.5 person-
months follow-
up 
canagliflozin  
Weight, kg: -2.14 (SD 2.8)  
Systolic blood pressure, mmHg: -6.5 (SD 10.8) 
Diastolic blood pressure, mmHg: -4.8 (SD 12)  
Serum creatinine, mmol/L: 9.7 (SD 14.6); eGFR, 
mL/min/1.732 : -4.3 (SD 12.2)  
No urinary/mycotic infections, AKI or acute rejection 
Mahling et al. 
Kidney Blood 
Press Res 
20192 
N=10 KTR with 
PTDM or T2D 
 
Observational 
study, 6.3 
person-years 
empagliflozin 
Weight, kg: -1.9 (-1.9 to 0.1)  
Systolic blood pressure, mmHg: -2.5 (-36.3 to 0.8) 
Diastolic blood pressure, mmHg: -0.5 (-9.5 to 7.5)  
2 episodes of UTI, 1 episode of AKI 
Alkindi et al. 
Transplant 
Proc 20203 
N=8 KTR with 
PTDM or T2D 
Retrospective 
chart review 
empagliflozin 
(6 patients), 
dapagliflozin 
(2 patients) 
 
BMI, kg/m2, 32.7±7.2 to 27.4±4.2 after 12 months 
(p<0.05) 
Systolic blood pressure, mmHg: 135±9.6 to 126.4±11.5 
after 12 months (p>0.05) 
Diastolic blood pressure, mmHg: 80.6±10 to 74.5±7.3 
after 12 months (p>0.05) 
eGFR, no significant change 
1 episode of UTI, no AKI, ketoacidosis, acute rejection 
Schwaiger et 
al. AJT 20184 
N=14 KTR with 
PTDM, 6 months 
post-transplant, 
eGFR ≥ 
30ml/min/1.73m2, 
stable on insulin 
therapy 
Open-label, 
single-arm, non-
inferiority study 
Single-centre 
study 
Treatment with 
empagliflozin  
10mg after 
discontinuation 
of insulin 
therapy, 4 
weeks 
Change in baseline to 4 week OGTT - fasting and 2‐hour 
glucose levels increased to 144 ± 45 mg/dL (P = .005) 
and 273 ± 116 mg/dL (P = .06), respectively 
Avg body weight: -1.6kg; Bioimpedance volume status: 
fluid overload decreased from 2.7 ± 2.1 (baseline) to 1.8 
± 1.8L (P = .006) 
5 episodes of urinary tract infection 
 
 
 
Randomized Control Trial 
Author, Year Participants 
Design 
Treatment 
Results 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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Halden et al. 
Diabetes 
Care5 
N=49 KTR with 
PTDM, 1 year post 
transplant, eGFR 
≥30m/min/1.73m2 
Double-blind 
RCT 
Single centre 
study 
1:1  
empagliflozin 
10mg vs. 
placebo, 24 
weeks 
Secondary Outcomes 
Change in median HbA1c (%): -0.2 (-0.6 to -0.1) with 
empagliflozin vs +0.1 (-0.1 to 0.4); p=0.025 
Body Weight: -2.5 kg (-4.0 to -0.05) with empagliflozin 
vs +1.0 kg (0.0 to 2.0); p=0.014 
24hr blood pressure – no difference in blood pressure 
between groups 
Safety Outcomes – no significant between group 
differences 
KTR: Kidney transplant recipients; SPKTR: Simultaneous pancreas-kidney transplant recipients; T2D: Type 2 diabetes; PTDM: Post-
transplant diabetes mellitus; eGFR: Estimated glomerular filtration rate; SD: Standard deviation. OGTT: Oral Glucose Tolerance Test 
 
1. Rajasekeran H, Kim SJ, Cardella CJ, et al. Use of canagliflozin in kidney transplant recipients for the treatment of type 2 
diabetes: A case series. Diabetes Care. 2017;40(7): e75-e76. 
2. Mahling M, Schork A, Nadalin S, Fritsche A, Heyne N, Guthoff M. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibition in 
Kidney Transplant Recipients with Diabetes Mellitus. Kidney Blood Press Res. 2019;44(5): 984-992. 
3. AlKindi F, Al-Omary HL, Hussain Q, Al Hakim M, Chaaban A, Boobes Y. Outcomes of SGLT2 Inhibitors Use in Diabetic 
Renal Transplant Patients. Transplant Proc. 2020;52(1): 175-178. 
4. Schwaiger E, Burghart L, Signorini L, et al. Empagliflozin in posttransplantation diabetes mellitus: A prospective, 
interventional pilot study on glucose metabolism, fluid volume, and patient safety. Am J Transplant. 2019;19(3): 907-919. 
5. Halden TAS, Kvitne KE, Midtvedt K, et al. Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With 
Posttransplant Diabetes Mellitus. Diabetes Care. 2019;42(6): 1067-1074. 
 
 
 

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Table 2: Study activities 
 
Screening 
Baseline 
Acute  
1 week 
Drug/Placebo 
Dosing 
Chronic  
12 week 
Drug/Placebo 
Follow-up 
Visit* 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10/EEOS 
Week 
-2 
-1 
0 
1 
3 
6 
9 
11 
12 
13 
Day 
-14 
-7 
0 
7 
21 
42 
63 
77 
82 
91 
Clinic Visit 
X 
 
X 
X 
 
X 
 
 
X 
X 
Phone/email 
visit 
 
X 
 
 
X 
 
X 
X 
 
 
Fasting visit 
 
 
X 
X 
 
 
 
 
X 
 
Demographics, 
medical Hx & 
ECG 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
 
X 
X 
 
X 
 
 
X 
X 
BMI and waist 
measurement 
X 
 
X 
X 
 
X 
 
 
X 
 
Pregnancy test 
X 
 
X 
X 
 
 
 
 
X 
 
Start modified 
dieta 
 
X 
Until 
V4 
X 
 
 
 
X 
 
 
Modified 
euglycemic 
clamp 
 
 
X 
X 
 
 
 
 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Take study 
medication 
 
 
 
X 
X 
X 
X 
X 
X 
 
Phone call 
 
 
 
 
X 
 
X 
 
 
 
Adverse events 
query 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Metabolic parameters 
Start HGMb 
 
X 
 
 
 
 
 
X 
 
 
Stop HGMb 
 
 
 
X 
 
 
 
 
 
X 
Vascular parameters 
Vital signs 
X 
 
X 
X 
 
X 
 
 
X 
X 
Arterial stiffness 
 
 
X 
X 
 
 
 
 
X 
 
NICOM 
 
 
X 
 
 
 
 
 
X 
 
Renal parameters 
Renal ultrasoundc 
 
 
X 
 
 
 
 
 
X 
 
Lithium tablet 
intakec 
 
 
X 
X 
 
 
 
 
X 
 
Blood and urine collection 
24 hour urine 
collection 
 
 
X 
X 
 
 
 
 
X 
 
Blood and urine 
samples 
X 
 
X 
X 
 
X 
 
 
X 
X 
Biobanking 
samples 
 
 
X 
X 
 
 
 
 
X 
 
Reactive oxygen 
species collection 
 
 
X 
 
 
 
 
 
X 
 
a The diet includes a target of 140 mmol of sodium per day to avoid salt depletion and consequence 
activation of the renin-angiotensin-aldosterone system 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 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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March 18, 2022 
49 
hyperfiltration). This has also been part of previous mechanistic studies in the Cherney Laboratory 
in patients with diabetes. bIn patients with T2D/PTDM c Renal ultrasound will be performed 
between visits 2 and 3 and between visits 8 and 9.  c Lithium tablet will be taken at 10pm the night 
before Visits 3,4 and 9. *Study visits are subject to PI’s discretion based on participants’ 
condition/safety/lab results. HGM; home glucose monitoring; NICOM; Non-invasive cardiac 
output monitoring; EEOS; early end of study 
 
 
 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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Table 3: Study variables included in data collection  
Category 
Demographic & 
medical history 
Imaging 
Physical 
examination 
Adverse events 
Laboratory 
(Blood) 
Laboratory 
(Urine) 
Variables 
 
Date of birth, age, 
race/ethnicity, sex, 
gender, cause of ERSD, 
modality and duration 
of RRT prior to 
transplant, date of 
transplant, type of 
transplant, induction 
immuno-suppression, 
maintenance immuno-
suppression, delayed 
graft function, acute 
rejection (date, type and 
treatment), history of 
urinary tract infection or 
mycotic infection (date, 
organism, and 
treatment), medication 
names, doses, allergy 
history 
Tissue 
hypoxia 
ultrasound of 
allograft 
Blood pressure, 
respiratory rate, 
heart rate, 
temperature, 
height, weight, 
abdominal 
circum- 
ference 
Hypotension, 
volume 
depletion,  
Hyper-kalemia, 
acute kidney 
injury, urinary 
infections, 
mycotic 
infections, 
amputation, 
allergic reaction, 
hypo-glycaemia, 
ketoacidosis 
Fasting blood 
glucose, flash 
glucose 
monitoring, 
hemoglobin 
A1C, complete 
blood count, 
sodium, 
potassium, 
chloride, bicar-
bonate, calcium, 
phosphate, 
albumin 
ALT, ALP, 
AST, total 
bilirubin, 
amylase, 
ketones, urea, 
creatinine, 
fasting 
cholesterol 
profile, CNI 
level, beta-HCG 
(if applicable), 
neurohomone – 
Aldosterone, 
Renin, Ang II, 
ANP, and 
catecholamines 
24 hour and/or 
spot urine 
collection for 
sodium, 
potassium, 
protein, urate, 
urea, creatinine, 
glucose, 
albumin, 
fractional 
lithium 
excretion (FE 
Li), fractional 
sodium 
excretion (FE 
Na) 

EffIcacy, mechaNisms and saFety of SGLT2 INhibitors in kIdney Transplant recIpients:  
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Biomarker 
biobanking 
Heart rate 
variability  
Death-censored 
graft failure, 
death with graft 
function, biopsy-
proven acute 
rejection 
GFR (iohexol),  
8-hydroxy-
deoxyguanosine,  
8-isoprostane 
8-hydroxy-
deoxyguanosine,  
8-isoprostane, 
urine adenosine, 
biomarker 
biobanking 
Arterial stiff-
ness, aortic pulse 
wave velocity, 
cardiac output, 
stroke volume, 
total peripheral 
resistance 
ESRD: End-stage renal disease; RRT: Renal replacement therapy; GFR: Glomerular filtration rate.