The Effect of Sodium-glucose Cotransporter (SGLT) 2 Inhibitors on Cystine Stone Formation: A Preliminary Study
Phase: PHASE2
Conditions: Cystinuria
Sponsor: University of California, San Francisco

 
 
 
 
 
University of California, San Francisco 
Clinical Research Protocol 
The effect of sodium-glucose cotransporter (SGLT) 
2 inhibitor on cystine stone formation: A 
preliminary study 
17AUG2021 
NCT# 04818034       

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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University of California, San Francisco 
 
 
Clinical Research Protocol 
SGLT2-01 
Protocol Number: 
SGLT2-01 
Version Date: 
8/17/2021 
Investigational Product: 
Dapagliflozin 
IND Number: 
TBD 
Development Phase: 
2 
Sponsor: 
Marshall Stoller, MD  
Department of Urology  
University of California, San Francisco  
400 Parnassus Ave, 6 th floor A632  
San Francisco, CA 94143 
Funding Organization: 
 
Principal Investigator: 
Name: Marshall Stoller 
 
Telephone: 415-353-8520 
 
Fax: 415-476-8849 
 
 
E-mail: marshall.stoller@ucsf.edu 
 
Medical Monitor: 
Name: Marshall Stoller 
 
Telephone: 415-353-8520 
 
Fax: 415-476-8849 
 
 
E-mail: marshall.stoller@ucsf.edu 
 
Coordinating Center: 
Single center 
 
Approval: 
 
 
 
PI or Sponsor Signature (Marshall Stoller, MD)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision as outlined 
in the protocol.  It is understood that all information pertaining to the study will be held 
strictly confidential and that this confidentiality requirement applies to all study staff at 
this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the 
procedures required to carry out the study in accordance with accepted GCP principles 
and to abide by the terms of this protocol. 
 
Protocol Number:  SGLT2-01 
 
Protocol Title:  The effect of sodium-glucose cotransporter-2 (SGLT-2) inhibitor on 
cystine stone formation 
 
Protocol Date:  8/17/2021 
 
 
 
 
Investigator Signature  
 
Date 
Marshall Stoller, MD 
Print Name and Title 
Site # 
Single center 
 
Site Name 
 
Department of Urology, University of California, San Francisco 
Address 
 
400 Parnassus Ave, 6 th floor A632 
 
 
San Francisco, CA 94143 
 
 
 
 
Phone Number 
 
415-353-8520 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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TABLE OF CONTENTS 
 
1 
BACKGROUND .................................................................................................................. 9 
      1.1    Overview of Clinical Studies…………………………………………………………9 
2 
STUDY RATIONALE ........................................................................................................ 15 
2.1 
Risk / Benefit Assessment ........................................................................................... 15 
3 
STUDY OBJECTIVES ....................................................................................................... 15 
3.1 
Primary Objective ........................................................................................................ 15 
4 
STUDY DESIGN ................................................................................................................. 15 
4.1 
Study Overview ........................................................................................................... 15 
5 
CRITERIA FOR EVALUATION ...................................................................................... 16 
5.1 
Primary Efficacy Endpoint .......................................................................................... 16 
5.2 
Safety Evaluations ....................................................................................................... 16 
6 
SUBJECT SELECTION ..................................................................................................... 16 
6.1 
Study Population .......................................................................................................... 16 
6.2 
Inclusion Criteria ......................................................................................................... 16 
6.3 
Exclusion Criteria ........................................................................................................ 17 
7 
CONCURRENT MEDICATIONS .................................................................................... 17 
7.1 
Allowed ........................................................................................................................ 17 
8 
STUDY TREATMENTS ..................................................................................................... 17 
8.1 
Method of Assigning Subjects to Treatment Groups ................................................... 17 
8.2 
Blinding ....................................................................................................................... 17 
8.3 
Test and Control Formulation ...................................................................................... 17 
8.4 
Supply of Study Medication at the Site ....................................................................... 18 
8.5 
Study Medication Accountability ................................................................................ 18 
8.6 
Measures of Treatment Compliance ............................................................................ 18 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 18 
9.1 
Clinical Assessments ................................................................................................... 18 
9.2 
Clinical Laboratory Measurements (include sections as appropriate) ......................... 19 
10 EVALUATIONS BY VISIT ............................................................................................... 19 
10.1 Visit 1 ........................................................................................................................... 19 
10.2 Visit 2 ........................................................................................................................... 20 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ........................ 20 
11.1 Adverse Events ............................................................................................................ 20 
11.2 Serious Adverse Experiences (SAE) ........................................................................... 21 
11.4 Medical Monitoring ..................................................................................................... 22 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................... 22 
12.1 Withdrawal of Subjects ................................................................................................ 23 
12.3 Replacement of Subjects .............................................................................................. 23 
13 PROTOCOL VIOLATIONS .............................................................................................. 23 
14  STATISTICAL METHODS AND CONSIDERATIONS ................................................ 24 
14.1 Data Sets Analyzed ...................................................................................................... 24 
14.2 Demographic and Baseline Characteristics ................................................................. 24 
14.3 Analysis of Primary Endpoint ...................................................................................... 24 
15.5 Interim Analysis ........................................................................................................... 24 
15.6 Sample Size and Randomization ................................................................................. 24 
15 DATA COLLECTION, RETENTION AND MONITORING ........................................ 25 
15.1 Data Collection Instruments ........................................................................................ 25 
15.2 Data Management Procedures ..................................................................................... 25 
15.3 Data Quality Control and Reporting ............................................................................ 25 
15.4 Archival of Data ........................................................................................................... 25 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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15.5 Availability and Retention of Investigational Records ................................................ 25 
15.6 Monitoring ................................................................................................................... 26 
15.7 Subject Confidentiality ................................................................................................ 26 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................... 27 
16.1 Protocol Amendments .................................................................................................. 27 
16.2 Institutional Review Boards and Independent Ethics Committees .............................. 27 
16.3 Informed Consent Form ............................................................................................... 28 
16.4 Publications .................................................................................................................. 28 
16.5 Investigator Responsibilities ........................................................................................ 28 
 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DM 
DMC 
Diabetes mellitus 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICP-OES 
inductively coupled plasma optical emission spectroscopy 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
SGLT 
serious adverse experience 
sodium-glucose cotransporter 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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PROTOCOL SYNOPSIS 
TITLE 
The effect of sodium-glucose cotransporter (SGLT) 2 inhibitor on 
cystine stone formation: A preliminary study 
SPONSOR 
Marshall Stoller, MD 
FUNDING 
ORGANIZATION 
 
NUMBER OF SITES 
1 
RATIONALE 
Cystinuria is an inherited autosomal recessive disorder of the kidney 
that is the result of an inability to reabsorb cystine from the urine. 
Supersaturation of cystine in the urine produces crystals that 
precipitate and form stones in the kidney, which can be a cause of 
obstruction, infection, and chronic kidney disease. Cystine stones 
constitute a major health challenge for affected individuals with 
cystinuria because of the frequent recurrence of painful symptoms and 
the current absence of effective, patient-accepting treatment. 
 
A mainstay of therapy is breaking or preventing the cystine bond on 
the molecular level such that cystine (which is formed from the 
joining of two cysteine amino acids and their corresponding sulfur 
atoms) cannot precipitate in the urine. It is hypothesized that a glucose 
molecule may be able to do this if introduced into the urine. SGLT-2 
inhibitors are a class of drug that are FDA approved to treat diabetes 
mellitus (DM) and heart failure by inhibiting an enzyme in the kidney 
that allows for reabsorption of glucose from the urine. This effectively 
increases the concentration of glucose in the urine. Our hypothesis 
suggests that administration of this drug to patients with cystine will 
introduce sufficient glucose into the urine to prevent the formation of 
cystine stones. To date, there has been no published data on the 
effectiveness of this therapy for this indication, although the dosage 
and administration would be identical to that already approved by the 
FDA for the treatment of DM and heart failure. 
STUDY DESIGN 
This study will be a single center, proof of concept study designed to 
assess how daily 10 mg dapagliflozin affects formation of cystine in 
the urine in patients with cystinuria. 
PRIMARY 
OBJECTIVE 
Use mass spectrometry to determine the effect of SGLT-2 inhibitor 
therapy on quantitative sulfur as a surrogate for presence of cysteine 
in freshly voided urine in patients with cystinuria. 
SECONDARY 
OBJECTIVES 
None 
NUMBER OF 
SUBJECTS 
10 
SUBJECT 
SELECTION 
Inclusion Criteria: males and females age 18 or older; documented 
cystinuria on prior 24-hour urine collection and/or stone analysis; 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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CRITERIA 
history of previous cystine kidney stones; and being able and willing 
to provide consent 
Exclusion Criteria: prior diagnosis of diabetes mellitus (type I or type 
II); current SGLT-2 inhibitor administration at the time of screening; 
SGLT-2 inhibitor administration within the last year prior to 
screening; vulnerable populations including incarceration status; 
anticipation of pregnancy during the study duration; unable to give 
informed consent; non-English primary language; pregnancy, 
lactation, or child- bearing age without birth control devices; and 
serious illness likely to cause death within the next 5 years. 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Dapagliflozin 10 mg administered orally once daily for 4 weeks 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
None 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 6 weeks 
• Screening: 1 week to determine eligibility 
• Treatment: 4 weeks after the initial visit (Day 0) 
• Follow-up: 1 week after the last visit (Day 28) 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: The participants will be allowed to continue any 
medications they are currently taking with the exception of those 
listed below under “prohibited”.  Importantly, patients will be allowed 
to continue potassium citrate as this is an important mainstay of 
cystinuria treatment as discontinuation may lead to clinically 
significant cystine stone formation. 
 
Prohibited: Medications commonly used to treat diabetes, such as but 
not limited to insulin, metformin, and glipizides. These medications 
may interfere with the action of SGLT-2 inhibitors by altering the 
manner in which the body metabolizes and regulates glucose.  
Medications commonly used to treat cystinuria: thiola, penicillamine, 
alpha lipoic acid 
 
EFFICACY 
EVALUATIONS 
Efficacy in this study will be determined by utilizing mass 
spectrometry to analyze for the presence of sulfur in the urine before 
and after initiation of therapy with SGLT-2 inhibitor in our patients 
with cystinuria.  Urinary cystine levels on 24-hour urine collection 
will also be measured. 
PRIMARY ENDPOINT Quantitative urinary sulfur via inductively coupled plasma optical 
emission spectroscopy (ICP-OES) in freshly voided urine 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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OTHER 
EVALUATIONS 
 
SAFETY 
EVALUATIONS 
After participants are enrolled at 1 week during the treatment period, a 
study coordinator will contact each participant to check compliance, 
tolerability, and side effects with SGLT-2 inhibitor therapy. Any 
concern for a potential adverse event will be reviewed by the study 
investigators. Patient clinical care will continue as per the current 
standard for the duration of this study. Tolerability and side effects 
will be reviewed at each of the two clinic visits. All reported adverse 
events will be reviewed by the study investigators. Depending on the 
severity of the adverse event, the participant may be advised to stop 
SGLT-2 inhibitor therapy intake if it is determined that SGLT-2 
inhibitor therapy is the cause. Most common AEs noted include male 
and female genital yeast infections, UTI, increased urination, 
discomfort with urination. 
PLANNED INTERIM 
ANALYSES  
When approximately 50% of patients have completed the study 
through Visit 2, an interim analysis for safety will be conducted. 
Serious adverse events will be monitored on an ongoing basis 
throughout the study. 
STATISTICS 
Primary Analysis Plan 
The primary efficacy endpoint will be assessed by comparing the 
qualitative and quantitative differences between the mass 
spectrometry output data between the participants’ freshly voided 
urine at the initial visit and at the follow up visit after initiation of 
SGLT-2 inhibitor therapy, specifically examining the quantitative 
sulfur content between the two samples as a surrogate for cysteine in 
the urine. 
Rationale for Number 
of Subjects 
This is a preliminary proof of concept study designed to show only 
that administration of SGLT-2 inhibitor medications alter the 
excretion of cystine in the urine of patients with documented 
cystinuria. If initial analyses are promising, further investigation will 
be undertaken to draw further meaningful, statistical conclusions on 
the efficacy of this medication. 
 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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1 
BACKGROUND 
Cystinuria is an inherited autosomal recessive disorder of the kidney that is the result of a 
defect in the dibasic amino acid transporter in the apical membrane of the renal proximal 
tubule and small intestine. The disease causes hyperexcretion of cystine, lysine, arginine, 
and ornithine into the urine. Of these amino acids, only cystine is poorly soluble in urine. 
Supersaturation of cystine in the urine produces crystals that precipitate and form calculi, 
which can be a cause of obstruction, infection, and chronic kidney disease.1 Cystine stone 
disease has an estimated prevalence of up to 1 in 1,000 in some parts of Europe and 1 in 
17,000 in the United States,2 and comprises up to 2% of all kidney stone disease overall 
and up to 10% of stone disease in children.3 As it is a rare disease, pharmaceutical 
treatments for cystinuria are considered “orphan drugs” based on the U.S. Orphan Drug 
Act of 1983, which was passed to encourage pharmaceutical companies to develop 
treatments for diseases with a small market.4 However, cystine stones constitute a major 
health challenge for affected individuals because of the frequent recurrence of painful 
symptoms and the current absence of effective, patient-accepting treatment.5, 6  
 
Two primary factors known to affect the solubility of cystine include are cystine 
concentration and pH.7 Therefore, the current mainstays of therapy include aggressive 
hydration to 2.5 to 3 liters of fluid intake daily, lowering of dietary sodium intake, urinary 
alkalinization to pH >7.0, and thiol derivative medications to bind urinary cystine to 
reduce urinary cystine concentrations to less than 250 mg/l, the level above which cystine 
becomes insoluble in urine.8 Thiol derivatives in current use including D-penicillamine 
and alpha-mercaptopropionylglycione increase the solubility of cystine by forming more 
soluble mixed amino acid-disulfide products. However, these medications are difficult to 
tolerate due to their side effect profiles and, therefore, compliance is poor.9 Furthermore, 
the medications require regular monitoring of complete blood count, liver enzymes, and 
urinary protein excretion. In our own kidney stone clinic population, even when 
compliance is high, cystinuric patients taking D-penicillamine and alpha-
mercaptopropionylglycione often continue to form recurrent cystine stones. It is not 
surprising that because cystinuria is a lifelong disease and current medical management is 
difficult to achieve and not very effective, these individuals have frequent stone 
recurrences and a higher risk of kidney loss compared to the average calcium oxalate 
stone former.10 Therefore, additional well-tolerated and effective medical therapies to treat 
cystinuria are desperately needed. 
 
1.1 
Overview of Clinical Studies 
Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is 
responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. 
Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces 
reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby 
increases urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and 
increases the delivery of sodium to the distal tubule. This may influence several 
physiological functions including, but not restricted to, lowering both pre-and afterload of 
the heart and downregulation of sympathetic activity. 
 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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Increases in the amount of glucose excreted in the urine were observed in healthy subjects 
and in patients with type 2 diabetes mellitus following the administration of dapagliflozin. 
Dapagliflozin doses of 5 or 10 mg per day in patients with type 2 diabetes mellitus for 12 
weeks resulted in excretion of approximately 70 grams of glucose in the urine per day at 
Week 12. A near maximum glucose excretion was observed at the dapagliflozin daily 
dose of 20 mg. This urinary glucose excretion with dapagliflozin also results in increases 
in urinary volume.  After discontinuation of dapagliflozin, on average, the elevation in 
urinary glucose excretion approaches baseline by about 3 days for the 10 mg dose. 
 
Following oral administration of dapagliflozin, the maximum plasma concentration 
(Cmax) is usually attained within 2 hours under fasting state. The Cmax and AUC values 
increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose 
range. The absolute oral bioavailability of dapagliflozin following the administration of a 
10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its 
Cmax by up to 50% and prolongs Tmax by approximately 1 hour, but does not alter AUC 
as compared with the fasted state. These changes are not considered to be clinically 
meaningful and dapagliflozin can be administered with or without food. 
 
Overview of Clinical Studies of FARXIGA for Type 2 Diabetes  
FARXIGA has been studied as monotherapy, in combination with metformin, 
pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), 
metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), 
compared to a sulfonylurea (glipizide), and in combination with a GLP-1 receptor agonist 
(exenatide extended-release) added-on to metformin. FARXIGA has also been studied in 
patients with type 2 diabetes and moderate renal impairment.  
Treatment with FARXIGA as monotherapy and in combination with metformin, 
glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant 
improvements in mean change from baseline at Week 24 in HbA1c compared to control. 
Reductions in HbA1c were seen across subgroups including gender, age, race, duration 
of disease, and baseline body mass index (BMI).  
Monotherapy  
A total of 840 treatment-naive patients with inadequately controlled type 2 diabetes 
participated in 2 placebo-controlled studies to evaluate the safety and efficacy of 
monotherapy with FARXIGA.  
In 1 monotherapy study, a total of 558 treatment-naive patients with inadequately 
controlled diabetes participated in a 24-week study (NCT00528372). Following a 2-week 
diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were 
randomized to FARXIGA 5 mg or FARXIGA 10 mg once daily in either the morning 
(QAM, main cohort) or evening (QPM), or placebo.  
At Week 24, treatment with FARXIGA 10 mg QAM provided significant improvements 
in HbA1c and the fasting plasma glucose (FPG) compared with placebo. 
 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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Initial Combination Therapy with Metformin XR  
A total of 1236 treatment-naive patients with inadequately controlled type 2 diabetes 
(HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled studies of 24-week duration 
to evaluate initial therapy with FARXIGA 5 mg (NCT00643851) or 10 mg 
(NCT00859898) in combination with metformin extended-release (XR) formulation. 
 
In 1 study, 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in 
period received: FARXIGA 10 mg plus metformin XR (up to 2000 mg per day), 
FARXIGA 10 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. 
Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a 
median dose achieved of 2000 mg.  
The combination treatment of FARXIGA 10 mg plus metformin XR provided statistically 
significant improvements in HbA1c and FPG compared with either of the monotherapy 
treatments and statistically significant reduction in body weight compared with metformin 
XR alone. FARXIGA 10 mg as monotherapy also provided statistically significant 
improvements in FPG and statistically significant reduction in body weight compared with 
metformin alone and was noninferior to metformin XR monotherapy in lowering HbA1c. 
 
In a second study, 603 patients were randomized to 1 of 3 treatment arms following a 1-
week lead-in period: FARXIGA 5 mg plus metformin XR (up to 2000 mg per day), 
FARXIGA 5 mg plus placebo, or metformin XR (up to 2000 mg per day) plus placebo. 
Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a 
median dose achieved of 2000 mg.  
The combination treatment of FARXIGA 5 mg plus metformin XR provided statistically 
significant improvements in HbA1c and FPG compared with either of the monotherapy 
treatments and statistically significant reduction in body weight compared with metformin 
XR alone. 
 
Add-On to Metformin  
A total of 546 patients with type 2 diabetes with inadequate glycemic control (HbA1c 
≥7% and ≤10%)  
participated in a 24-week, placebo-controlled study to evaluate FARXIGA in combination 
with metformin (NCT00528879). Patients on metformin at a dose of at least 1500 mg per 
day were randomized after completing a 2-week, single-blind, placebo lead-in period. 
Following the lead-in period, eligible patients were randomized to FARXIGA 5 mg, 
FARXIGA 10 mg, or placebo in addition to their current dose of metformin.  
As add-on treatment to metformin, FARXIGA 10 mg provided statistically significant 
improvements in HbA1c and FPG, and statistically significant reduction in body weight 
compared with placebo at Week 24 (see Table 9 and Figure 3). Statistically significant (p 
<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to 
placebo plus metformin were −4.5 mmHg and −5.3 mmHg with FARXIGA 5 mg and 10 
mg plus metformin, respectively. 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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Active Glipizide-Controlled Study Add-On to Metformin  
A total of 816 patients with type 2 diabetes with inadequate glycemic control (HbA1c 
>6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, noninferiority 
study to evaluate FARXIGA as add-on therapy to metformin (NCT00660907). Patients on 
metformin at a dose of at least 1500 mg per day were randomized following a 2-week 
placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and 
were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL,  
<6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and FARXIGA 10 
mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-
titration to prevent hypoglycemia.  
At the end of the titration period, 87% of patients treated with FARXIGA had been 
titrated to the maximum study dose (10 mg) versus 73% treated with glipizide (20 mg). 
FARXIGA led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), 
compared with glipizide, thus demonstrating noninferiority (see Table 10). FARXIGA 
treatment led to a statistically significant mean reduction in body weight from baseline at 
Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. 
Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure 
relative to glipizide plus metformin was −5.0 mmHg with FARXIGA plus metformin. 
 
Add-On Combination Therapy with a Sulfonylurea  
A total of 597 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% 
and ≤10%) were randomized in this 24-week, placebo-controlled study to evaluate 
FARXIGA in combination with glimepiride (a sulfonylurea) (NCT00680745).  
Patients on at least half the maximum recommended dose of glimepiride as monotherapy 
(4 mg) for at least 8 weeks lead-in were randomized to FARXIGA 5 mg, FARXIGA 10 
mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 
2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration 
of glimepiride was allowed.  
In combination with glimepiride, FARXIGA 10 mg provided statistically significant 
improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in 
body weight compared with placebo plus glimepiride at Week 24 (see Table 11). 
Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic 
blood pressure relative to placebo plus glimepiride were −2.8 mmHg and −3.8 mmHg 
with FARXIGA 5 mg and 10 mg plus glimepiride, respectively.  
Add-on Combination Therapy with Metformin and a Sulfonylurea  
A total of 218 patients with type 2 diabetes and inadequate glycemic control (HbA1c ≥7% 
and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate FARXIGA in 
combination with metformin and a sulfonylurea (NCT01392677). Patients on a stable 
dose of metformin (immediate-or extended-release formulations) ≥1500 mg/day plus 
maximum tolerated dose, which must be at least half the maximum dose, of a sulfonylurea 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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for at least 8 weeks prior to enrollment were randomized after an 8week placebo lead-in 
period to FARXIGA 10 mg or placebo. Dose-titration of FARXIGA or metformin 
 
Add-On Combination Therapy with a Thiazolidinedione  
A total of 420 patients with type 2 diabetes with inadequate glycemic control (HbA1c 
≥7% and ≤10.5%) participated in a 24-week, placebo-controlled study to evaluate 
FARXIGA in combination with pioglitazone (a thiazolidinedione [TZD]) alone 
(NCT00683878). Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per 
day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week 
lead-in period to 5 or 10 mg of FARXIGA or placebo in addition to their current dose of 
pioglitazone. Dose titration of FARXIGA or pioglitazone was not permitted during the 
study.  
In combination with pioglitazone, treatment with FARXIGA 10 mg provided 
statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of 
patients achieving HbA1c <7%, and a statistically significant reduction in body weight 
compared with the placebo plus pioglitazone treatment groups (see Table 11) at Week 
24. A statistically significant (p <0.05) mean change from baseline in systolic blood 
pressure relative to placebo in combination with pioglitazone was −4.5 mmHg with 
FARXIGA 10 mg in combination with pioglitazone.  
Add-On Combination Therapy with a DPP4 Inhibitor  
A total of 452 patients with type 2 diabetes who were drug naive, or who were treated 
at entry with metformin or a DPP4 inhibitor alone or in combination, and had 
inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), 
participated in a 24-week, placebo-controlled study to evaluate FARXIGA in 
combination with sitagliptin (a DPP4 inhibitor) with or without metformin 
(NCT00984867).  
Eligible patients were stratified based on the presence or absence of background 
metformin (≥1500 mg per day), and within each stratum were randomized to either 
FARXIGA 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg 
once daily. Endpoints were tested for FARXIGA 10 mg versus placebo for the total 
study group (sitagliptin with and without metformin) and for each stratum (sitagliptin 
alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug 
naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% 
were on a DPP4 inhibitor plus metformin. Dose titration of FARXIGA, sitagliptin, or 
metformin was not permitted during the study.  
In combination with sitagliptin (with or without metformin), FARXIGA 10 mg 
provided statistically significant improvements in HbA1c, FPG, and a statistically 
significant reduction in body weight compared with the placebo plus sitagliptin 
(with or without metformin) group at Week 24 (see Table 11). These improvements 
were also seen in the stratum of patients who received FARXIGA 10 mg plus 
sitagliptin alone (placebo-corrected mean change for HbA1c −0.56%; n=110) 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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compared with placebo plus sitagliptin alone (n=111), and the stratum of patients 
who received FARXIGA 10 mg plus sitagliptin and metformin (placebo-corrected 
mean change for HbA1c −0.40; n=113) compared with placebo plus sitagliptin with 
metformin (n=113).  
Add-On Combination Therapy with Insulin  
A total of 808 patients with type 2 diabetes who had inadequate glycemic control (HbA1c 
≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled study to evaluate 
FARXIGA as add-on therapy to insulin (NCT00673231). Patients on a stable insulin 
regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at 
least 8 weeks prior to enrollment and on a maximum of 2 oral antidiabetic medications 
(OADs), including metformin, were randomized after completing a 2-week enrollment 
period to receive either FARXIGA 5 mg, FARXIGA 10 mg, or placebo in addition to their 
current dose of insulin and other OADs, if applicable. Patients were stratified according to 
the presence or absence of background OADs. Up-or down-titration of insulin was only 
permitted during the treatment phase in patients who failed to meet specific glycemic 
goals. Dose modifications of blinded study medication or OAD(s) were not allowed 
during the treatment phase, with the exception of decreasing OAD(s) where there were 
concerns over hypoglycemia after cessation of insulin therapy.  
In this study, 50% of patients were on insulin monotherapy at baseline, while 50% were 
on 1 or 2 OADs in addition to insulin. At Week 24, FARXIGA 10 mg dose provided 
statistically significant improvement in HbA1c and reduction in mean insulin dose, and a 
statistically significant reduction in body weight compared with placebo in combination 
with insulin, with or without up to 2 OADs (see Table 11); the effect of FARXIGA on 
HbA1c was similar in patients treated with insulin alone and patients treated with insulin 
plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood 
pressure relative to placebo in combination with insulin was −3.0 mmHg with FARXIGA 
10 mg in combination with insulin.  
At Week 24, FARXIGA 5 mg (−5.7 IU, difference from placebo) and 10 mg (−6.2 IU, 
difference from placebo) once daily resulted in a statistically significant reduction in mean 
daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with 
insulin, and a statistically significantly higher proportion of patients on FARXIGA 10 mg 
(19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%). 
 
Combination Therapy with Exenatide-Extended Release as Add-On to Metformin  
A total of 694 adult patients with type 2 diabetes and inadequate glycemic control 
(HbA1c ≥8.0 and ≤12.0%) on metformin, were evaluated in a 28-week double-blind, 
active-controlled study to compare FARXIGA in combination with exenatide extended-
release (a GLP-1 receptor agonist) to FARXIGA alone and exenatide extended-release 
alone, as add-on to metformin (NCT02229396). Patients on metformin at a dose of at 
least 1,500 mg per day were randomized following a 1-week placebo lead-in period to 
receive either FARXIGA 10 mg once daily (QD) in combination with exenatide 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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extended-release 2 mg once weekly (QW), FARXIGA 10 mg QD, or exenatide 
extended–release 2 mg QW.  
At Week 28, FARXIGA in combination with exenatide extended-release provided 
statistically significantly greater reductions in HbA1c (-1.77%) compared to FARXIGA 
alone (-1.32%, p=0.001) and exenatide extended-release alone (-1.42%, p=0.012). 
FARXIGA in combination with exenatide extended-release provided statistically 
significantly greater reductions in FPG (-57.35 mg/dL) compared to FARXIGA alone (-
44.72 mg/dL, p=0.006) and exenatide extended-release alone (-40.53, p <0.001). 
2 
STUDY RATIONALE 
It is hypothesized that glucose can serve as an agent to reduce the bond between the sulfur 
molecules in a cystine molecule, therefore breaking the disulfide bond that is the target of 
other therapies and forming soluble compounds with cysteine amino acid constituents in 
the urine. SGLT-2 inhibitors are an existing therapy that has already been FDA approved 
for the treatment of diabetes through inhibition of sodium-glucose cotransporter proteins 
within the renal tubules, therefore leading to regulation of blood glucose through loss in 
the urine. This therapy therefore sharply increases the glucose concentration in the urine 
as will ideally provide the substrate for the reduction reaction necessary to break the 
disulfide bond in a safe and tolerable fashion with far fewer side effects and greater 
tolerability than existing therapies. 
2.1 
Risk / Benefit Assessment 
Risks of treatment are relatively low in this therapy that has received FDA approval for 
treatment of diabetes mellitus and heart failure. See below for a list of incidence of 
common adverse events the most common of which were mild and include male and 
female genital yeast infections, UTI, increased urination, discomfort with urination. 
Potential benefit includes a novel and effective therapy for the debilitating disorder 
cystinuria. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to use mass spectrometry to determine the effect of 
SGLT-2 inhibitor therapy on quantitative sulfur as a surrogate of cysteine in freshly 
voided urine in patients with cystinuria 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a single center, proof of concept prospective cohort trial designed to assess the 
effect of daily oral administration of dapagliflozin 10 mg on cystine formation in freshly 
voided urine. Ten subjects are planned, each with previously diagnosed cystinuria and 
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Each subject will have an initial visit during which screening data will be reviewed to 
determine subject eligibility. Subjects who meet all inclusion criteria and none of the 
exclusion criteria will be entered into the study. Consent will be obtained as well as an 
initial examination and collection/analysis of freshly voided urine with mass spectrometry 
to serve as a baseline. The therapy under investigation, dapagliflozin 10 mg, will then be 
administered orally to each participant daily for four weeks, at which time each subject 
will return for a second visit for an analysis of freshly voided urine using mass 
spectrometry. The different urine collections will be compared and analyzed for 
differences with the prescribed therapy. No placebo will be used during this proof-of-
concept study. 
Total duration of subject participation with be up to six weeks. Total duration of the study 
is expected to be six weeks. 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The primary endpoint will be assessed via analysis using mass spectrometry of freshly 
voided urine and examining the resultant signals which signify the presence or absence of 
cystine as well as unbound cysteine amino acids and other reduction byproducts through 
the reaction with glucose. These will be assessed after 4 weeks of treatment with daily 
oral dapagliflozin 10 mg. 
5.2 
Safety Evaluations 
After the one-week treatment period, each participant will undergo a check of compliance, 
tolerability, and side effects with dapagliflozin therapy. Any concern for a potential 
adverse event will be reviewed by the study investigators. In addition, during the informed 
consent process, all potential side effects and drug interactions will be discussed. Enrolled 
participants will be provided the email address of the study coordinator and a 24-hour 
contact phone number of a physician if any adverse events occur during the study period. 
When 50% of participants have been in the study for 1 week, an interim analysis will be 
performed. 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects 18 of age and older with a diagnosis of cystinuria who meet the inclusion and 
exclusion criteria will be eligible for participation in this study.   
6.2 
Inclusion Criteria 
Male or female ≥ 18 years of age at Visit 1; Documentation of a cystinuria diagnosis as 
evidenced by one or more clinical features of the disease and one or more of the following 
criteria: (1) 24-hour urine collection in the past consistent with cystinuria or (2) Prior 
stone analysis after stone intervention proving cystine stone formation; Written informed 
consent (and assent when applicable) obtained from subject or subject’s legal 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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representative and ability for subject to comply with the requirements of the study; 
Absence of exclusion criteria 
6.3 
Exclusion Criteria 
Pregnant, breastfeeding, or unwilling to practice birth control during participation in the 
study; Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data; Diagnosis of diabetes 
mellitus (type I or type II); Current SGLT-2 inhibitor administration at the time of 
screening or SGLT-2 inhibitor administration within the last year prior to screening; 
Vulnerable populations including incarceration status; Anticipation of pregnancy during 
the study duration; Unable to give informed consent; Non-English primary language; 
pregnancy, lactation, or child- bearing age without birth control devices; Serious illness 
likely to cause death within the next 5 years. 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies.  However, 
patients will who are on medications commonly used to treat diabetes, such as but not 
limited to insulin, metformin, and glipizides will not be allowed to continue these while 
on study. These medications may interfere with the action of SGLT-2 inhibitors by 
altering the manner in which the body metabolizes and regulates glucose.  Participants 
will also be asked to stop any medications commonly used to treat cystinuria they may be 
taking for the duration of the study as well: thiola, penicillamine, alpha lipoic acid. 
7.1 
Allowed Medications and Treatments 
All medications the participant is on are allowed with the exception of: insulin, 
metformin, and glipizides.  These medications may interfere with the action of SGLT-2 
inhibitors by altering the manner in which the body metabolizes and regulates glucose.  
Participants will also be asked to stop any medications commonly used to treat cystinuria 
they may be taking for the duration of the study as well: thiola, penicillamine, alpha lipoic 
acid. 
8 
STUDY TREATMENTS 
8.1    Method of Assigning Subjects to Treatment Groups 
All participants will be assigned one treatment which includes daily oral administration of 
dapagliflozin 10 mg for 1 week duration. 
8.2    Blinding 
This is a nonblinded proof of concept study. 
8.3 
Formulation of Test and Control Products 
8.3.1 Formulation of Test Product 
Dapagliflozin 10mg as prescribed by local pharmacy.  No control product is being used. 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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8.4 
Supply of Study Drug at the Site 
Participants will be given a prescription for dapagliflozin 10mg to be taken orally daily for 
4 weeks by the study PI or his assistant MD. 
8.4.1 
Dosage/Dosage Regimen 
10mg of dapagliflozin will be taken orally once daily for 4 weeks. Participants will be 
encouraged to take the study tablet in the morning to facilitate consistent bioavailability 
between participants. 
8.4.2 
Dispensing 
Dapagliflozin will be given to the participant with sufficient quantity for administration at 
home, with a 4 week supply (28 tablets). At the subsequent visit, remaining pills will be 
counted and counts recorded to reflect compliance for participants. 
8.4.3 
Administration Instructions  
Dapagliflozin 10 mg is to be taken orally once daily every morning. 
8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
8.6 
Measures of Treatment Compliance 
Participants will be asked to keep a diary noting the day and date they take their study 
drug and any adverse events. They will be asked to bring their participant diary to each 
study visit along with all used and unused study drug containers. 
9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Visit 1 and at 
Visits 28.  Dose, route, unit frequency of administration, and indication for administration 
and dates of medication will be captured. 

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9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Visit 1. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Visit 1. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a sub-
investigator who is a physician at the initial visit. Qualified staff (MD, NP, RN, and PA) 
may complete the abbreviated physical exam at all other visits.  New abnormal physical 
exam findings must be documented and will be followed by a physician or other qualified 
staff at the next scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes on each scheduled visit. 
9.1.6 
Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to study 
drug will be recorded on the case report form (CRF). 
9.2 
     Clinical Laboratory Measurements 
9.2.1        Urinalysis 
Urine will be obtained and sent to each site’s clinical laboratory for determination of 
color, specific gravity, pH, protein, glucose, ketones, and blood 
Urine will be collected for ICP-OES assessment of sulfur.   
10 EVALUATIONS BY VISIT 
10.1 Visit 1 (Day 0) 
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, including a history of cystinuria, diagnosis date, and prior 
treatments. 
5. 
Record concomitant medications. 
6. 
Perform a complete physical examination. 
7. 
Perform and record vital signs. 
8. 
Perform and record results of blood pressure testing. 
9. 
Schedule subject for Visit 2 in 28 days. 

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10. 
Collect urinalysis. 
11. 
Collect freshly voided urine samples and obtain baseline analysis using mass 
spectrometry. 
12. 
Prescribe study drug and provide a participant diary. 
10.2 Visit 2 (Day 28) 
1. 
Record any Adverse Experiences and/or Review subject diary for adverse 
experiences and dosing compliance. 
2. 
Concomitant medications review. 
3. 
Perform abbreviated physical examination. 
4. 
Perform and record vital signs. 
5. 
Collect urinalysis. 
6. 
Collect freshly voided urine samples and obtain treatment analysis using mass 
spectrometry. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 

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Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  

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Adverse Reactions: Dapagliflozin 
The most common adverse reactions associated with dapagliflozin (5% or greater 
incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract 
infections.  Other reported adverse reactions include: 
• back pain 
• nausea 
• influenza 
• dyslipidemia 
• constipation 
• discomfort with urination 
• pain in the extremity 
• male genital mycotic infections 
• hypotension 
• ketoacidosis 
• acute kidney injury 
• 
Urosepsis and Pyelonephritis  
• 
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues  
• 
Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)  
 
11.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
11.3 Medical Monitoring 
Marshall Stoller, MD should be contacted directly at these numbers to report medical 
concerns or questions regarding safety. 
Phone: 415-353-8520 
Pager: 415 443-9138 
   
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation: 
• 
Subject withdrawal of consent  

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• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of 
the subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
• 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents. 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Visit 2) should have an early discontinuation 
visit.   
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
Subjects who withdraw from the study will be replaced.   
 
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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• 
Failure to meet inclusion/exclusion criteria 
• 
Use of a prohibited concomitant medication 
• 
Failure to orally intake prescribed dosage on a daily basis 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Investigator will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
 
14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
14.1 Data Sets Analyzed 
Data sets from all participants enrolled in the study will be analyzed. The primary efficacy 
endpoint will be assessed by medical history and physical exam, in addition to mass 
spectrometry data obtained at each study visit. 
14.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized: race, gender, age. 
14.3 Analysis of Primary Endpoint 
The primary endpoint will be analyzed through quantitative comparison between the 
baseline urine mass spectrometry analysis and the treatment urine mass spectrometry 
analysis. 
14.4  Interim Analysis 
When approximately 50% of patients have completed the study through Visit 2, an interim 
analysis for safety will be conducted. Serious adverse events will be monitored on an 
ongoing basis throughout the study. 
14.5  Sample Size and Randomization 
Sample size of ten was determined to be adequate for this proof-of-concept prospective 
cohort study. Future research will be considered with proper power and stronger statistical 
analysis if promising results from this study. 

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15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study drug.   
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  
15.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
15.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. The 
study database will be updated in accordance with the resolved queries.  All changes to 
the study database will be documented. 
15.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
15.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each subject must be maintained that includes 
the signed Informed Consent, HIPAA Authorization and Assent Form and copies of all 
source documentation related to that subject.  The Investigator must ensure the reliability 
and availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, etc.) must be kept 
secured for a period of two years following marketing of the investigational product or for 
two years after centers have been notified that the IND has been discontinued.  There may 

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be other circumstances for which the Sponsor is required to maintain study records and, 
therefore, the Sponsor should be contacted prior to removing study records for any reason. 
15.6 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to the 
U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6).    By signing 
this protocol, the Investigator grants permission to the Sponsor (or designee), and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation submitted 
to the Sponsor.  Additional subject confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
The study investigator will work with the study team to ensure that participants’ privacy 
and information is protected. They both have access to experienced clinical trials offices 
and expertise in conducting clinical research similar to the one proposed in this 
application, ensuring that safe and ethical practices will be followed.  
 
Physical risk will be minimized by the study design since routine clinical care will not be 
altered with inclusion in this study. All health-system source/legacy data files will be 
stored at the UCSF local health system and will be accessed only by the 
programmers/analysts working on this study. Since confidential information will be 
collected from the medical charts, we will not directly link personal identifiers with the 
data collected nor will we use personal identifiers in any reports, materials, or 
presentations that emanate from this work.  
 
All electronic files containing personal identifiers will be stored only on the UCSF site file 
servers located behind a firewall. Information transferred to the server for backup 
purposes will be done via secure ftp. Files may be transferred to other computers 
temporarily via the Internet to facilitate central upload. In these circumstances, the files 
will be protected by encryption. The UCSF site file servers are only accessible by network 
support specialists working in secure locations. The on-site file server will be 
electronically accessible only to study investigators through user password protection.  
 
Access to study data is protected and participant to the same security protections as other 
confidential health system data. Computer passwords are changed on a regular basis. 
Individual identifiers such as names and medical record numbers will be removed from 
study data files in the data processing steps and will not be accessible to collaborators 
accessing the database for further study as described in this study application. The 
participating collaborators will maintain a data link from the study data but not to the 
personal identifiers (to permit reanalysis of the data files). In addition, all investigators 
and support staff involved with collection or entry of clinical data are HIPAA certified 
and have completed and are current with regard to IRB training. Investigators and project 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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staff will sign confidentiality pledges annually HIPAA training annually. Datasets shared 
with external collaborators will be stripped of any identifying information according to 
HIPAA policy. 
 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
16.1 Protocol Amendments 
Protocol amendments cannot be implemented without prior written IRB/IEC approval 
except as necessary to eliminate immediate safety hazards to patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRBs are notified within five working days. 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated. This approval must refer to the study by exact protocol title 
and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   

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The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
16.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
16.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 

SGLT2-02, Marshall Stoller , MD                                                                                       
 
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4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 

SGLT2-02, Marshall Stoller , MD                                                                                 
 
 
 
 
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APPENDIX 1.  
 
VISIT 1 
(Day 0) 
VISIT 2 
(Day 28) 
Informed Consent 
X 
 
Medical History 
X 
 
Complete Physical Exam 
X 
 
Abbreviated Physical Exam 
 
X 
Height  
X 
X 
Weight  
X 
X 
Vital Signs  
X 
X 
Urinalysis 
X 
X 
Dispensing or Administration of 
Study Drug 
X 
 
Counting of Returned Study Drug 
 
X 
Initiate Subject Diary 
X 
 
Subject Diary Review 
 
X 
Concomitant Medication Review 
X 
X 
Adverse Experiences 
 
X 
Mass Spectrometry Analysis 
X 
X 

SGLT2-02, Marshall Stoller, MD                                                                                 
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