Clinical trial NCT03190694
Conditions: Chronic Kidney Diseases Proteinuria
Keywords: chronic kidney disease non diabetic
Sponsor: Hiddo Lambers Heerspink
Start date: 2017-11-12; Completion date: 2019-12-01
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study tests the hypothesis that dapagliflozin lowers proteinuria in patients with non-diabetic chronic kidney disease.

Detailed description:
Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS) inhibitors, many patients with non-diabetic kidney disease show progressive kidney function loss, which is associated with high residual proteinuria. Novel treatment strategies are therefore required to further decrease proteinuria and to slow kidney function decline.

Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the reabsorption of glucose and sodium in the proximal tubule. The increased natriuresis following dapagliflozin administration normalizes tubuloglomerular feedback resulting in a reduction in intra-glomerular hypertension, which is in turn manifested by acute reversible reductions in glomerular filtration rate and albuminuria. Since many etiologies of non-diabetic nephropathy are characterized by intraglomerular hypertension, we hypothesize that dapagliflozin acutely decreases GFR and proteinuria in patients without diabetes at risk of progressive kidney function loss via a glucose independent hemodynamic mechanism.

Arms: arm 1: Participants first received Dapagliflozin 10mg tablet for 6 weeks. After a washout period of 6 weeks, they then received Placebo tablet for 6 weeks (matching Dapagliflozin 10mg).

Dapagliflozin 10 mg: Green, plain, diamond shaped, film coated tablet (orally) Placebo: Green, plain, diamond shaped, film coated tablet. Does not contain active ingredient arm 2: Participants first received Placebo tablet for 6 weeks. After a washout period of 6 weeks, they then received Dapagliflozin 10mg tablet for 6 weeks (matching Dapagliflozin 10mg).

Placebo: Green, plain, diamond shaped, film coated tablet. Does not contain active ingrediënt Dapagliflozin 10 mg: Green, plain, diamond shaped, film coated tablet (orally)
Interventions: intervention 1: Dapagliflozin 10mg
Intervention descriptions: intervention 1: Tablet

Protocol documents:
Prot_000.pdf: 
Effects of dapagliflozin in non-diabetic patients with proteinuria
1 
A study to assess the Renoprotective Effects of 
the SGLT2 Inhibitor Dapagliflozin in Non-
Diabetic Patients with Proteinuria: a 
Randomized Double Blind 6-Weeks Cross-Over 
Trial
EudraCT 2017-001090-16
 NCT03190694


Effects of dapagliflozin in non-diabetic patients with proteinuria
2
PROTOCOL TITLE: A STUDY TO ASSESS THE RENOPROTECTIVE EFFECTS OF THE 
SGLT2 INHIBITOR DAPAGLIFLOZIN IN NON-DIABETIC PATIENTS WITH 
PROTEINURIA: A RANDOMIZED DOUBLE BLIND 6-WEEKS CROSS-OVER TRIAL
Protocol ID
EUDRA-CT
2017003001
2017-001090-16
Short title
Effect of dapagliflozin on albuminuria in non-
diabetes
EudraCT number 
2017-001090-16
Version
4.0 (Global)
Date
Feb 2018
Coordinating 
investigator/project leader
Dr. H.J. Lambers Heerspink
Department of Clinical Pharmacology
University Medical Center Groningen
Groningen
Tel: 050-3617859
E-mail: h.j.lambers.heerspink@umcg.nl
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/
uitvoerder)
Prof. H.J. Lambers Heerspink
Department of Clinical Pharmacology
University Medical Center Groningen
Groningen
Tel: 050-3617859
E-mail: h.j.lambers.heerspink@umcg.nl
Prof. D. Cherney
Division of Nephrology
University Health Network, University of Toronto
Toronto
Tel: 416 340 4151
E-mail: david.cherney@uhn.ca 
Sponsor (in Dutch: 
verrichter/opdrachtgever)
University Medical Center Groningen
Hanzeplein 1
PO Box 30 001
9700 RB  Groningen
Netherlands
Subsidising party
Astra Zeneca (study medication)




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4
TABLE OF CONTENTS
1. 
INTRODUCTION AND RATIONALE.................................................................................9 
2. 
OBJECTIVES..................................................................................................................11 
3. 
STUDY DESIGN .............................................................................................................12 
3.1 
Population (base).....................................................................................................18 
3.2 
Inclusion criteria.......................................................................................................18 
3.3 
Exclusion criteria......................................................................................................19 
3.4 
Sample size calculation ...........................................................................................20 
4. 
TREATMENT OF SUBJECTS ........................................................................................21 
4.1 
Investigational product/treatment.............................................................................21 
4.2 
Use of co-intervention (if applicable)........................................................................22 
5. 
INVESTIGATIONAL PRODUCT .....................................................................................23 
5.1 
Name and description of investigational  product(s) ................................................23 
5.2 
Summary of findings from non-clinical studies.........................................................23 
5.3 
Summary of findings from clinical studies................................................................23 
5.4 
Summary of known and potential risks and benefits................................................24 
5.5 
Description and justification of route of administration and dosage.........................27 
5.6 
Dosages, dosage modifications and method of administration................................27 
5.7 
Preparation and labelling of Investigational Medicinal Product................................27 
5.8 
Drug accountability ..................................................................................................27 
5.9 
Handling and Dispensing .........................................................................................28 
5.10 
Drug Ordering ..........................................................................................................28 
6. 
NON-INVESTIGATIONAL PRODUCT ............................................................................29 
6.1 
Name and description of non-investigational product(s)..........................................29 
6.2 
Summary of findings from non-clinical studies.........................................................29 
6.3 
Summary of findings from clinical studies................................................................29 
6.4 
Summary of known and potential risks and benefits................................................29 
6.5 
Description and justification of route of administration and dosage.........................30 
6.6 
Dosages, dosage modifications and method of administration................................30 
6.7 
Preparation and labelling of Non Investigational Medicinal Product ........................30 
6.8 
Drug accountability ..................................................................................................30 
7. 
METHODS ......................................................................................................................31 
7.1 
Study parameters/endpoints....................................................................................31 
7.3 
Study procedures ................................................................................................31 
7.4   Withdrawal of individual subjects................................................................................35 
7.5  
Replacement of individual subjects after withdrawal ............................................35 
7.6 
Follow-up of subjects withdrawn from treatment......................................................35 
7.7 
Premature termination of the study..........................................................................35 
8. 
SAFETY REPORTING....................................................................................................35 
8.1 
Section 10 WMO event ............................................................................................35 
8.2 
AEs, SAEs and SUSARs .........................................................................................36 
8.2.1 
Adverse events (AEs).......................................................................................36 


Effects of dapagliflozin in non-diabetic patients with proteinuria
5
8.2.2 
Serious adverse events (SAEs)........................................................................36 
8.2.3 
Adverse events of interest ................................................................................37 
8.4 
Serious Adverse Event Collecting and Reporting ....................................................40 
8.4.1 
Suspected unexpected serious adverse reactions (SUSARs)..........................41 
8.5 
Pregnancy................................................................................................................43 
8.5.1 
Maternal exposure............................................................................................43 
8.6 
Overdose .................................................................................................................43 
8.7 
Annual safety report.................................................................................................43 
8.8 
Data Safety Monitoring Board (DSMB) / Safety Committee] ...................................44 
9. 
STATISTICAL ANALYSIS...............................................................................................45 
9.1 
Primary study parameter(s) .....................................................................................45 
9.2 
Secondary study parameter(s).................................................................................45 
9.3 
Other study parameters ...........................................................................................45 
9.4 
Interim analysis........................................................................................................45 
N/A .........................................................................................................................................45 
10. 
ETHICAL CONSIDERATIONS ....................................................................................46 
10.1 
Regulation statement...............................................................................................46 
10.2 
Recruitment and consent .........................................................................................46 
10.3 
Objection by minors or incapacitated subjects (if applicable) ..................................46 
10.4 
Benefits and risks assessment, group relatedness..................................................46 
10.5 
Compensation for injury ...........................................................................................47 
10.6 
Incentives (if applicable) ..........................................................................................47 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION..........................48 
11.1 
Handling and storage of data and documents .........................................................48 
11.2 
Monitoring and Quality Assurance ...........................................................................48 
11.3 
Amendments............................................................................................................48 
11.4 
Annual progress report ............................................................................................48 
11.5 
End of study report...................................................................................................49 
11.6 
Public disclosure and publication policy...................................................................49 
12. 
STRUCTURED RISK ANALYSIS................................................................................50 
12.1 
Potential issues of concern......................................................................................50 
12.2 
Synthesis .................................................................................................................52 
13. 
REFERENCES............................................................................................................53 


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


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WMO
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen
SUMMARY
Rationale:
Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS) inhibitors, many 
patients with non-diabetic kidney disease show progressive kidney function loss, which is 
associated with high residual albuminuria. Novel treatment strategies are therefore required to 
further decrease albuminuria and to slow kidney function decline.
Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the reabsorption of 
glucose and sodium in the proximal tubule. The increased natriuresis following dapagliflozin 
administration normalizes tubuloglomerular feedback resulting in a reduction in intra-
glomerular hypertension, which is in turn manifested by acute reductions in glomerular filtration 
rate and albuminuria. Since many etiologies of non-diabetic nephropathy are characterized by 
intraglomerular hypertension, we hypothesize that dapagliflozin acutely decreases GFR and 
albuminuria in patients without diabetes at risk of progressive kidney function loss via a glucose 
independent hemodynamic mechanism.
Objective:
Primary: 
To assess the change baseline in 24-hr proteinuria with dapagliflozin for six weeks 
relative to placebo treatment in patients with non-diabetic kidney disease and 
proteinuria > 500 mg/day on stable ACEi or ARB treatment. 
Secondary: 
To assess the effect of dapagliflozin 10 mg/d compared to placebo on Glomerular 
Filtration Rate (GFR) using iohexol clearance.
To assess the effect of dapagliflozin 10 mg/d compared to placebo on systolic/diastolic 
blood pressure
To assess the effect of dapagliflozin 10 mg/d compared to placebo on body weight
To assess the effect of dapagliflozin 10 mg/d on selected neurohormones/biomarkers:
o
Hormones of the RAAS (plasma and urine)
o
Natriuretic peptides
o
Urinary adenosine
o
Co-peptin


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o
Immunoglobulin G (plasma and urine)
To characterize the safety of dapagliflozin vs. placebo by determining the number of 
hypoglycemic episodes between groups, and serious adverse events.
Study design:
Randomized placebo controlled double blind cross-over trial
Eligible participants will be randomly assigned to one of the two treatment orders: placebo-
dapagliflozin or dapagliflozin-placebo. Each treatment period lasts 6 weeks followed by a 6
week wash-out period to avoid cross-over effects. Patients will have their study visit in the 
morning in fasted condition. 
Study population: Male and female subjects with Chronic Kidney Disease aged between 18 
and 75 years, proteinuria levels between 500 and 3500 mg/24-hour, and an eGFR 
25 
ml/min/1.73m2 will be enrolled. Patients with type 1 or type 2 diabetes, polycystic kidney 
disease, glomerulonephritis with flares (lupus or anti-neutrophil cytoplasmic antibodies (ANCA) 
associated vasculitis) or ongoing active renal inflammation will be excluded. Patients have to 
be treated with a stable dose of an ACEi or ARB for at least 4 weeks prior to enrolment.
Intervention: Dapagliflozin 10 mg/day or matched placebo
Main study parameters/endpoints: Change in 24-hr proteinuria
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: Patients visit the outpatient clinic on a more regular base than standard 
patient care - i.e. at study inclusion and at start and end of each treatment period (9 hospital 
visits in a total study duration of 25 or up to 41 weeks) - for clinical assessment. A fasting blood 
sample is collected with venipuncture. Non-radioactive iohexol GFR measurements are 
performed at start and end of each treatment period as well as at the end of the wash-out 
period. 24hr urine will be collected one day prior to the hospital visit, except for the screening 
visit when patients collect 24hr urine after informed consent is obtained. No other invasive 
measurements will be executed. Patients receive restitution of all travel costs. Patients receive 
no priority in treatment of other diseases in the clinic during this study. There are no direct 
benefits for the patients to be included and participation is on a voluntary basis.


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1. INTRODUCTION AND RATIONALE
Inhibition of sodium–glucose cotransporter 2 (SGLT2i) reduces plasma glucose and HbA1c in 
patients with type 2 diabetes by increasing urinary glucose excretion. Beneficial effects of 
SGLT2i beyond glycemic control in patients with type 2 diabetes have been suggested by the 
EMPA-REG OUTCOME trial, in which empagliflozin treatment added to standard care 
significantly reduced the composite primary endpoint (i.e. death from cardiovascular causes, 
nonfatal myocardial infarction, or nonfatal stroke), compared to participants allocated to the 
placebo group 1.  In this study, dramatic cardiovascular protective effects were reported, even 
though HbA1c was only reduced by 0.36% at the end of the study. The preliminary renal 
outcome data were recently reported showing that individuals treated with empagliflozin had a 
39% reduced risk of new onset of nephropathy; and a 46% reduced risk of the composite renal 
endpoint consisting of doubling of serum creatinine, end stage kidney disease (ESKD) or death 
due to renal disease 2.  In light of modest glucose-lowering effects in EMPA-REG Outcome, 
renal and cardiovascular benefits have been attributed to natriuretic properties of the class, 
leading to hemodynamic effects in both the renal and systemic vascular circulations.
In the renal microcirculation, SGLT2i “normalizes” tubuloglomerular feedback mechanisms 
seen in the hyperfiltration stage of diabetic nephropathy 3. Furthermore, effects of SGLT2i at 
the afferent arteriole likely account for the acute “dip” in eGFR observed in patients with and 
without impaired renal function, which likely reflects a reduction in intraglomerular hypertension 
at the single nephron level across the spectrum of renal function. It is believed that natriuresis 
leading to increased tubuloglomerular feedback at least partially mediates the beneficial effects 
of SGLT2i via this glucose-independent hemodynamic mechanism. However, it is unclear if
the renal protection of SGLT2i can be similarly applied to other proteinuric kidney diseases 
that are unrelated to diabetic nephropathy.
One of the general physiological principles that applies to progression of both diabetic and 
non-diabetic chronic kidney disease (CKD) is the concept of elevated intraglomerular pressure 
as a risk factor for CKD progression. More specifically, in the setting of CKD, remnant nephrons 
can hyperfunction – or hyperfilter - to compensate for the loss of mass due to injury from the 
primary disease. What started as a compensatory mechanism to maintain GFR through 
elevated single nephron filtration becomes a maladaptive response leading to glomerular 
hypertrophy and hyperfiltration over time. Intraglomerular hypertension is thought to ultimately
contribute to progressive loss of renal function in diverse glomerular nephropathies, including
focal segmental glomerular sclerosis, IgA nephropathy and membranous glomerulonephritis 4.


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To reduce intraglomerular hypertension, current guidelines recommend the use of RAAS 
blockers as the gold standard therapy for individuals with non-diabetic nephropathy and 
proteinuria 5. However, despite the use of these agents, renal function continues to decline.
Therefore, there is a need to widen the therapeutic armamentarium for individuals with non-
diabetic nephropathy. SGLT2i lowers the threshold of proximal glucose reabsorption resulting 
in glycosuria, and increases distal tubular sodium delivery to macula densa cells. Macula 
densa cells are specialized epithelial cells located at the distal convoluted tubule that sense 
sodium delivery and mediate afferent arteriolar vasoconstriction in response to an increase in 
tubular sodium. SGLT2 inhibition increases the delivery of glucose and sodium in the distal 
tubule and to the juxtaglomerular apparatus, which is sensed as an increase in glomerular 
perfusion. This leads to a tubuloglomerular feedback signal causing afferent arteriolar 
vasoconstriction, and acute fall in intraglomerular pressure. These effects are clinically 
manifested as acute reductions in GFR and hence albuminuria, followed by renal function 
preservation in the longer term – as recently reported in EMPA-REG Outcome. Furthermore, 
natriuresis diminishes extracellular plasma volume and blood pressure. Thus, SGLT2i 
specifically alters renal hemodynamic function by reducing intraglomerular pressure, which 
could be expected to translate into improved long-term kidney outcomes - including individuals 
without diabetes. 
SGLT2i are oral anti-hyperglycemic agents that decrease HbA1c through insulin-independent 
effects via glycosuria. They therefore have negligible hypoglycemic risk as compared to other 
classes of anti-hyperglycemic agents, since the degree of glucose lowering depends on the 
filtered load of glucose which, in non-diabetic patients, is very low 6, 7. The low risk of 
hypoglycemia offers the opportunity to test these drug classes in non-diabetic proteinuric renal 
disease. 
In conclusion, SGLT2i has a plausible therapeutic potential in individuals with non-diabetic 
nephropathy at risk of renal progression, and are likely to be well tolerated. Exploring the 
beneficial effects of these agents in non-diabetic proteinuric kidney disease may pave the way 
for a new indication for this class of drugs. In addition, trials in non-diabetic kidney disease 
may help to further characterize the non-glucose dependent effects, which may help to 
differentiate SGLT2i from other glucose lowering agents. 


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2. OBJECTIVES
Primary Objective:
To assess the change from baseline in 24-hr proteinuria with dapagliflozin for six weeks 
relative to placebo treatment in patients with non-diabetic kidney disease and 
proteinuria > 500 mg/day on stable ACEi or ARB treatment. 
Secondary Objectives
To assess the effect of dapagliflozin 10 mg/d compared to placebo on Glomerular 
Filtration Rate (GFR) using iohexol clearance
To assess the effect of dapagliflozin 10 mg/d compared to placebo on systolic/diastolic
blood pressure
To assess the effect of dapagliflozin 10 mg/d compared to placebo on body weight
To assess the effect of dapagliflozin 10 mg/d compared to placebo on selected 
neurohormones/biomarkers:
o
Hormones of the RAAS (plasma and urine)
o
Natriuretic peptides
o
Urinary adenosine
o
Co-peptin
o
Immunoglobulin G (plasma and urine)
To characterize the safety of dapagliflozin vs. placebo by determining the number of 
hypoglycemia episodes between groups and serious adverse events.


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3. STUDY DESIGN
A double blind randomized placebo controlled cross-over study will be conducted in subjects 
with Chronic Kidney Disease aged between 18 and 75 years, proteinuria levels between 500
and 3500 mg/24-hour, and an eGFR 
25 ml/min/1.73m2 will be enrolled. Patients with type 1 
or type 2 diabetes, polycystic kidney disease, glomerulonephritis with flares (lupus or anti-
neutrophil cytoplasmic antibodies (ANCA) associated vasculitis) or ongoing active renal 
inflammation will be excluded. Since each subject is his/her own control, this design requires 
fewer patients as compared with a parallel study design. A wash-out period after each 
treatment period has been included in the design to avoid cross-over effects.
The study will consist of a screening visit, a 4-week (up to a maximum of 16-weeks) run-in 
phase for those subjects not on stable ACEi/ARB treatment, 2 consecutive 6-week double 
blind treatment periods separated by 6-week wash-out period. Subjects will be randomly 
assigned to one of the treatment orders as depicted in figure 1.
Figure 1: Study design
Screening
Run-in
4 weeks
Placebo
6 weeks
Wash-out
6 weeks
Dapa 10 mg
6 weeks
Wash-out
6 weeks
Screening
Run-in
4 weeks
Dapa 10 mg
6 weeks
Wash-out
6 weeks
Placebo
6 weeks
Wash-out
6 weeks
The target population will be invited for screening. Subjects who meet all entry criteria and 
who are already on a stable dose (no changes in dose or type of drug) of ACEis or ARBs for 
at least 4 weeks proceed directly to randomization. Subjects who had their ACEi or ARB 
medication changed during the preceding 4 weeks of the screening visit proceed to a run-in 
phase during which the type and dose of these drugs are stabilized. Subjects will be 
randomly assigned to one of the two treatment orders as depicted in figure 1. Each treatment 
period lasts 6 weeks followed by a 6 week wash-out period to avoid cross-over effects. 
Subjects will have their study visit in the morning in fasted condition.
Subjects will be instructed to take the study medication once daily, in the morning, except on
study days; on those days, the study drug will be taken after or during the patient visit. 
Measurements:
During the double blind treatment period, and wash-out period patients will collect a 24-
hour urine collection at each visit for measurement of 24-hour protein, albumin, sodium,


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potassium, creatinine, and urea excretion. Twenty-four hour urine collections will be 
performed at:  
o
Screening visit
o
Run-in, day 1, week 3, and week 6 (last day on treatment) of each treatment period,
and six weeks after the second treatment period (after the last wash-out period).
Office systolic and diastolic blood pressure measurements will be performed at day 1,
week 3 and 6 (last day on treatment) of each treatment period, and six weeks after the 
second treatment period.
Vital signs (heart rate, blood pressure) and body weight, height
Blood will be sampled for measurement of laboratory assessment outlined in the Table 1
and analysis will be performed by the local laboratory.
Additional blood will be sampled at Day 1 and week 6 of each treatment period, and six 
weeks after the second treatment period for shipment to the UMCG for biomarker 
measurement including RAAS biomarkers, natriuretic peptides, co-peptin, immunoglobulin 
G, and urinary adenosine.
Blood and urine samples will be stored for future exploratory biomarker analyses to study 
the effect of dapagliflozin in this study population
At the screening visit Demography and significant medical history as defined below will be 
assessed and recorded on the Medical History/Kidney Diagnosis section of the eCRF.
-
Kidney diagnosis
-
Condition related to kidney disease (i.e. recurrent electrolyte disturbances, 
hypovolemia, prior events such as Acute Kidney Injury)
-
Cardiovascular diseases
-
Recurrent/severe urinary tract infections, genital infections, urosepsis
-
Recent hospital admission, and reason for admission (within the last year)
-
Reactions to radio-contrast media


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Time and Events Table
a Informed consent is obtained before any study specific procedure is done.
b Total 24-hr urinary dapagliflozin excretion will also be measured at the end of each treatment period
c WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent 
units of HCG) within 0 to 72 hours before the first dose of study drug.
d Subject will be asked to collect 24 hour urine after informed consent is obtained.  The subject will be requested 
to return the urine sample to the site on the following day.
e Specify details about specimen collection will be provided in the laboratory manual. Table 1-2 will list the laboratory 
assessment to be performed. 
f Specify details about specimen collection, storage and processing will be provided in the laboratory manual.
g Visit 6 Serum or Urine Pregnancy Test is required for Canada sites per local regulatory requirement 
Parameter
Scree
ninga
Run-
in
Treatment Period 1
W/O
Treatment Period 2
W/O
Visits
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
Week
0
1
3
6
12
13
15
18
24
Informed Consenta
x
Randomization
x
Significant Medical 
History & Kidney 
disease diagnosis
x
Serum or Urine 
Pregnancy test
xc
Xc, g
24-hour urineb
xd
x
x
x
x
x
x
x
x
GFR-iohexol
x
x
x
x
x
Plasma PK sample
x
x
Vital signs 
x
x
x
x
x
x
x
x
Blood samplinge
x
x
x
x
x
x
x
x
x
Additional blood 
sampling
‘Biomarker samples’f
x
x
x
x
x
Physical exam
x
x
x
x
x
x
x
x
Telephone visit
x
x
Dispense Medication
x
x
Drug accountability
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
Review medications
x
x
x
x
x
x
x
x
DNA collection
x


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Study Periods and Procedures:
Screening
Chronic Kidney Disease aged between 18 and 75 years, proteinuria levels between 500 and
3500 mg/24-hour, and an eGFR 
25 ml/min/1.73m2 who are on an ACEi or ARB, or can start 
with and ACEi or ARB, will be eligible for protocol-specific assessment during the screening 
period. Signature of the protocol-specific informed consent form constitutes the first procedure 
of the screening period, followed by the assignment of a unique subject number. Protocol-
specific assessments and procedures may then be performed, as part of the screening visit, 
to evaluate the subject’s eligibility. During the screening period, subjects will maintain their 
stable doses of commercially available ACEis or ARBs, and diuretic medication.
When all inclusion and exclusion criteria have been evaluated and the requirements for entry 
into the study have been met, the entry into run-in period or double blind treatment period will 
be scheduled. If the patient does not qualify based on the laboratory data, the patient is allowed 
to be re-screened within 3 weeks of the original screening date. The laboratory data based on 
which the patient failed should be repeated. 
Run-in Period:
Potentially eligible subjects who complete the screening visit will enter the run-in period if they 
are not using an ACEi or ARB, or if they are not using a maximum tolerated dose of an ACEi 
or ARB. During the run-in period, ACEi or ARB will be started or uptitrated towards the 
maximum tolerated antihypertensive dose. If a patient does not tolerate the maximum dose of 
an ACEi or ARB, this should be documented in the eCRF and the patient can proceed to the 
double blind treatment period if all other entry criteria are met.
Visit 1
Subjects who entered the run-in period will return for the run-in visit 4 weeks after starting an 
ACEi/ARB or after ACEi/ARB dose adjustments. The subject has to be on a stable dose of an 
ACEi or ARB for at least 4 weeks before randomisation. More visits may be required to make 
sure that the subject still meet all entry criteria at the end of the run-in period. The run-in period 
may take up to a maximum of 16 weeks. If the eGFR remains 25 ml/min/1.73m2 and the 
proteinuria level remains between 500 mg/24hr and 3500 mg/24hr at the end of the run-in 
period, the patient qualifies to proceed to the double blind treatment period. 
Double-Blind Treatment Period:
Eligible subjects will enter in the randomized, double-blind, treatment period if their ACEi/ARB 
and diuretic medication is stable for at least 4 weeks and all entry criteria are met. The 


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randomization codes generated by University Medical Center Groningen will be programmed 
into the IBM Clinical Development Merge to randomly assign subjects to a treatment arm. The
investigational drug will be dispensed by the principal investigator or delegated based on the 
randomization number. 
Subjects will continue to maintain their stable doses of commercially available ACEI or ARB,
and diuretics if applicable, throughout the double blind phase. Patients will be counseled to 
maintain a stable habitual dietary salt intake
Visit 2
The randomization visit procedures should be completed on a single day. The randomization 
visit procedures will include GFR measurement by plasma clearance of nonradioactive iohexol 
after a single intravenous dose. The GFR measurement will last approximately 4 hours for 
patients. The first dose of blinded study medication should only be administered on Day 1 
AFTER ALL randomization visit procedures have been completed. Patient will be treated in 
random order with dapagliflozin 10 mg QD or matching placebo QD.
Visit 3, 4, and 5
Subjects will be followed for a total of 6 weeks on double-blind study medication in each active 
treatment period. A telephone visit will be scheduled after 1 week to assess tolerability. If the 
patient does not tolerate medication a visit to the out-patient clinic will be scheduled. The next 
scheduled visit (visit 4) occurs 3 weeks after randomization. A visit window of +/- 3 days is 
allowed for each out-patient clinic visit. Patients are asked to collect a 24-hr urine and blood 
will be sampled for clinical chemistry measurement. The last scheduled visit in the first 
treatment period is scheduled after 6 weeks. The last visit of the treatment period will include 
GFR measurement by plasma clearance of nonradioactive iohexol after a single venous dose,
collection of a 24-hr urine sample and clinical chemistry measurements. At the end of the 
treatment period, the patient will take study medication BEFORE the GFR measurement 
procedure. In addition to using blood samples for GFR measurements, the samples will also 
be used to measure plasma concentration dapagliflozin and its metabolite dapagliflozin-3O-
glucuronide.
Visit 6,7,8, and 9
Following the last visit of the first treatment period subjects proceed to a 6 weeks wash-out 
period. After 6 weeks the second double blind treatment period will start. All visits and
procedures in the second treatment period are similar to the first treatment period. 


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Visit 10
Six weeks after the second treatment period another visit will be scheduled. Procedures during 
this visit include GFR measurement with non-radioactive iohexol, 24-hr urine collection, blood 
pressure recording and blood sampling for clinical chemistry assessment.
Subjects who discontinue prematurely from the treatment period prior to visit 4, will have an 
abbreviated Week 12/ET visit, which will exclude measurements of GFR.
Clinical Lab Assessments
All protocol required local laboratory assessments, as defined in Table 1-2, must be conducted 
in accordance with the Laboratory Manual, and Time and Event Table.   
Table 1
Plasma Laboratory Assessments
Parameters
Hematology
Hemoglobin
Hematocrit
Clinical Chemistry
Urea
Bilirubin
Creatinine
Phosphate
AST
Calcium
ALT
Glucose
Total Protein
Lipid Parameters
LDL
HDL
Electrolytes
Sodium
Potassium
Chloride
Bicarbonate
Other Laboratory Test
NT-proBNP1
HbA1C
Urine/Serum 
Pregnancy Test2
1 Sites that are unable to perform NTproBNP will arrange for samples to be sent to UMCG for central analysis.
2 Pregnancy test: negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 0 to 72 hours before the first dose of study drug.
Table 2
24-Hour Urine 
Laboratory Assessments
Parameters
Clinical Chemistry
Sodium
Creatinine
Potassium
Albumin
Urea
Protein


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Biomarker analysis
Serum, plasma and urine will be collected and stored for potential future analysis for 
exploratory biomarkers to assess correlations with disease activity and effects of study drug.
These samples will be shipped and stored to a central storage facility in Groningen. The results 
of this biomarker research will be reported either in the main publication, or separately in a 
scientific report or publication.  The results of this biomarker research may be pooled with 
biomarker data from other dapagliflozin studies to generate hypotheses to be tested in future 
research. Potential biomarkers to be measured include plasma albumin, RAAS biomarkers, 
natriuretic peptides, co-peptin, immunoglobulin G, urinary adenosine, and urinary vesicles.
DNA
Patients are asked to donate DNA as well. Participation in the pharmacogenetics study is 
optional and DNA will only be collected if patients consented for participation in this part of the 
study. 
STUDY POPULATION
3.1
Population (base)
The study population will be selected from the outpatient clinical from hospitals based in 
the Netherlands (Groningen, Almelo, Amsterdam), Canada, (Toronto, Calgary, 
Vancouver) and Malaysia (Kuala Lumpur).
3.2
Inclusion criteria
Age 18 and 75 years
Urinary protein excretion > 500 mg/24hr and
3500 mg/24hr in a 24-hr urine 
collection
eGFR 
25 mL/min/1.73m2
On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization
Willing to sign informed consent
Women of Child-Bearing Potential (WOCBP):
o
WOCBP must be using an acceptable method of contraception to avoid 
pregnancy throughout the study and for up to 4 weeks after the last dose of 
study drug in such a manner that the risk of pregnancy is minimized. 


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o
WOCBP must have a negative serum or urine pregnancy test result (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the 
first dose of study drug. 
o
Women must not be breast-feeding.
WOCBP comprises women who have experienced menarche and who have not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or who are not post-menopausal.
3.3
Exclusion criteria
Diagnosis of type 1 or type 2 diabetes mellitus
Urinary protein excretion > 3500 mg/day
Peripheral Vascular Disease
Autosomal dominant polycystic kidney disease or autosomal recessive polycystic 
kidney disease, lupus nephritis, or ANCA-associated vasculitis
Indication for immunosuppressants as per the treating physician’s judgment.
Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for 
primary or secondary renal disease within 6 months prior to enrolment. 
Active malignancy aside from treated squamous cell or basal cell carcinoma of the
skin.
Use of the co-interventional treatments (outlined in section 4.2) within 6 weeks of 
screening will not be allowed.
Any medication, surgical or medical condition which might significantly alter the
absorption, distribution, metabolism, or excretion of medications including, but not
limited to any of the following:
o
History of active inflammatory bowel disease within the last six months;
o
Major gastrointestinal tract surgery such as gastrectomy, 
gastroenterostomy, or bowel resection;
o
Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last 
six months;
o
Pancreatic injury or pancreatitis within the last six months;
o
Evidence of hepatic disease as determined by any one of the following: 
ALT or AST values exceeding 3x ULN at the screening visit, a history of 
hepatic encephalopathy, a history of esophageal varices, or a history of 
portocaval shunt;
o
Evidence of urinary obstruction or difficulty in voiding at screening
History of severe hypersensitivity or contraindications to dapagliflozin


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History of hypersensitivity or contraindications to iodinated contrast media
Subject who, in the assessment of the investigator, may be at risk for dehydration 
or volume depletion that may affect the interpretation of efficacy or safety data
Participation in any clinical investigation within 3 months prior to initial dosing.
Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing.
History of drug or alcohol abuse within the 12 months prior to dosing, or evidence 
of such abuse as indicated by the laboratory assays conducted during the 
screening.
History of noncompliance to medical regimens or unwillingness to comply with the 
study protocol.
Any surgical or medical condition, which in the opinion of the investigator, may 
place the patient at higher risk from his/her participation in the study, or is likely to 
prevent the patient from complying with the requirements of the study or 
completing the study.
Pregnancy or breastfeeding
WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and up to 4 weeks after the last dose of 
study drug. 
Any disqualifying proteinuria or eGFR level may be repeated one time, at the discretion of 
the investigator and where there is a clinical reason to do so. The repeat value should be 
assessed prior to the subject recorded as having screen failed. If the repeat value falls 
within the ranges defined by the protocol and the patient meets all other inclusion criteria, 
the patient is eligible for the study.
3.4
Sample size calculation
With a sample size of 50 patients completing the study and assuming a conservative 
standard deviation of 0.7 in log transformed proteinuria (within-subject standard deviation 
of 0.475), the trial will have 80% power to detect a mean reduction in albuminuria of 25% 
(i.e, delta=0.288 on the log-transformed proteinuria scale) or more with dapagliflozin 
compared to placebo (alpha 0.05). This calculation is based on individual patient data 
from various clinical trials on the anti-proteinuric effects of different agents in diabetes and
non-diabetes trials for which we have the individual patient data including ROAD, 
RENAAL and IDNT trials. For calculation of the sample size, the percent change in 
proteinuria is log-transformed to take into account the skewed distribution of proteinuria.
Under the assumption that no carry-over effects and no period effects occur, a paired-t-


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test is deemed appropriate to calculate the sample size. Using these assumptions, we 
calculate that 50 patients completing the study will provide 80% power to detect a 25% 
reduction in albuminuria. Assuming that approximately 5% of patients will discontinue the
study prematurely, we intend to enrol 53 subjects. 
We believe a reduction of >25% with dapagliflozin versus placebo can be detected. We
recently published a large analysis of patients with diabetes and demonstrated that 
dapagliflozin decreased proteinuria by 33%. Trials with other SGLT2 inhibitors have also 
documented proteinuria reductions of approximately 30%.  
4. TREATMENT OF SUBJECTS
4.1
Investigational product/treatment
Dapagliflozin and matching placebo tablets will be provided by Astra Zeneca. Patients will 
take 10 mg dapagliflozin (once daily) or matching placebo according to randomised 
treatment scheme.
The marketed 10 mg dose has been demonstrated to be well tolerated and effective for the 
treatment of type 2 diabetes and post-hoc analyses in patients with CKD and proteinuria 
have shown that this dose is effective in reducing renal risk markers (i.e. blood pressure, 
proteinuria) independent of its glucose lowering effect8-10. In addition, in a dedicated CKD 
clinical trial this dose was found to be well tolerated9. From a pharmacokinetic and 
pharmacodynamic perspective dapagliflozin 10 mg is appropriate for use in patients with 
CKD. 
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 the subject specific dispensing process is maintained.
Returned and unused drugs are destroyed by the local pharmacy department at the end of 
the study.


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4.2
Use of co-intervention (if applicable)
Use of the following treatments will not be allowed from 6 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. 
Aldosterone antagonists
Direct renin inhibitors
Systemic corticosteroids and immunosuppressants 
Patients who are receiving such medication(s) should be excluded, or if ethically justified, 
the medication(s) may be withdrawn according to the manufacturer's/investigator's 
instructions prior to start of the screening period. Withdrawal of medication is done after 
consultation with the patient and patients’ physician.
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 non-steroidal anti-inflammatory drugs
(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. Continuous NSAID use is not permitted during the study. 
NSAIDs use for several days for pain management is permitted as long as it is not during 
the days prior to GFR / proteinuria assessments.
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 and should not be resumed for at 
least 24 hours following iohexol injection.


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5. INVESTIGATIONAL PRODUCT
5.1
Name and description of investigational  product(s)
Drug name: dapagliflozin (Forxiga, AstraZenaca, 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 
Tablet
10 mg Green, plain, diamond shaped, film 
coated tablet (orally)
Astra Zeneca
Placebo Matching
Dapagliflozin Tablet
Green, plain, diamond shaped, film coated 
tablet. Does not contain active ingredient
Astra Zeneca
5.2
Summary of findings from non-clinical studies
This is not applicable as dapagliflozin is already registered as antihyperglycemic agent for 
the treatment of type 2 diabetes in humans. 
5.3
Summary of findings from clinical studies
Dapagliflozin:
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 (Heerspink ADA 2016). 
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 


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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.
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 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.
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 
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% 
for 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 
treated 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.11
5.4
Summary of known and potential risks and benefits
Dapagliflozin has global market approval and based on global cumulative sale figures up to 
March 2016 it is estimated that dapagliflozin has been administered during >1000000 patient 


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years.  Details regarding potential risks associated with administration of dapagliflozin once 
daily are provided in the Investigator’s Brochure (IB).
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 III 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.
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.


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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 
hypoglycemia12e. 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 event13.
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.
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 type 2 diabetes.


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Patients are also expected to receive some benefit in the form of increased medical 
care/attention when participating in study procedures.
Informed consent and alternatives to participation
All prospective participants will be fully informed of the possible risks and benefits associated 
with this study, and their consent will be obtained prior to performing any study-specific 
activity.  Should a prospective participant elect to not participate in the study or to withdraw 
from the study, other medications are available to treat their CKD, and other possible 
concomitant diseases according to the discretion of their treating physician, and the patient 
will not be disadvantaged in any way.
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.
5.5
Description and justification of route of administration and dosage
Dapagliflozin is absorbed from the digestive tract and can therefore be orally administered.
5.6
Dosages, dosage modifications and method of administration
Dapagliflozin will be administered in a dose of 10 mg/day.
5.7
Preparation and labelling of Investigational Medicinal Product
Study medication (dapagliflozin and matching placebo) will be provided by Astra Zeneca. 
The pharmacy department of the University Medical Center Groningen will be responsible 
for labelling and distribution of study medication to the participating sites. 
5.8
Drug accountability
All study medications will be stored at room temperature (<25°C) in a secure location of 
each participating centre. Study medication will be dispensed by the principal investigator 
or delegate at each participating centre. Unused and partially used study drug will be 
returned by the subject to the site for drug accountability and be made available for site 
monitor verification during onsite monitoring visit. Returned and unused study drug will be 


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locally destroyed per local procedure and destruction must be documented on the drug 
destruction record.
5.9
Handling and Dispensing
The investigational product should be stored in a secure area according to local regulations. 
The investigator is responsible for ensuring that it is dispensed only to study subjects and 
only from official study sites by authorized personnel, as dictated by local regulations.
The investigator is responsible for ensuring that the investigational product is stored under 
the appropriate environmental conditions (temperature, light, and humidity). If concerns 
regarding the quality or appearance of the investigational product arise, the investigational 
product will not be dispensed and Astra Zeneca will be contacted immediately.
5.10 Drug Ordering
Initial Orders
Contact the protocol manager at the University Medical Center Groningen for information. 
Re-Supply
Contact your site monitor or the protocol manager at the University Medical Center 
Groningen (trials@apoth.umcg.nl) 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.


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6. NON-INVESTIGATIONAL PRODUCT
6.1
Name and description of non-investigational product(s)
Omnipaque 300 (iohexol)
6.2
Summary of findings from non-clinical studies
Iohexol has a very low acute intravenous toxicity in mice and rats. Animal studies have 
shown that iohexol has a very low protein binding and is well tolerated by the kidneys. The 
cardiovascular and neurotoxicity are low. The histamine release ability and the
anticoagulant activity has been shown to be less than for ionic contrast media. 
6.3
Summary of findings from clinical studies
For most of the hemodynamic, clinical-chemical and coagulation parameters examined 
following intravenous injection of iohexol in healthy volunteers, no significant deviation 
from preinjection values has been found. The few changes observed in the laboratory 
parameters were minor and considered to be of no clinical importance. 
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 approximately 2 hours in patients with normal renal function. No metabolites have been 
detected. The protein binding of Omnipaque is so low (<2%) that it has no clinical 
relevance and can therefore be neglected. 
6.4
Summary of known and potential risks and benefits
Measurement of GFR by plasma clearance of iohexol has not been associated with 
reports of adverse events, but should be avoided in subjects with known reactions to 
radio-contrast media. The small amount of iohexol used for these studies is unlikely to 
affect GFR. Iohexol is an iodinated radio-contrast material. Adverse reactions to iohexol 
may include anaphylactoid reactions, which may include urticaria, angioedema, dyspnea, 
and shock, and typically occur within one hour of administration. These reactions are non-
immunological, and are likely related to the whole molecule rather than free iodine. While 
allergic individuals have a somewhat increased risk of adverse reaction to radiocontrast 
agents, no special risk is conferred by either seafood allergy or hypersensitivity to iodine. 
Personnel qualified to diagnose and treat anaphylactoid reactions, as well as necessary 
medication and equipment, should be readily available to persons receiving iohexol.


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6.5
Description and justification of route of administration and dosage
Iohexol (Omnipaque 300) will be intravenously administered. 
6.6
Dosages, dosage modifications and method of administration
Omnipaque 300 mg iodine per millilitre contains 647 mg/ml iohexol.  Exactly 5 mL of 
iohexol solution (drawn in a 5 mL syringe), containing 3.225g of iohexol will be injected 
intravenously through an injection catheter. 
6.7
Preparation and labelling of Non Investigational Medicinal Product
The Iohexol ordered by the institution will be used.  The institution may purchase Iohexol 
from an external vendor as appropriate.  The institution must seek sponsor approval prior 
to use of alternative brand of Iohexel mentioned in the protocol.
6.8
Drug accountability
Iohexol will be stored at the temperature specified in the package insert in a secure location 
at the site. 


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7. METHODS
7.1
Study parameters/endpoints
7.1.1
Main study parameter/endpoint
24-hour proteinuria
7.1.2
Secondary study parameters/endpoints (if applicable)
Glomerular Filtration Rate measured with iohexol
Systolic/diastolic blood pressure
Neurohormones/biomarkers
o
Hormones of the RAAS (renin, aldosterone in plasma and urine)
o
Natriuretic Peptides
o
Urinary adenosine
o
Co-peptin
o
Immunoglobulin G
7.1.3
Other study parameters (if applicable)
Number of hypoglycaemic episodes
Serious Adverse Events
Drug related adverse events (causality to investigational product assessed 
by research physician).
7.2
Randomization, blinding and treatment allocation
Treatment sequence of dapagliflozin and placebo will be randomized. A 4-block 
randomization method is used. The randomization is done by hand by a UMCG 
pharmacist. The generated codes will be used to set-up the randomization module and
subjects will be randomized by IBM Clinical Development Merge. The investigational drug 
will be dispensed by the principal investigator or delegate based on the randomisation 
number generated in Merge.The pharmacy of each participating centre will store the 
randomization code. 
7.3
Study procedures
Physical examination
Patients will be subjected to physical examination by the principal investigator or 
delegate as specified in Time and Event table. This physical examination entails a 


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routine investigation of heart, lungs, and abdomen. At each visit patients will be asked 
for adverse events related to urinary tract infections or genital infections. 
24hr urine collection
Patients are asked to collect 24hr urine at start and end of each treatment period to 
monitor albuminuria. In total, nine 24hr urines are collected during the course of this 
study. 24hr urine collection instructions will be provided to each patient. The volume of 
the urine containers is determined when the patient delivers the urine at each visit. 
Subsequently part of the urine is used for clinical chemistry measurement and the other 
part stored per instructions in the laboratory manual. 
GFR measurements
GFR measurements by plasma clearance of non-radioactive iohexol will be performed 
at the randomization and Week 6,12,18, 24 or early termination visits. This test involves 
a single dose injection of 5 mL of iohexol, a non-radioactive iodinated x-ray contrast 
agent. GFR is estimated on the basis of plasma disappearance curves.
The central laboratory of the UMCG will be providing detailed instructions for the GFR 
measurement procedure in a separate laboratory manual. The iohexol solution will be 
bought by the investigational site and should be used in accordance with the approved 
product label and manual instructions.
The following should be considered prior to performing GFR measurements: 
•
Subjects should be well hydrated prior to and following administration of iohexol.
•
If not obtained within 72 hours of the GFR measurement procedure, the 
subject’s weight and height should be measured and recorded
Subject preparation: 
After a 10-hr fast, two intravenous (IV) catheters, one in each arm, will then be placed
in the subject’s antecubital vein. One line will be used for the single dose injection of
nonradioactive iohexol. The second line will be used for intermittent blood sampling. At 
the beginning of each treatment period (i.e. visit 2 and 6), study medication will be taken 
AFTER the iohexol GFR measurement procedure. At the end of the treatment period 
(i.e. visit 5 and 9) study medication will be taken BEFORE the iohexol GFR 
measurement procedure.
Iohexol injection (time -2 to 0 minutes): 


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•
Exactly 5 mL of iohexol solution (drawn in a 5 mL syringe), containing 3.225 g 
of iohexol, will be injected slowly into the injection catheter.
The 5 mL solution should be injected over a period of 2 minutes.
The exact time of the injection will be recorded in the eCRF and in the source 
document. For consistency, the same digital clock should be used throughout 
the procedure.
The total, exact, volume of the solution injected must be recorded on the central
laboratory requisition form and in the source document.
Blood samples must not be taken from the arm receiving the iohexol solution.
Blood Collection:
Blood samples for the determination of GFR by plasma clearance of iohexol will
collected prior the injection of the iohexol solution as well as during the last 2 hours of
the procedure. Initiation of the GFR procedure will occur at time - 2 minutes and 
is defined as the time at which the iohexol solution is injected. Time 0 represents
the end of the iohexol injection. The timing for the blood samples are relative to 
the end of the iohexol injection (time 0).
The table below summarizes the timepoints 
Timepoint
Suggested Time 
Procedure
Prior to Time -2 min
~7:57 AM
Baseline blood and PK sample
Time -2 min 
~7:58 AM
Start iohexol injection
Time 0 min
~8:00 AM
End of iohexol injection
Time 30 mina
~8:30AM
Blood sample PK
Time 60 mina
~9:00 AM
Blood sample PK
Time 90 mina
~9:30 AM
Blood sample PK
Time 120 min
~10:00 AM
Blood sample GFR / PK
Time 150 min
~10:30 AM
Blood sample GFR / PK
Time 180 min
~11:00 AM
Blood sample GFR / PK
Time 210 min
~11:30 AM
Blood sample GFR / PK
Time 240 min
~12:00 AM
Blood sample GFR / PK
a PK samples are only collected at the end of the active treatment period
Blood pressure measurements
Blood pressure will be measured by office blood pressure during the outpatient visits.
Patients will be in a semi-supine position during the blood pressure measurement. 


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Average of three readings will be used. The blood pressure measurement should be 
performed per local practise and the same arm should be used to take the reading for 
each visit.
Venipuncture
At each of the visits, approximately 20 ml will be taken for routine blood tests 
(approximately 20 ml/ 9 visits = 180 ml).  At each of the 5 visits to assess kidney 
function, approximately 24 ml will be taken (total 120 ml), plus another 20 ml at each 
kidney function visit for measurement of hormones and other factors associated with 
kidney disease (approximately 20 ml for each of the 5 kidney visits = 100 ml). At the 
end of each of the 2 treatment periods, 9 blood samples of 1ml will be taken for 
dapagliflozin PK analysis (total 18ml). A total of approximately 418 ml of blood will be 
collected over a 6 month (24 week) period
Laboratory measurements 
All routine laboratory measurements of this study will be assessed at the local 
laboratories of participating centres.
Dapagliflozin plasma concentration measurement
At the end of the treatment period, during the GFR assessment, 9 blood samples of 1 
ml will be drawn for dapagliflozin and its metabolite dapagliflozin-3O-glucuronide
measurement.


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7.4
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.
7.5
Replacement of individual subjects after withdrawal
Patients that meet inclusion criteria will be invited for participation in the study. When patient 
agrees to participate in the study, informed consent is signed. The patient proceeds to the 
randomization visit if the proteinuria values are within the predefined window (i.e. >500
mg/24hr and 3500 mg/24hr). When patients decide to withdraw after start of the treatment 
period, no new patients can be admitted to the study due to a limited availability of study 
medication. Although, in our sample size calculation we have taken into account a certain 
amount of withdrawal and according to our experience, we don’t expect withdrawal to 
exceed this number.
7.6
Follow-up of subjects withdrawn from treatment
Subjects who withdraw from the study will be followed up according to the routine terms of 
patient care at the outpatient clinic or revered back to their general practitioner.
7.7 Premature termination of the study
There are no predefined criteria for premature termination of the study. If, however, during 
the conductance of the study information becomes available showing that continuation of 
the study would result in a significant safety risk for the patients, the principal investigator 
and project leader will decide to terminate the study. 
8. SAFETY REPORTING
8.1
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 jeopardise the subjects’ health. The investigator will take care that all subjects are 
kept informed.


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8.2
AEs, SAEs and SUSARs
8.2.1
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)
8.2.2
Serious adverse events (SAEs)
A serious adverse event is any untoward medical occurrence or effect that at any 
dose:
-
results in death;
-
is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have     
caused death if it were more severe;
-
requires hospitalisation or prolongation of existing inpatients’ hospitalisation;
-
results in persistent or significant disability or incapacity;
-
is a congenital anomaly or birth defect;
-
is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)
Per Health Canada requirement, sites in Canada will collect and record all Adverse 
Events in the eCRF.  For Netherlands and Malaysia sites AEs should be recorded in 
the eCRF only if it qualifies as:
An SAE
If the AE is the reason for permanent discontinuation from investigational 
product (DAE), if the AE leading to Investigational Product interruption or dose 
reduction
An AE of interest


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Urinary Tract Infection or Genital Infections
Potential DKAs 
Volume depletion 
Fractures 
Major hypoglycaemic events
Acute kidney injury 
Amputation or related events
8.2.3
Adverse events of interest
Urinary tract infection or genital infections
All potential events of urinary tract infection or genital infections will be recorded in 
the eCRF. 
Diabetic ketoacidosis (DKA)
All potential events of DKA will be recorded in the eCRF.
Volume depletion
Events of volume depletion (eg, dehydration, hypovolemia, or hypotension) will be 
collected on the eCRF as AEs.
Fractures
All fractures will be recorded in the eCRF as AEs.
Major hypoglycaemic event
A major hypoglycaemic event is defined as an event that requires assistance of 
another person to actively administer carbohydrates, glucagon, or take other 
corrective actions. Plasma glucose concentrations may not be available during an 
event, but neurological recovery following the corrective actions is considered 
sufficient evidence that the event was induced by a low plasma glucose 
concentration. Major hypoglycaemic episodes will be recorded in the eCRF as an AE.
Acute Kidney Injury
Acute kidney injury is defined as an increase of 40% in serum creatinine from the 
previous visit or hospitalization due to acute kidney injury. All acute kidney injury 
events will be recorded as an AE.
Amputation and related events: 


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Amputations and related events will be recorded in the eCRF. Information on the 
actual amputations will be captured as an AE.
8.3 Recording of Adverse Events
Time Period for Collection of Adverse Events
For this study, SAEs, discontinuations due to AEs (DAEs), and AEs of special interest
will be collected from the time of signing the informed consent and throughout the 
study, including the run-in and wash-out periods. Information about all adverse events
(serious or not) will be recorded in source documents (eg, progress notes)
according to good clinical practice, and retained at the investigative sites.
Follow-up of Unresolved Adverse Events
Any SAEs, DAEs, or AE of special interest 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 of special interest:
AE (verbatim).
The date and time when the AE started and stopped.
Intensity.
Whether the AE is serious or not.
Investigator causality rating against the study drug (yes or no).
Action taken with regard to study drug.
AE caused patient’s withdrawal from study (yes or no).
Outcome.
In addition, the following variables will be collected for SAEs:
Date AE met criteria for a serious AE.
Date Investigator became aware of the SAE.
AE is serious due to.
a.
Date of hospitalisation (if applicable).
b.
Date of discharge (if applicable).
c.
Probable cause of death (if applicable).


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d.
Date of death (if applicable).
e.
Autopsy performed (if applicable).
f.
Causality assessment in relation to Study procedure(s).
g.
Causality assessment in relation to other medication (e.g., concomitant 
medication, background therapy).
Description of intensity.
The intensity of the reported SAEs/DAEs/AE of interest will be assessed according to 
the following scale:
o
Mild (awareness of sign or symptom, but easily tolerated).
o
Moderate (discomfort sufficient to cause interference with normal activities).
o
Severe (incapacitating, with inability to perform normal activities).
It is important to distinguish between serious and severe AEs. Severity is a measure 
of intensity whereas seriousness is defined by the criteria in Section 8.2.2. An AE of 
severe intensity need not necessarily be considered serious. For example, nausea 
that persists for several hours may be considered severe nausea, but not a SAE 
unless it meets the criteria shown in Section 8.2.2. On the other hand, a stroke that 
results in only a limited degree of disability may be considered a mild stroke but would 
be a SAE when it satisfies the criteria shown in Section 8.2.2.
Causality Collection
The Investigator will assess causal relationship between Investigational Product and 
each SAE/DAE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is 
a reasonable possibility that the event may have been caused by the investigational 
product?’
Adverse Events Based on Signs and Symptoms
All SAEs/DAEs/AE of special interest spontaneously reported by the patient or 
reported in response to the open question from the study personnel: ‘Have you had 
any health problems since the previous visit/you were last asked?’, or revealed by 
observation will be collected and recorded in the eCRF. When collecting 
SAEs/DAEs/AEs of special interest, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known 
and there are other signs or symptoms that are not generally part of the diagnosis, the 
diagnosis and each sign or symptom will be recorded separately.


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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 of special 
interest 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.
8.4
Serious Adverse Event Collecting and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs will be collected that occur 
during the screening period and within 30 days of discontinuing dosing. If applicable, 
SAEs must be collected that relate to any later protocol-specific procedure (such as 
follow-up skin biopsy).
The investigator should report any SAE occurring after these time periods that is 
believed to be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its 
status of seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially 
related to the conditions of the study (such as withdrawal of previous therapy, or a 
complication of a study procedure), the relationship should be specified in the 
narrative section of the SAE Report Form.


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SAEs that result in death or are life threatening should be reported expedited to the 
competent authorities. The expedited reporting will occur not later than 7 days after 
the responsible investigator has first knowledge of the adverse reaction. This is for a 
preliminary report with another 8 days for completion of the report. Concurrently, the
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 e-mail box 
AEMailboxClinicalTrialTCS@AstraZeneca.com within the same timelines. 
8.4.1
Suspected unexpected serious adverse reactions (SUSARs)
Adverse reactions are all untoward and unintended responses to an investigational 
product related to any dose administered.
Unexpected adverse reactions are SUSARs if the following three conditions are met:
1.
the event must be serious (see chapter 8.2.2);
2.
there must be a certain degree of probability that the event is a harmful and an 
undesirable reaction to the medicinal product under investigation, regardless of 
the administered dose;
3.
the adverse reaction must be unexpected, that is to say, the nature and severity 
of the adverse reaction are not in agreement with the product information as 
recorded in:
Summary of Product Characteristics (SPC) for an authorised medicinal 
product;
Investigator’s Brochure for an unauthorised medicinal product.
Health Authority and METC Reporting
The sponsor will report expedited the following SUSARs through the web portal 
ToetsingOnline to the METC in the Netherlands or accredited ethics committees in 
other countries:
SUSARs that have arisen in the clinical trial that was assessed by the METC;
SUSARs that have arisen in other clinical trials of the same sponsor and with the
same medicinal product, and that could have consequences for the safety of the
subjects involved in the clinical trial that was assessed by the METC.
The remaining SUSARs are recorded in an overview list (line-listing) that will be
submitted once a year to the METC. This line-listing provides an overview of all


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SUSARs from the study medicine, accompanied by a brief report highlighting the 
main points of concern.
The expedited reporting of SUSARs through the web portal ToetsingOnline is 
sufficient as notification to the competent authority.
The sponsor will report expedited all SUSARs to the competent authorities in other 
Member States, according to the requirements of the Member States. Concurrently, 
sponsor will report SUSARs to AstraZeneca via the e-mail box 
AEMailboxClinicalTrialTCS@AstraZeneca.com within the same timelines.
Sponsor will report SAE expedited SAR to competent authorities in each member 
state. The expedited reporting will occur not later than 15 days after the sponsor has 
first knowledge of the adverse reactions. For fatal or life threatening cases the term 
will be maximal 7 days for a preliminary report with another 8 days for completion of 
the report. Concurrently, the investigator (sponsor) will report SAEs accompanied by 
a cover page mentioning the study code, patient number, country, investigator, 
seriousness to AstraZeneca via the e-mail box 
AEMailboxClinicalTrialTCS@AstraZeneca.com within the same timelines.
In an emergency, unblinding can be performed in the electronic data capture (EDC) 
system IBM Clinical Development (eClinicalOS) 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 at the UMCG (sponsor) and the site 
monitor that the on 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 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 described 
in the Time and Events Table. At the conclusion of the study, the occurrence of any 
unblinding can be reported.  


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8.5
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor and 
AstraZeneca.
8.5.1Maternal exposure
If a patient becomes pregnant during the course of the study IP should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive 
medication.  Congenital abnormalities/birth defects and spontaneous miscarriages 
should be reported and handled as SAEs.  Elective abortions without complications 
should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy. 
If any pregnancy occurs in the course of the study, then the Investigator or other 
site personnel informs the sponsor’s representatives within 1day of when he/she 
became aware of it.
8.6
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.  Suspected single intake of less than 50 tablets of 
10 mg dapagliflozin tablets or repeated intake of less than 10 tablets of 10 mg 
dapagliflozin tablets should not be reported on the eCRF overdose module unless the 
patient is experiencing a symptomatic overdose. Overdose on IMP will be recorded in the 
eCRF dosing record module. 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.
8.7
Annual safety report


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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;
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.
8.8
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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9. STATISTICAL ANALYSIS
9.1
Primary study parameter(s)
The log-transformed 24-hour proteinuria values will be analyzed by a Proc Mixed 
statement in SAS with sequence, treatment, and period as fixed factors and patients 
(nested in sequence) as a random factor. A contrast statement will be used to determine 
difference among treatment groups. Statistical analyses will be conducted with SAS 
version 9.4.
9.2
Secondary study parameter(s)
The change in secondary outcomes, GFR, systolic blood pressure, and neurohormones
will be analyzed by a Proc Mixed statement in SAS with sequence, treatment, and period 
as fixed factors and patients (nested in sequence) as a random factor. Statistical analyses 
will be conducted with SAS version 9.4.
9.3
Other study parameters
Descriptive statistics will be used to analyse the means and distribution between all the 
study variables. The means of the normal distributed variables will be compared with the
student T-test and non-parametric tests (Mann-Whitney U-test for continued and Chi-
Square test for nominal variables) will be used for the variables that do not follow a normal 
distribution. Missing values will be imputed using multiple imputation techniques. Before
introducing multiple imputation techniques the pattern of missing values will be examined. 
If the pattern of missing values indicate that missing values occur randomly a PROC MI
statement in SAS will be implemented to impute missing values.
In case patients require rescue medication this will be recorded in the database. During 
the data-analysis sensitivity analyses will be conducted by adding an additional covariate 
in the mixed model to account for rescue medication required during the study. 
9.4
Interim analysis
N/A


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10. ETHICAL CONSIDERATIONS
10.1 Regulation statement
The study will be conducted according to the principles of the Declaration of Helsinki 
(Fortaleza, 2013) and in accordance with the Medical Research Involving Human Subjects 
Act (WMO). The Medical Ethical Committee of all participating centers will approve the 
study.
10.2 Recruitment and consent
Patients will be enrolled to the trial from centers in the Netherlands, Canada, and
Malaysia.  Prior to their visit to the outpatient clinic, patients will be invited to participate in 
the study by verbal invitation when they attend the clinic or by sending an invitation letter. 
In this letter, patients will find a full explanation of the study, advantages and 
disadvantages of participating, and contact information of the research team members 
working on this study. Moreover, the letter contains contact information of an independent 
physician, to whom subjects can address questions about the research before, during 
and after a study. The patients will be given 2 weeks to consider their decision and will 
then be asked to sign their written informed consent before they take part in the study.
10.3 Objection by minors or incapacitated subjects (if applicable)
No minors or incapacitated adults will be included in this study
10.4 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. The risks 
associated with the use of dapagliflozin in patients with non-diabetic kidney disease are 
considered low. First, dapagliflozin has been used in non-diabetic individuals in doses up 
to 500 mg/day without reports of adverse events. Secondly, safety data in patients with 
diabetic kidney disease has been generated in phase 3 trials and demonstrated no 
additional side effects compared to type 2 diabetes patients without kidney disease. Given 
the SGLT2i mode of action no further safety issues are anticipated in non-diabetic CKD 
patients as compared to generally more vulnerable diabetic kidney disease patients 
included in the past phase 3 studies.  
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 


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the outpatient clinic. All further performed measurements are non-invasive and therefore 
only minor risks are associated with participation.
10.5 Compensation for injury
The sponsor has a liability insurance which is in accordance with article 7, subsection 6 of
legal requirements in the Netherlands (Article 7 WMO). This insurance applies to all 
participating sites in the Netherlands. An additional liability insurance has been arranged 
for the participating sites in Canada and Malaysia.
The sponsor University Medical Center Groningen (UMCG) has an insurance for all 
participating sites in the Netherlands, which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for 
Clinical Research in Humans of 23th June 2003). This insurance provides cover for 
damage to research subjects through injury or death caused by the study. The insurance 
applies to the damage that becomes apparent during the study or within 4 years after the 
end of the study. All patients will receive written information about this insurance.
For the participating sites in Canada and Malaysia the sponsor has another insurance to
cover damage to research subjects in these countries. This insurance policy is in 
accordance with the legal requirements in Canada and Malaysia.
10.6 Incentives (if applicable)
Participation of patients in the study is a free-will decision. Patients will receive restitution 
of all costs for transportation. Patients do not receive priority for treatment of other diseases 
in the clinic during this clinical trial.


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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION
11.1 Handling and storage of data and documents
A subject identification code list will be made to link the data to the subject in order to be 
able to trace data to an individual subject. This code will not be based on the patient initials 
and birth-date. The key to the code will be safeguarded by the investigator since the data 
will be kept for a period of 15 years. The handling of personal data will comply with privacy 
laws, legislation, codes and/or guidelines that apply in the applicable jurisdictions the study 
is conducted.
11.2 Monitoring and Quality Assurance
Independent monitors will monitor the study in each country according to a pre-specified 
monitoring plan.  The monitors are trained in GCP and will be trained on study specific 
tasks and processes.  As part of George Clinical’ s Quality Management Strategy monitor
oversight will be implemented through regular documentation reviews and co-monitoring 
activities.
11.3 Amendments
A ‘substantial amendment’ is defined as an amendment to the terms of the ethics 
committee (METC) application, or 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 METC and to the competent authority.
Non-substantial amendments will not be notified to the accredited METC and the 
competent authority, but will be recorded and filed by the sponsor.
11.4 Annual progress report
The sponsor’s principal investigator and project leader will submit a summary of the 
progress of the trial to the accredited METC once a year. Information will be provided on 
the date of inclusion of the first subject, numbers of subjects included and numbers of 


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subjects that have completed the trial, serious adverse events/ serious adverse reactions, 
other problems, and amendments. 
11.5 End of study report
The sponsor will notify the accredited METC and the competent authority of the end of 
the study within a period of 90 days. The end of the study is defined as the last patient’s 
last visit.
In case the study is ended prematurely, the sponsor will notify the accredited METC and
the competent authority within 15 days, including the reasons for the premature 
termination.
Within one year after the end of the study, the principal investigator and project leader 
from the UMCG will submit a final study report with the results of the study, including any 
publications/abstracts of the study, to the accredited METC and the Competent Authority. 
11.6 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 sponsor, nor the principal 
investigator has a right of veto regarding the way of publishing the results.


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12. STRUCTURED RISK ANALYSIS
12.1 Potential issues of concern
a. Level of knowledge about mechanism of action
The Sodium glucose co-transporter 2 (SGLT2), located in the proximal tubule of the 
kidney, is an effective transporter system which is responsible for the nearly complete 
reabsorption of glucose in order to maintain appropriate glucose levels. Each glucose 
molecule that is reabsorbed is accompanied by reabsorption of a sodium molecule in a 
1:2 ratio. SGLT2 inhibitors reversely inhibit the SGLT-2 transporter which leads to 
enhanced glucose and sodium excretion and a reduction in plasma glucose and Hba1c.
The effects of dapagliflozin on the SGLT2 transporter are well characterized and sufficient 
knowledge is available about the mechanisms of action.14, 15
b. Previous exposure of human beings with the test product(s) and/or products with a
similar biological mechanism
Twelve phase 3 randomized controlled clinical trials were conducted involving more than 
6000 patients with type 2 diabetes of whom ~4000 were treated with dapagliflozin. Eleven 
studies were 24-weeks in duration with extension in 6 studies up to 78 weeks. One study 
was 52 weeks in duration with extension of another 52 weeks. 
Another SGLT2 inhibitor is registered in the US and filed for registration in Europe 
(canagliflozin). A third SGLT2 inhibitor (empagliflozin) is filed for registration in the US and 
Europe. In addition, a number of other SGLT-2 inhibitors are in various stages of clinical 
development. 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo 
human cell material?
Various animal models and cell lines are available to study the effect of SGLT2 inhibitors 
in more detail at a tissue/cell level.   
d. Selectivity of the mechanism to target tissue in animals and/or human beings
SGLT2 is highly localized to the kidney and major effects are expected to be related to 
glycosuria and natriuresis.
e. Analysis of potential effect
In placebo controlled clinical trials the following adverse reactions have been identified: 
Infections and infestations: vulvovaginitis, balanitis and genital infections,
urinary tract infections (Common)


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Metabolism and nutrition disorders: Hypoglycemia; volume depletion 
(uncommon)
Gastrointestinal disorders: Constipation (uncommon)
Musculoskeletal: Back pain (Common)
Renal and urinary disorders: Dysuria; Polyuria (Common); Nocturia 
(uncommon)
Common (>1/100 to <1/10) and uncommon (>1/1000 to <1/100)
Few adverse events led to discontinuation of treatment and adverse events were 
balanced across study groups. The most commonly reported events leading to 
discontinuation in patients treated with dapagliflozin 10 mg/day were increased blood 
creatinine (0.4%), urinary tract infections (0.3%), nausea (0.2%), and rash (0.2%). It 
should be noted that the transient rise in serum creatinine may reflect a reduction in intra-
glomerular pressure which may be associated with long-term structural renal protection. 
A pooled analysis of 3152 patients who received dapagliflozin in doses between 2.5 and 
10 mg/day showed that the incidence of urinary tract infection was increased with 
dapagliflozin dosage. Most diagnosed infections were mild to moderate and responded to 
standard antimicrobial treatment.16
Safety data in patients with diabetic kidney disease has been generated in phase 3 trials 
and demonstrated no additional side effects compared to type 2 diabetes patients without 
kidney disease. Given the SGLT2i mode of action no further safety issues are anticipated 
in non-diabetic CKD patients as compared to generally more vulnerable diabetic kidney 
disease patients included in the past phase 3 studies.  
Overdose:
Dapagliflozin did not show any toxicity in healthy subjects at single oral doses up to 500 
mg (50 times the dose aimed to be used in the present study). These subjects had 
detectable glucose in the urine for a dose-related period of time (at least 5 days for the 
500 mg dose) with no reports of dehydration, hypotension, or electrolyte imbalance and 
with no clinically meaningful effect on QTc interval. The incidence of hypoglycaemia was 
similar to placebo. In clinical studies where once-daily dosing of up to 100 mg 
dapagliflozin were administered for 2 weeks in healthy subjects and type 2 diabetes 
subjects the incidence of hypoglycaemia was slightly higher than placebo and was not 
dose-related. 
f. Pharmacokinetic considerations
In in-vitro- studies, dapagliflozin neither inhibited cytochrome P450, CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4 nor induces CYP1A2, CYP2B6, 
CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of 
coadminstered medicinal products that are metabolized by these enzymes. 


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Interaction studies conducted in healthy subjects, using mainly a single dose design, 
suggest that the PK of dapagliflozin is not altered by metformin, pioglitazone, sitagliptin, 
glimepiride, hydrochlorothiazide, bumetanide, valsartan, or simvastatin. 
g. Study population
The enrolled population is in a stable condition and no unexpected serious adverse events 
are foreseen. 
h. Interaction with other products
See f
i. Predictability of effect
Efficacy is monitored by measuring albuminuria / blood pressure / Hba1c which are 
accepted and accurate surrogates to evaluate efficacy.
j. Can effects be managed?
Patients are regularly monitored and asked about adverse effects of urinary tract 
infections or infestations. As reported above, dapagliflozin administration is associated 
with an increased risk of infections which can be managed with standard antimicrobial 
treatment. 16
12.2 Synthesis
The available data show that dapagliflozin decreases HbA1c, blood pressure and body 
weight in patients with type 2 diabetes. The drug received marketing approval from the 
EMA and is registered in various EU-countries. Dapagliflozin increases incidence of 
urinary tract infections. This adverse effect led in rare instances to treatment 
discontinuation and is manageable with standard antimicrobial treatment.


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13. REFERENCES
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and 
Mortality in Type 2 Diabetes. N Engl J Med 2015; 373: 2117-2128.
2. Christoph Wanner JML, David H. Fitchett, Silvio E. Inzucchi, Maximilian von Eynatten, 
Michaela Mattheus, Odd Erik Johansen, Hans-J rgen Woerle, Uli Christian Br dl, 
Bernard Zinman. W rzburg, Germany. Empagliflozin and Cardiovascular Outcomes 
in Patients with Type 2 Diabetes and Chronic Kidney Disease. ASN renal week High 
Impact Clinical trial 2015.
3. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-
glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation
2014; 129: 587-597.
4. Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med 2013; 368: 2402-2414.
5. group Kcpgw. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int 2012; 2.
6. Sha S, Devineni D, Ghosh A, et al. Canagliflozin, a novel inhibitor of sodium glucose co-
transporter 2, dose dependently reduces calculated renal threshold for glucose 
excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes 
Metab 2011; 13: 669-672.
7. Sarashina A, Koiwai K, Seman LJ, et al. Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 
2 (SGLT2) inhibitor, in healthy Japanese subjects. Drug Metab Pharmacokinet 2013; 
28: 213-219.
8. Fioretto P, Stefansson BV, Johnsson E, et al. Dapagliflozin reduces albuminuria over 2 
years in patients with type 2 diabetes mellitus and renal impairment. Diabetologia
2016; 59: 2036-2039.
9. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and 
moderate renal impairment shows that dapagliflozin reduces weight and blood 
pressure but does not improve glycemic control. Kidney international 2014; 85: 962-
971.
10.
Kohan DE, Fioretto P, Johnsson K, et al. The effect of dapagliflozin on renal function 
in patients with type 2 diabetes. Journal of nephrology 2016; 29: 391-400.
11.
Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients 
with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann 
Intern Med 2012; 156: 405-415.
12.
DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal 
glucose reabsorption in response to dapagliflozin in healthy subjects and subjects 
with type 2 diabetes. Diabetes care 2013; 36: 3169-3176.
13.
Lundkvist P, Sjostrom CD, Amini S, et al. Dapagliflozin once-daily and exenatide 
once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study 
examining effects on body weight and prediabetes in obese adults without diabetes. 
Diabetes, obesity & metabolism 2017; 19: 49-60.
14.
Obermeier M, Yao M, Khanna A, et al. In vitro characterization and pharmacokinetics 
of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II 
inhibitor, in animals and humans. Drug Metab Dispos 2010; 38: 405-414.


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15.
Defronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of Renal 
Glucose Reabsorption in Response to Dapagliflozin in Healthy Subjects and Subjects 
With Type 2 Diabetes. Diabetes Care 2013.
16.
Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with 
diabetes treated with dapagliflozin. J Diabetes Complications 2013; 27: 473-478.

SAP_001.pdf: 
Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
 
Statistical Analysis Plan 
 
Page 1 of 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
The DIAMOND trial 
 
A study to assess the Renoprotective Effects of the SGLT2 
Inhibitor Dapagliflozin in Non-Diabetic Patients with 
Proteinuria: a Randomized Double Blind 6-Weeks Cross-Over 
Trial 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Version 1.5  
13 September 2019 
 
 
Prepared by: 
Gian Luca Di Tanna 
Hiddo Lambers Heerspink 
Qiang Li 
 
 
 
 
 
 
 
 
 
NCT03190694


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
Page 2 of 14 
Approved by:  ____ Hiddo Lambers Heerspink_______ 
Role: __________________________________________
Signature: _______________________________________________ 
Date: ________________________________________
Approved by:   ___ David Cherney __________ 
Role: __________________________________________ 
Signature: _______________________________________________ 
Date: ________________________________________ 
Approved by:   ___ Gian Luca Di Tanna_______ 
Role: ___Head of Statistics, Australia, The George Institute for Global Health___ 
Signature: _______________________________________________ 
Date: 13 September 2019 
Principal Investigator
16 Sep 2019
co-Principal Investigator
September 18, 2019


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
 
Statistical Analysis Plan 
 
Page 3 of 14 
 
1. Study synopsis 
 
Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS) inhibitors, many patients 
with non-diabetic kidney disease show progressive kidney function loss, which is associated with high 
residual albuminuria. Novel treatment strategies are therefore required to further decrease albuminuria 
and to slow kidney function decline.  
Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the reabsorption of glucose and 
sodium in the proximal tubule. The increased natriuresis following dapagliflozin administration 
normalizes tubuloglomerular feedback resulting in a reduction in intra-glomerular hypertension, which 
is in turn manifested by acute reductions in glomerular filtration rate and albuminuria. Since many 
etiologies of non-diabetic nephropathy are characterized by intraglomerular hypertension, we 
hypothesize that dapagliflozin acutely decreases GFR and albuminuria in patients without diabetes at risk 
of progressive kidney function loss via a glucose independent hemodynamic mechanism.   
SGLT2 has a plausible therapeutic potential in individuals with non-diabetic nephropathy at risk of renal 
progression, and are likely to be well tolerated. Exploring the beneficial effects of these agents in non-
diabetic proteinuric kidney disease may pave the way for a new indication for this class of drugs. In 
addition, trials in non-diabetic kidney disease may help to further characterize the non-glucose dependent 
effects, which may help to differentiate SGLT2i from other glucose lowering agents. 
2. Study objectives 
 
Our aim is to investigate two interventions that will be administered to the enrolled patients: Dapagliflozin 
10 mg/day and matched placebo. 
 
2.1. Primary Objective 
 
 
To assess the change baseline in 24-hr proteinuria with dapagliflozin for six weeks relative to 
placebo treatment in patients with non-diabetic kidney disease and proteinuria > 500 mg/day on 
stable ACEi or ARB treatment  
 
2.2. Secondary Objectives 
 
 
To assess the effect of dapagliflozin 10 mg/d compared to placebo on Glomerular Filtration Rate 
(GFR) using iohexol clearance.  
 
To assess the effect of dapagliflozin 10 mg/d compared to placebo on systolic/diastolic blood 
pressure  
 
To assess the effect of dapagliflozin 10 mg/d compared to placebo on body weight  
 
To assess the effect of dapagliflozin 10 mg/d on selected neurohormones/biomarkers:   
o Hormones of the RAAS (plasma and urine)  
o Natriuretic peptides  
o Urinary adenosine  
o Co-peptin  
o Immunoglobulin G (plasma and urine)  
 
To characterize the safety of dapagliflozin vs. placebo by determining the number of hypoglycemic 
episodes between groups, and serious adverse events.  


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
 
Statistical Analysis Plan 
 
Page 4 of 14 
 
 
3. Study design 
 
Randomized placebo controlled double blind cross-over trial. Eligible participants will be randomly 
assigned to one of the two treatment orders: placebo-dapagliflozin or dapagliflozin-placebo. Each 
treatment period lasts 6 weeks followed by a 6 week wash-out period to avoid cross-over effects. Patients 
will have their study visit in the morning in fasted condition.  
3.1. General Design and Plan 
 
A double blind randomized placebo controlled cross-over study will be conducted in subjects with Chronic 
Kidney Disease aged between 18 and 75 years, proteinuria levels between 500 and 3500 mg/24-hour, and 
an eGFR ≥ 25 ml/min/1.73m2 will be enrolled. Patients with type 1 or type 2 diabetes, polycystic kidney 
disease, glomerulonephritis with flares (lupus or anti-neutrophil cytoplasmic antibodies (ANCA) 
associated vasculitis) or ongoing active renal inflammation will be excluded. Since each subject is his/her 
own control, this design requires fewer patients as compared with a parallel study design. A wash-out 
period after each treatment period has been included in the design to avoid cross-over effects.  
The study will consist of a screening visit, a 4-week run-in phase for those subjects not on stable ACEi/ARB 
treatment, 2 consecutive 6-week double blind treatment periods separated by 6-week wash-out period. 
Subjects will be randomly assigned to one of the treatment orders as depicted in figure 1.  
 
Figure 1: Study design 
Screening Run-in 
4 weeks 
Placebo 
6 weeks 
Wash-out 
6 weeks 
Dapa 10 mg 
6 weeks 
Wash-out 
6 weeks 
Screening Run-in 
4 weeks 
Dapa 10 mg 
6 weeks 
Wash-out 
6 weeks 
Placebo 
6 weeks 
Wash-out 
6 weeks 
 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 5 of 14 
 
3.2. Sample Size 
 
Sample size calculations estimated 50 patients completing the study would provide 80% 
power to detect a 25% reduction in albuminuria. Assuming that approximately 5% of patients 
will discontinue the study prematurely, we intend to enrol 53 subjects. This calculation 
assumed a conservative standard deviation of 0.7 in log transformed proteinuria (within-
subject standard deviation of 0.475) in order to detect (with alpha at 0.05) at least the 25% 
reduction in mean albuminuria (i.e, delta=0.288 on the log-transformed proteinuria scale) in 
dapagliflozin compared to placebo.  
4. Study population 
 
Male and female subjects with Chronic Kidney Disease aged between 18 and 75 years, 
proteinuria levels between 500 and 3500 mg/24-hour, and an eGFR ≥ 25 ml/min/1.73m2 
will be enrolled. Patients with type 1 or type 2 diabetes, polycystic kidney disease, 
glomerulonephritis with flares (lupus or anti-neutrophil cytoplasmic antibodies (ANCA) 
associated vasculitis) or ongoing active renal inflammation will be excluded. Patients have to 
be treated with a stable dose of an ACEi or ARB for at least 4 weeks prior to enrolment.  
 
The study population will be selected from the outpatient clinical from hospitals based in the 
Netherlands (Groningen, Almelo, Amsterdam), Canada, (Toronto, Calgary, Vancouver) and 
Malaysia (Kuala Lumpur) with the following pre-specified inclusion and exclusion criteria. 
 
Inclusion criteria 
 
Age ≥18 and ≤75 years 
 
Diagnosis of IgA nephropathy, focal segmental glomerulosclerosis, or membranous 
nephropathy. A biopsy proven diagnosis is not a prerequisite for participation in this 
study. 
 
Urinary protein excretion > 300 mg/g and ≤ 3500 mg/g in a 24-hr urine collection 
 
eGFR ≥ 25 mL/min/1.73m2 
 
On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization 
 
Willing to sign informed consent 
 
Women of Child-Bearing Potential (WOCBP): 
o WOCBP must be using an acceptable method of contraception to avoid 
pregnancy throughout the study and for up to 4 weeks after the last dose of 
study drug in such a manner that the risk of pregnancy is minimized.  
o WOCBP must have a negative serum or urine pregnancy test result (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the 
first dose of study drug.  
o Women must not be breast-feeding. 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 6 of 14 
WOCBP comprises women who have experienced menarche and who have not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or who are not post-menopausal. 
 
 
Exclusion criteria 
 
 Diagnosis of type 1 or type 2 diabetes mellitus 
 Urinary protein excretion > 3500 mg/day 
 Autosomal dominant polycystic kidney disease 
 Indication for immunosuppressants as per the treating physician’s judgment.   
 Treatment with corticosteroids or immunosuppressant within the last 6 months 
 Active malignancy aside from treated squamous cell or basal cell carcinoma of the 
skin. 
 Any medication, surgical or medical condition which might significantly alter the 
absorption, distribution, metabolism, or excretion of medications including, but not 
limited to any of the following: 
o History of active inflammatory bowel disease within the last six months; 
o Major 
gastrointestinal 
tract 
surgery 
such 
as 
gastrectomy, 
gastroenterostomy, or bowel resection; 
o Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within 
last six months; 
o Pancreatic injury or pancreatitis within the last six months; 
o Evidence of hepatic disease as determined by any one of the following: ALT 
or AST values exceeding 3x ULN at inclusion visit, a history of hepatic 
encephalopathy, a history of esophageal varices, or a history of portocaval 
shunt; 
o Evidence of urinary obstruction of difficulty in voiding at screening 
 
History of severe hypersensitivity or contraindications to dapagliflozin 
 
Subject who, in the assessment of the investigator, may be at risk for dehydration 
or volume depletion that may affect the interpretation of efficacy or safety data 
 
Participation in any clinical investigation within 3 months prior to initial dosing. 
 
Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing. 
 
History of drug or alcohol abuse within the 12 months prior to dosing, or evidence 
of such abuse as indicated by the laboratory assays conducted during the 
screening. 
 
History of noncompliance to medical regimens or unwillingness to comply with 
the study protocol. 
 
Any surgical or medical condition, which in the opinion of the investigator, may 
place the patient at higher risk from his/her participation in the study, or is likely 
to prevent the patient from complying with the requirements of the study or 
completing the study. 
 
Pregnancy or breastfeeding 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 7 of 14 
 
WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period and up to 4 weeks after the last dose of study 
drug.  
 
4.1. Patients recruitment, eligibility and measurements 
 
The target population will be invited for screening. Subjects who meet all entry criteria and 
who are already on a stable dose (no changes in dose or type of drug) of ACEis or ARBs for at 
least 4 weeks proceed directly to randomization. Subjects who had their ACEi or ARB 
medication changed during the preceding 4 weeks of the screening visit proceed to a run-in 
phase during which the type and dose of these drugs are stabilized. Subjects will be randomly 
assigned to one of the two treatment orders as depicted in figure 1. Each treatment period 
lasts 6 weeks followed by a 6 week wash-out period to avoid cross-over effects. Subjects will 
have their study visit in the morning in fasted condition.  
Subjects will be instructed to take the study medication once daily, in the morning, except on 
study days; on those days, the study drug will be taken after the patient visit.  
 
Measurements 
 
During the double blind treatment period, and wash-out period patients will collect a 
24-hour urine collection at each visit for measurement of 24-hour protein, albumin, 
glucose, sodium, potassium, creatinine, and urea excretion. Twenty-four hour urine 
collections will be performed at:  
o Screening visit  
o Day 1, week 3, and week 6 (last day on treatment) of each treatment period  
 
Office systolic and diastolic blood pressure measurements will be performed at day 
1, week 3 and 6 (last day on treatment) of each treatment period  
 
Vital signs (heart rate and body weight) and blood will be sampled for measurement 
of HbA1c, glucose, complete blood count, plasma albumin, RAAS biomarkers, 
natriuretic peptides, co-peptin, neurohormones at day 1, week 3 and 6 of each 
treatment period.  
 
Blood and urine samples will be stored for future exploratory biomarker analyses to 
study the effect of dapagliflozin in this study population.  
4.2. Randomization and blinding 
 
Treatment sequence of dapagliflozin and placebo will be randomized. A computer generated 
randomized code generated by the sponsor will be used. The pharmacy of each participating 
centre will store the randomization code. Unblinding is not to be performed for any reason, 
other than an emergency where unblinding is required. 
 
   


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 8 of 14 
5. Statistical analysis 
The flow of patients through the study (screened, fulfilled eligibility criteria, excluded, 
randomized and potential drop-outs) will be graphically displayed in a CONSORT diagram. 
Baseline characteristics will be described by sequence group. All tests are to be two-sided 
with nominal level alpha set at 5%.  
Descriptive statistics will be used to analyse the means and distribution between all the study 
variables. The means of the normal distributed variables will be compared with the student 
T-test and non-parametric tests (Mann-Whitney U-test for continuous and Chi-Square test 
for categorical variables) will be used for the variables that present a particularly skewed 
distribution. 
The base-case analyses of the treatment effects will be unadjusted (with the exception of the 
period effect).  
 
5.1. Analysis of primary outcome 
 
 
The log-transformed 24-hour proteinuria values will be analyzed by a mixed-effects general 
linear regression model with treatment and period as fixed factor and patients (nested in 
sequence) as a random factor. This type of model, which accounts for repeated observations 
within individuals (measurement occasion at level one, individuals at level two) will allow us 
to estimate the treatment effect (estimated by restricted maximum likelihood). We will also 
explore the period-specific treatment effect adding in the model the interaction between the 
treatment and period covariates. If the baseline characteristics will be considerably different 
across the three regions included (Malaysia, North America, Europe) we shall consider to 
include region as a layer in the multilevel model fitted or as fixed effect covariate. We will also 
analyse the log-transformed 24-hour albuminuria values (a specific protein using the same 
model as described above). 
 
The change in secondary outcomes, mGFR, eGFR, body weight and systolic blood pressure 
will be analyzed by the same model as showed for the proteinuria outcome. 
 
In general, the models employed will be: 
 
𝑦𝑖𝑡= 𝛽0𝑖+ 𝛽1𝑇𝑟𝑒𝑎𝑡𝑖𝑡+ 𝛽2𝑃𝑒𝑟𝑖𝑜𝑑𝑖𝑡+ 𝛽3𝐼𝑛𝑡𝑒𝑟𝑎𝑐𝑡𝑖𝑜𝑛+ 𝜀𝑖𝑡 
 
𝛽0𝑖= 𝛽0 + 𝑢0𝑖 
 
𝜀𝑖𝑡~𝑁(0, 𝜎𝜀2) 
 
Where 𝑦𝑖𝑡 is the outcome for the individual i at time point t, 𝛽0𝑖 is the intercept for individual 
i comprised of a sample-average fixed effect 𝛽0 and an individual effect 𝑢0𝑖 and 𝜀𝑖𝑡 is the 
residual error.  


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 9 of 14 
Complete case analyses, that is analysing records that present the whole set of information 
(outcome and covariates) for every visit of the patients will be performed. Patterns of missing 
data (for the outcomes and the covariates) will be reported. If the proportion of missing 
records is higher than 5% and/or we will suspect of particular missing mechanisms we will 
impute the missing values by multiple imputation using the full conditional specification. 
Further, if there will be baseline measurements that are missing we will use the values 
measured at the screening visit: we will document the frequency of this imputation. 
As a complementary analysis we will also include week 3 (mid-period 1 visit) and week 15 
(mid-period 2 visit) data points so to explore potential “immediate” treatment effects: this 
will be done for the primary outcome and the secondary outcomes for which the data is 
available (for instance, no eGFR is collected at week 3 and 15) .  
A fully-adjusted model will be also considered for the primary outcome including – among 
the others – the following time-varying variables: mGFR, systolic blood pressure, body weight 
and Hba1c. 
5.2. Subgroup and sensitivity analyses 
The primary and secondary outcomes will be analyzed in the following subgroups: 
 
1. Age (≥ or < 60 years or median) 
2. Gender (Male / Female) 
3. Region (Asia, Europe, North Am) 
4. Proteinuria (≥ or < 1000 mg/24hr) 
5. mGFR (≥ or < 45 ml/min/1.73m2 or median) 
6. Systolic blood pressure (≥ or < 130 mmHg or median) 
7. Body mass index (≥ or < 25 kg/m2 or median) 
8. Kidney Diagnosis 
9. Diuretic use (Yes/No) 
 
We will flag patients who have started or changed the dose of  any medication that my 
influence the primary outcome (e.g. NSAID, corticosteroids, diuretic treatment, 
mineralocorticoid receptor antagonists, and Vitamin D during the double blind treatment 
periods and perform a sensitivity analysis on the primary outcome excluding them. 
 
Another sensitivity analysis will be performed on the primary outcome where we will use the 
average of the screening and randomization 24-hr proteinuria value. 
 
All the analyses described in the SAP are based on the intention to treat principle (that is, 
patients analysed according to the group they were originally assigned). We will also perform 
the analyses on the primary outcome(s) considering “on treatment” patients defined as those 
with adherence to study medication ≥80% (as determined by pill count). 
 
 
5.3. Supplementary analyses 
 
We will assess the change in primary and secondary outcomes during the dapagliflozin 
treatment periods with the change in proteinuria/albuminuria after stopping dapagliflozin; 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 10 of 14 
This will be assessed by a longitudinal model as described above assessing the appropriate 
contrasts.  
 
We will also assess the effect of dapagliflozin using 24-hr protein:creatinine ratio (and 
albumin:creatinine ratio as dependent variables. The model used for the primary outcome 
analysis will be used for this analysis. 
 
Finally, the proportion of patients who achieve a proteinuria level <500 mg/g during follow-
up will be summarized between dapagliflozin and placebo periods. Additionally, the 
proportion of patients with 30%, 40%, 50% reduction in proteinuria during follow-up will 
also be summarized between dapagliflozin and placebo group. McNemar and/or Mainland-
Gart tests will be conducted depending on the nature of proportions and on the importance 
of the sequence order 
 
Adherence on treatment, defined as pill count at least 80% during follow-up, will be 
summarized by treatment arm and study visits.  
 
 
6. Evaluation of safety parameters 
 
Counts and percentage per treatment arm will generally summarize all categorical indicators. 
A breakdown of SAEs stratified by fatal/non fatal status will be presented.  
 
7. Proposed tables and figures 
 
Table 1: Baseline characteristics for all randomised subjects by treatment group and in 
overall 
Baseline Characteristics 
Dapa 
Placebo 
Overall 
(N=xxx) 
(N=xxx) 
(N=xxx) 
  
  
  
  
Categorical variables: n/N (%) 
  
  
  
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
  
  
  
  
  
Continuous variables:  
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
   Q1  Q2  Q3 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
   min   max 
xxx xxx 
xxx xxx 
xxx xxx 
  
 
 
 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 11 of 14 
Table 2: Baseline characteristics for all randomised subjects by group and by period 
 
Baseline Characteristics 
Group 1 
Period 1 
Group 1 
Period 2 
Group 2 
Period 1 
Group 2 
Period 2 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
  
  
  
  
  
Categorical variables: n/N (%) 
  
  
  
  
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
xxx xxx 
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
xxx xxx 
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
xxx xxx 
   XXX 
xxx xxx 
xxx xxx 
xxx xxx 
xxx xxx 
  
 
  
  
  
  
 
Continuous variables:  
  
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
   Q1  Q2  Q3 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
   min   max 
xxx xxx 
xxx xxx 
xxx xxx 
xxx xxx 
  
 
 
 
 
 
Table 3: Descriptive results of follow-up measurements by visits 
Variables during follow-up 
Group 1 
Group 2 
Overall 
(N=xxx) 
(N=xxx) 
(N=xxx) 
  
  
  
 
Vital signs, BP, Biomarkers:  
  
  
 
  Week0 
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week3 (if applicable)  
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week6 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week12 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week15 (if applicable) 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week18 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week24 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
 
 
 
 
 
 
 
 
 
 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 12 of 14 
 
 
Table 4: Descriptive results for primary outcome by visits  
Variables during follow-up 
Group 1 
Group 2 
Overall 
(N=xxx) 
(N=xxx) 
(N=xxx) 
  
  
  
 
Primary outcome:  
  
  
 
  Week0 
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week3 (if applicable)  
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week6 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week12 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week15 (if applicable) 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week18 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week24 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
 
 
 
 
Table 5: Descriptive results for secondary outcomes by visits 
Variables during follow-up 
Group 1 
Group 2 
Overall 
(N=xxx) 
(N=xxx) 
(N=xxx) 
  
  
  
 
Secondary outcome:  
  
  
 
  Week0 
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week3 (if applicable)  
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week6 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week12 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week15 (if applicable) 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week18 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
  Week24 
  
  
  
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
 
 
 
 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 13 of 14 
 
 
 
 
 
Table 6: Treatment effect for primary outcome 
Primary outcome 
Dapa 
Placebo 
Difference  
(Dapa – Placebo) 
p-value 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
  
  
  
 
 
Primary outcome:  
  
  
 
 
  Change from baseline in overall 
  
  
 
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Change from baseline in period 1 
  
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Change from baseline in period 2 
  
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
 
 
 
 
 
 
Table 7: Treatment effect for secondary outcomes 
Secondary outcomes 
Dapa 
Placebo 
Difference  
(Dapa – Placebo) 
p-value 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
  
  
  
 
 
Secondary outcomes:  
  
  
 
 
  Change from baseline in overall 
  
  
 
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Change from baseline in period 1 
  
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Change from baseline in period 2 
  
  
  
 
   N   Mean (SD) 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
 
 
 
 
 
 
Table 8: Treatment effect for primary outcome by pre-specified subgroups 
Primary outcome 
Dapa 
Placebo 
Difference  
(Dapa – Placebo) 
p-value 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
  
  
  
 
 
  Change from baseline in overall 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Subgroup1 
  
  
  
 
   Yes 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
   No 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Subgroup2 
  
  
  
 
   Yes 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
   No 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Subgroup3 
  
  
  
 
   Yes 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
   No 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Subgroup4 
  
  
  
 


Effects of dapagliflozin in non-diabetic patients with proteinuria 
September 2019 
Statistical Analysis Plan 
 
Page 14 of 14 
   Yes 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
   No 
xxx xxx xxx 
xxx xxx xxx 
xxx xxx xxx 
xxx 
  Subgroup XXX 
  
  
  
 
 
 
 
 
 
 
Figure 1: Patients flow chart based on CONSORT 
 
Figure 2: Primary outcome over time by treatment groups and periods. ( 
 
 
Figure 3: Bar charts with changes from baseline to week 6 for primary/secondary outcomes  
 
Figure 4: Process measurements over time 
 
Similar figure as above, but could add more time points in week 3 and week 15. 
 
Figure 5: Forest plot for subgroup analysis for primary outcome 
 
 
 
72
73
74
75
76
77
78
0
2
4
6
8
10
12
14
16
18
20
Primary outcome
Visit in weeks
Group1 in Dapa
Group1 in Placebo
Group2 in Dapa
Group2 in Placebo