Conditions: Type II; Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
To determine the role of plasma glucagon and insulin in the rise of endogenous glucose production (EGP) following the SGLT2 inhibition.

Detailed description:
The increase in plasma glucagon conc and/or decrease in plasma insulin conc in response to glucosuria is (are) important signal(s) responsible, at least in part, for the increase in EGP, which the investigators anticipate will be derived primarily from the liver. Insulin and glucagon are powerful regulators of HGP. Therefore, the investigators anticipate that, at least in part, an increase in HGP secondary to the rise in plasma glucagon concentration and decrease in plasma insulin concentration in response to dapagliflozin-induced glucosuria will account for the majority of increase in EGP in both NGT and T2DM subjects. This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Eligible subjects will receive three 5-hour measurements of endogenous glucose production (EGP), which is the biosynthesis of new glucose, with administration of study drug after a 3-hour tracer equilibration period. Hepatic glucose production (HGP), which is the net release of glucose from the liver, will be measured for 5 hours after drug administration to allow sufficient time for a significant increase in HGP above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for 5 hours after dapagliflozin (10 mg) or placebo administration. This is the control study. The investigators expect to observe the "paradoxical" rise in EGP following dapagliflozin. Study 2 will be performed under glucose clamp conditions (i.e. maintaining the plasma glucose concentration stable at each subject's fasting level). This study will define whether the decline in plasma glucose concentration is the trigger to stimulate EGP. Study 3 will be performed under pancreatic clamp conditions (maintaining the plasma glucagon and insulin concentrations constant at the basal level). This study will define whether the increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP. Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16 subjects will receive placebo. Each study will be performed on a separate day, after a 10-12 hour overnight fast within 1-2 week period. Following studies 1-3, subjects will return for a renal (kidney) MRI-measurement to record kidney size.

Arms:
arm 1: 32 subjects will receive dapagliflozin 10mg arm 2: 16 subjects will receive placebo

Interventions: intervention 1: Dapagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Three 5-hour measurements (after dapagliflozin 10mg administration) of endogenous glucose production (EGP) will be performed on separate days. intervention 2: Three 5-hour measurements (after placebo administration) of endogenous glucose production (EGP) will be performed on separate days.

Protocol document:
Prot_SAP_000.pdf: 
 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
1 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: Paradoxical Stimulation of Hepatic Glucose                 
Production with Dapagliflozin 
 
 
NCT number:   
NCT02984644 
 
 
IRB Approval Date: 09/18/2017 
 
 
Unique Protocol ID: HSC20160586H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
2 
Paradoxical Stimulation of Hepatic Glucose Production with Dapagliflozin (P2). 
Subjects: 48 T2DM subjects (age = 18-70 years; BMI = 21-45 kg/m2; males or females) according to ADA 
criteria. Subjects taking drugs known to affect glucose metabolism (other than metformin and sulfonylurea) will 
be excluded. Other than diabetes, subjects must be in good general health as determined by physical exam, 
medical history, blood chemistries, CBC, TSH, T4, EKG and urinanalysis. Only subjects whose body weight 
has been stable (± 3 lbs) over the preceding three months and who do not participate in an excessively heavy 
exercise program will be included.  Individuals with evidence of proliferative diabetic retinopathy, plasma 
creatinine >1.4 females or >1.5 males, or 24-hour urine albumin excretion > 300 mg will be excluded.  Diabetic 
subjects will be recruited from the South Texas Veterans Health Care System and Texas Diabetes Institute 
(TDI) in San Antonio (Deputy Director = Ralph A. DeFronzo, MD). TDI is the largest institute in the United 
States that provides comprehensive care for ~ 10,000 unduplicated T2DM patients. Therefore, we do not 
anticipate any problem in recruiting the required number of patients for this study. 
Study Design: After screening, eligible subjects will receive three 5-hour measurements of endogenous 
glucose production (EGP), which is the biosynthesis of new glucose, with administration of study drug after a 
3-hour tracer equilibration period. Hepatic glucose production (HGP), which is the net release of glucose from 
the liver, will be measured for 5 hours after drug administration to allow sufficient time for a significant increase 
in HGP above baseline after dapagliflozin administration (10). In study 1, HGP will be measured for 5 hours 
after dapagliflozin (10 mg) or placebo administration. This is the control study.  We expect to observe the 
“paradoxical” rise in EGP following dapagliflozin as described in the data section.  Study 2 will be 
performed under glucose clamp conditions (i.e. maintaining the plasma glucose concentration stable at each 
subject’s fasting level).  This study will define whether the decline in plasma glucose concentration is the 
trigger to stimulate EGP.  Study 3 will be performed under pancreatic clamp conditions (maintaining the 
plasma glucagon and insulin concentrations constant at the basal level). This study will define whether the 
increase in plasma glucagon and/or the decrease in plasma insulin are the trigger to stimulate EGP.  
Subjects will be randomized in a 2:1 ratio; 32 subjects will receive dapagliflozin and 16 subjects will receive 
placebo. Each study will be performed on a separate day, after a 10-12 hour overnight fast within 1-2 week 
period.  Following studies 1-3, subjects will return for a renal (kidney) MRI-measurement to record kidney size. 
Screening Visit.  Medical history is obtained and physical exam performed. Blood is drawn for FPG, blood 
chemistries, lipid profile, HbA1c, and thyroid function. Urine analysis, EKG and pregnancy test are performed. 
Study 1: Effect of Dapagliflozin on EGP: EGP will be measured with 3-3H-glucose infusion. The 3-3H-
glucose infusion will be started at 6 AM and arterialized blood samples will be drawn from a catheter placed 
retrogradely in a vein on the dorsum of the hand to measure the basal rate of EGP.  The hand will be placed in 
a box heated to 50-60°C (122-140°F) to ensure arterialization of the venous blood.  After a 3 hour tracer 
equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or placebo, and blood samples will be 
drawn every 20 minutes for 5 hours (until 2 PM) for the measurement of plasma glucose, insulin, C-peptide, 
glucagon, cortisol, catecholamine concentrations and [3-3H]-glucose specific activity. The total amount of blood 
taken during this time is 266 ml or 18 tablespoons. Urine will be collected from 6 to 9 AM and from 9 AM to 2 
PM. Urinary volume and glucose conc will be measured and the rate of urinary glucose excretion quantitated. 
The study will end at 2 PM and subjects will be allowed to return home.  
Study 2: Effect of Dapagliflozin on EGP With Glucose Clamp: EGP will be measured with 3-3H-glucose 
infusion as described in Study 1 above. The 3-3H-glucose infusion will be started at 6 AM to measure the basal 
rate of EGP. After a 3 hour tracer equilibration period (at 9 AM) subjects will receive dapagliflozin (10 mg) or 
placebo, and the plasma glucose conc will be measured every 5 minutes for 5 hours (from 9AM to 2 PM). A 
variable infusion of 20% dextrose will be adjusted to clamp the plasma glucose conc at the fasting level (+5%) 
until the end of the study (5 PM). Blood samples will be drawn every 20 minutes for 5 hours (2 PM) for the 
measurement of plasma glucose, insulin, C-peptide, glucagon, cortisol, catecholamine concentrations and [3-
3H]-glucose specific activity. The total amount of blood taken during this time is about 296 ml or 20 
tablespoons. Urine will be collected from 6 to 9 AM and from 9 AM to 2 PM. Urinary volume and glucose 
concentration will be measured and the rate of urinary glucose excretion quantitated. The study will end at 2 
PM and subjects will be allowed to return home. Subjects will be asked to collect a 24- Hour Urine Collection to 
determine creatinine excretion.  
Study 3: Effect of Dapagliflozin on EGP with Pancreatic Clamp: In this study, EGP will be measured as 
described in Study 1 above and plasma insulin and glucagon concentrations will be clamped at the basal level 
using the pancreatic clamp technique (17,62), while the plasma glucose concentration will be allowed to 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
3 
decrease spontaneously after dapagliflozin and placebo administration. Somatostatin (750 µg/h) infusion will 
be started at 5:45 AM (15 minutes before the start of [3-3H]-glucose infusion [6 AM]) along with basal infusions 
of glucagon (0.3 ng/kg.min) and insulin (0.1 mU/kg.min) to replace basal plasma glucagon and insulin 
concentrations. The somatostatin, glucagon, and insulin infusions will be continued for the entire duration of 
the study (until 2 PM). At 6 AM a prime (0.4 uCi x FPG) – continuous (0.4 uCi/min) infusion of [3-3H]-glucose 
will be started and continued to 2 PM. At 9AM, subjects will ingest dapagliflozin (10 mg) or placebo (2:1 
randomization ratio) and blood samples will be drawn at -30, -20, -10, 5 and 0 minutes before and every 20 
minutes after drug administration (until 2 PM) for the measurement of plasma glucose, insulin, C-peptide, 
glucagon, cortisol, catecholamine concentrations, and plasma [3-3H]-glucose specific activity. The total amount 
of blood taken during this time is about 266 ml or 18 tablespoons. Urine will be collected from 6 to 9 AM and 
from 9 AM to 2 PM. Urinary volume and glucose concentration will be measured and the rate of urinary 
glucose excretion will be calculated. The study will end at 2 PM. 
Study 4: Renal (Kidney) MRI: A renal MRI will be performed on subjects for the measurement of kidney size. 
Before entering the MRI scanner, the subject will be surveyed for magnetic articles on his/her person or 
clothing and briefed regarding the safety requirements of the MRI study.   
Data Analysis and Statistical Methods:  Under steady-state postabsorptive conditions, the basal rate of 
endogenous glucose appearance (Ra = bEGP) equals the 3-3H-glucose infusion rate divided by steady state 
plasma tritiated glucose specific activity. After drug administration, non-steady conditions for 3-3H-glucose 
specific activity prevail and the rate whole body of glucose appearance (Ra) is calculated from Steele’s 
equation (57). During the glucose clamp study, the rate of EGP after drug administration equals Ra minus 
glucose infusion rate, while, during the pancreatic clamp, Ra = EGP since no cold glucose is infused. The 
difference in EGP during the last hour of the study (240-300 minute) between subjects receiving dapagliflzin 
and subjects receiving placebo represents the increase in EGP caused by dapagliflozin (glucosuria-stimulated 
increase in EGP). The glucosuria-stimulated increase in EGP will be compared among the three studies with 
ANOVA. Post hoc testing will be performed with a Bonferroni correction for multiple comparisons. Only 
subjects who complete all three protocols will be analyzed. The difference in glucosuria-stimulated 
increase in EGP between study 2 and study 1 represents the contribution of the decrease in plasma 
glucose conc to the increase in EGP, while the difference between study 3 and study 1 represents the 
contribution of change in islet hormones (insulin/glucagon) to the increase in EGP. 
Anticipated Results and Potential Limitations.  We believe that the increase in plasma glucagon conc 
and/or decrease in plasma insulin conc in response to glucosuria is (are) important signal(s) responsible, at 
least in part, for the increase in EGP, which we anticipate will be derived primarily from the liver. Insulin and 
glucagon are powerful regulators of HGP. Therefore, we anticipate that, at least in part, an increase in HGP 
secondary to the rise in plasma glucagon concentration and decrease in plasma insulin concentration in 
response to dapagliflozin-induced glucosuria will account for the majority of increase in EGP in both NGT and 
T2DM subjects (to be explored in Protocol HSC20160596H).. Because the decrease in FPG conc in our 
published study (10) was comparable in dapgliflozin-treated and placebo-treated individuals, while the increase 
in plasma glucagon conc occurred only in dapagliflozin-treated subjects (Figure 2), we believe that the 
decrease in the FPG brought about by dapagliflozin plays only a minor (if any) role in triggering the increase in 
glucagon secretion and EGP. Moreover, previous studies with dapagliflozin in NGT subjects have reported no 
change in FPG following 2-weeks of treatment with dapagliflozin (55,56). Although EGP was not measured in 
these studies (58,59), glucose production had to increase following dapagliflozin to match the 72 grams of 
glucosuria and maintain the plasma glucose conc constant at the basal level.  Based upon these observations, 
we believe that a decrease in peripheral plasma glucose conc plays very little direct or indirect (via stimulation 
of glucagon secretion and decrease in insulin secretion) role in the glucosuria-induced increase in EGP. 
Measurement of glucose production under glucose clamp conditions (Study 2) will provide a definitive answer 
to this question. Thus, we anticipate that the increase in plasma glucagon, decrease in plasma insulin, and 
increase in EGP will take place despite clamping plasma glucose conc at the fasting level in T2DM subjects. 
 
We anticipate that clamping the pancreatic hormones (glucagon and insulin) with somatostatin in T2DM 
(Study 3) will prevent, in part, the increase in EGP/HGP. We believe that, under these pancreatic clamp 
conditions, the decrease in plasma glucose conc produced by dapagliflozin will be greater than the decrease 
observed without the pancreatic clamp (study 1). If this scenario is correct, the clinical implications would be 
enormous. If the rise in EGP following dapagliflozin-induced glucosuria can be prevented by inhibition of 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
4 
glucagon and stimulation of insulin secretion, the decrease in plasma glucose conc and HbA1c could be 
greatly amplified by concomitant administration of a GLP-1 receptor agonist to inhibit the increase in EGP. 
 
Recently, SGLT2 receptors have been identified on the alpha cell and addition of a SGLT2 inhibitor to 
cultured alpha cells resulted in an increase in glucagon secretion (55).  Although this, in part, could explain the 
increase in plasma glucagon secretion, as discussed below, we believe that other mechanisms also must 
contribute to the stimulation of glucagon secretion. 
 
The mechanism by which glucosuria stimulates glucagon secretion is not clear. Although it is possible 
that the decrease in fasting plasma glucose conc results in inhibition of insulin secretion and stimulation of 
glucagon secretion, we believe that this is an unlikely scenario. Another possible mechanism responsible for 
the increase in glucagon secretion is a neural reflex which is activated by glucosuria and involves the CNS. 
Thus, the glucosuria produced by inhibiting SGLT2 with dapagliflozin results in a decreased return of glucose 
from the tubular lumen to the renal vein. This will result in a widening of the glucose A-V difference between 
renal artery and renal vein. Since dapagliflozin inhibits the reuptake of ~50% of the filtered glucose (47), the 
plasma glucose conc in the renal vein will be at least ~10% lower than that in the renal artery. In PROTOCOL 
11038 (HSC20160596H), we will measure the effect of dapagliflozin on the renal A-V glucose conc difference. 
A widening of the A-V glucose conc difference could provide a neural stimulus to the brain (independent of any 
change in plasma glucose conc) and (i) stimulate glucagon secretion, (ii) inhibit insulin secretion, and/or (iii) 
directly stimulate HGP, independent of changes in plasma glucagon or insulin, to compensate for the urinary 
glucose loss. A temporal relationship between the magnitude of renal glucose A-V difference and the increase 
in plasma glucagon/decrease in plasma insulin conc or increase in EGP (measured in PROTOCOL 11038) will 
support this hypothesis. Although the existence of such an A-V glucose signal across the kidney never has 
been demonstrated, a similar A-V glucose conc difference between the hepatic artery and portal vein has been 
shown to activate a neural reflex that plays an important role in the regulation of hepatic glucose production 
and uptake (6,60,61). If the pancreatic clamp study prevents the paradoxical rise in EGP, this will 
provide strong evidence for an important role of glucagon (increased) and/or insulin (decreased) 
secretion in the stimulation of EGP.  The specific contribution of change in plasma concentration of 
each hormone (increase in glucagon versus decrease in insulin) to the increase in EGP will be 
examined in a separate set of studies by clamping each hormone (glucagon alone and insulin alone) 
individually. 
Sample Size Calculation: The mean difference in EGP during the last hour of EGP measurement in 
dapagliflozin-treated and placebo-treated subjects was 0.70±0.34 (mean+SD) (10). To detect a 50% decrease 
in this difference at alpha <0.05 during the glucose clamp (Study 2) or during the pancreatic clamp (Study 3) 
with 90% power and alpha =0.05, we computed that 48 subjects, 32 dapagliflozin-treated and 16 placebo 
treated are required at 2:1 randomization. Therefore, we have set the sample size at 50 to account for drop 
outs since subjects must complete all three studies to be included in the data analysis. 
Risk/Benefit 
Potential risks include the following:  
a) 
Blood withdrawal.  All studies involve the withdrawal of blood.  Total blood drawn during the 
study will not exceed 500 ml, or one pint of blood over a 4 week period.  We do not believe that 
this amount of blood loss will pose any risk to the subject’s health. Subjects will be questioned 
about their history of blood donation and subjects who have donated blood in the previous two 
months will not be studied. The subjects will be told that they should not donate blood for two 
months after the study.  Blood hematocrit will be measured in every subject during the 
screening visit and any subject with a hematocrit of less than 34% will not be studied.   
b) 
IV lines.  Catheters will be placed in an anticubital vein and a hand vein for the measurement of 
glucose production.  Local hematomas occur in about 1% of catheterization.  Infection is 
possible (<1%), but we have not experienced this complications.  One instance of 
thrombophlebitis has been observed (<0.1%).  The hand with the catheter will be placed in a 
warm (65oC) transparent plastic box to arterialize venous blood.  We have observed one 
instance of skin burning (2nd degree) using the heated box (<0.01%).  Subjects will be informed 
to tell us if their hand feels excessively warm or uncomfortable. 
c) 
Tritiated glucose is given during these studies.  The radiation exposure from tritiated glucose is 
well within guidelines (Shreve WW et al. Proc 2nd International Conference on Peaceful Uses of 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
5 
Atomic Energy, Geneva, 1958; U.S. Department of Commerce National Bureau of Standards 
Handbook 69, 1969).  The cumulative radiation exposure also is well within the dose range 
(1,000 µCi) approved by the University of Texas Health Science Center Radiation Committee.  
The Radiation Safety Committee will approve these studies before anyone is enrolled.  At these 
low exposures, risk is minimal. 
d) 
The procedures for minimizing risk are listed above in context with the specific risks.   
e) 
Information learned about all subjects will be kept confidential and handled in strict accordance 
with HIPAA guidelines.  Subjects will not be identified in any way in any publication. With the 
precautions outlined above, the risk/benefit ratio in the study is very low. 
f) 
Serious hypersensitivity reactions to dapagliflozin have been described.  Anyone with a history 
of hypersensitivity reaction to dapagliflozin will be excluded. 
g) 
Diabetic subjects with severe renal impairment (eGFR < 45 ml/min), end-stage renal disease, or 
dialysis will be excluded. 
h) 
Subjects with uncontrolled hypertension (BP > 160/100 mmHg) will be excluded; subjects with 
orthostatic hypotension (decrease in BP > 15/10 mmHg) when standing will be excluded. 
i) 
Ketoacidosis  
The U.S. Food and Drug Administration (FDA) has warned that dapagliflozin may lead to ketoacidosis, 
a serious condition where the body produces high levels of blood acids called ketones that may require 
hospitalization. 
Patients will be asked to pay close attention for any signs of ketoacidosis and call us immediately if they 
experience symptoms such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and 
unusual fatigue or sleepiness. We will evaluate for the presence of acidosis, including ketoacidosis in 
patients experiencing these signs or symptoms and discontinue dapagliflozin if acidosis is confirmed 
and take appropriate measures to correct the acidosis and monitor sugar levels. 
j) 
Urosepsis and Pyelonephritis  
Rarely, dapagliflozin treatment has been associated with bladder and kidney infection.  If you 
experience pain or burning urination, pass cloudy or blood-tinged urine, or experience fever and chills, 
please call us immediately so that we can examine your urine and obtain a urine culture. 
We also identified 19 cases of life-threatening blood infections (urosepsis) and kidney infections 
(pyelonephritis) that started as urinary tract infections with the SGLT2 inhibitors reported to FAERS 
from March 2013 through October 2014.  All 19 patients were hospitalized, and a few required 
admission to an intensive care unit or dialysis in order to treat kidney failure. 
k) 
Hypoglycemia may occur with dapagliflozin, especially when dapagliflozin is given in 
combination with a sulfonylurea or insulin.  During the study we will measure your blood glucose 
level frequently to prevent this complication. 
l) 
Genital mycotic (fungal) infections may occur in individuals who take dapagliflozin.  They occur 
in about 6-8% of females and 1-2% of males.  If you have any genital discomfort (itching, 
burning, discharge), please let us know so that we can give you something to treat the infection. 
m) 
Dapagliflozin can cause an increase in the LDL cholesterol.  We will check your LDL cholesterol 
and if it is greater than 120 mg/dl you will not be able to take part in the present study. 
n) 
If you have a history of bladder cancer or currently have bladder cancer, please let us know, 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
6 
since individuals with bladder cancer are excluded from the study. 
 
Based upon the above considerations, the benefit (knowledge to be gained) to risk ratio is very favorable. 
Safety 
Definition of adverse events  
An adverse event is the development of an undesirable medical condition or the deterioration of a pre-existing 
medical condition following or during exposure to a pharmaceutical product, whether or not considered 
causally related to the product.   
The term AE is used to include both serious and non-serious AEs. 
Definitions of serious adverse event 
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
Results in death 
Is immediately life-threatening 
Requires in-patient hospitalization or prolongation of existing hospitalization  
Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal 
life functions 
Is a congenital abnormality or birth defect 
Is an important medical event that may jeopardize the subject or may require medical intervention to prevent 
one of the outcomes listed above 
The causality of SAEs (their relationship to all study treatment) will be assessed by the investigator(s) and 
communicated to AstraZeneca (AZ). 
Recording of adverse events 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last AE assessment at the end of the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF. AstraZeneca retains 
the right to request additional information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. 
 
 
The following variables will be collected for each AE: 
AE (verbatim) 
The date and time when the AE started and stopped 
Whether the AE is serious or not 
Investigator causality rating against the Investigational Product (yes or no) 
Action taken with regard to investigational product: (AE caused subject’s withdrawal from study (yes or no) 
Outcome 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
7 
In addition, the following variables will be collected for SAEs: 
Date AE met criteria for serious AE 
Date Investigator became aware of serious AE 
Date of hospitalization 
Date of discharge 
Probable cause of death 
Date of death 
Autopsy performed 
Causality assessment in relation to Study drug(s) 
Causality assessment in relation to Other medication 
Causality assessment in relation to Additional Study Drugs 
Description of AE. 
Causality assessment: 
The Investigator will assess causal relationship between Investigational Product and each Adverse Event, 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?’ 
For SAEs, a causal relationship will also be assessed for other concomitant medications, study procedures, 
and comparator study drugs.  Note that for SAEs that could be associated with any study procedure 
the causal relationship is implied as ‘yes’. 
Reporting of serious adverse events  
Investigators will inform the IRB of the UTHSCSA within 24 hours of any adverse events.  Investigators and 
other site personnel will inform the FDA, via a MedWatch/AdEERs form, of any serious or unexpected adverse 
events that occur in accordance with the reporting obligations and will concurrently forward all such reports to 
AZ.  A copy of the MedWatch/AdEERs report will be faxed to AZ at the time the event is reported to the FDA.  
It is the responsibility of the investigator to compile all necessary information and ensure that the FDA receives 
a report according to the FDA reporting requirement timelines and to ensure that these reports are also 
submitted to AZ at the same time. 
When reporting to AZ, a cover page will accompany the MedWatch/AdEERs form indicating the following: 
Investigator Sponsored Study (ISS)  
The investigator’s name and address 
The trial name/title and AZ ISS reference number 
Investigative site will also indicate, either in the SAE report or in the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined by the (PI). 
The SAE report and accompanying cover page will be sent by way of fax to AZ’s designated fax line: 1-302-
886-4114 or via email: AEMailboxClinicalTrialTCS@astrazeneca.com. 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
8 
Serious adverse events that do not require expedited reporting to the FDA will be reported to AZ using the 
MedDRA coding language for serious adverse events.   
In the case of blinded trials, AZ will request that the Sponsor either provide a copy of the randomization 
code/code break information or unblind those SAEs which require expedited reporting. 
All SAEs will be reported to AZ, whether or not considered causally related to the investigational product.  All 
SAEs will be documented.  The investigator will be responsible for informing the WCMC-Institutional Review 
Board (IRB) of the SAE.  
Safety assessments 
 Safety assessments will consist of monitoring and recording all TEAEs, SAEs, AEs leading to 
discontinuation/withdrawal from study, laboratory evaluation for hematology, blood chemistry, and urine values; 
pregnancy testing; measurement of vital signs and ECGs; and performance of physical examinations. 
 
AstraZeneca is the manufacturer of the study drug/medication. 
Label, storage and distribution are a sponsor’s responsibility.   
 
Investigational products  
 
Description or Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
 
 
 
Dapagliflozin 10 mg 
Green, plain, diamond shaped, film coated 10 mg 
tablet 
AstraZeneca 
Matching placebo for 
dapagliflozin  10 mg 
Green, plain, diamond shaped, film coated  tablet AstraZeneca 
 
 
 
The tablets contain lactose, which may cause discomfort in lactose-intolerant individuals. 
Dapagliflozin and its matching placebo will be supplied in bottles. 
 
Labeling 
The sponsors will label the study medication in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines for labeling (the labels will fulfill GMP Annex 13 requirements for labeling).   
 
Storage    
All study drugs should be kept in a secure place under appropriate storage conditions. The investigational 
product label on the bottle specifies the appropriate storage. 
 
    
 
 
 
 


 
16-586H, Cersosimo, Protocol, 09-18-17, AMD 
9 
 
P2 Flow Sheet 
 
Time (min)  
Glucose 
3-H-glucose 
Insulin 
C-peptide 
Glucagon Cortisol/NE/Epi 
-180 
X 
X 
 
 
 
 
-30 
X 
X 
 
 
 
 
-20 
X 
X 
X 
X 
X 
X 
-10 
X 
X 
X 
X 
X 
X 
-5 
X 
X 
 
 
 
 
0 
X 
X 
X 
X 
X 
X 
 
Administer 
Drug 
Dapa or 
Placebo 
 
 
10 
X 
X 
X 
X 
X 
 
20 
X 
X 
X 
X 
X 
X 
30 
X 
X 
X 
X 
X 
 
40 
X 
X 
X 
X 
X 
X 
50 
X 
X 
X 
X 
X 
 
60 
X 
X 
X 
X 
X 
X 
75 
X 
X 
X 
X 
X 
 
90 
X 
X 
X 
X 
X 
X 
105 
X 
X 
X 
X 
X 
 
120 
X 
X 
X 
X 
X 
X 
140 
X 
X 
X 
X 
X 
 
160 
X 
X 
X 
X 
X 
 
180 
X 
X 
X 
X 
X 
X 
200 
X 
X 
X 
X 
X 
 
220 
X 
X 
X 
X 
X 
 
240 
X 
X 
X 
X 
X 
X 
260 
X 
X 
X 
X 
X 
 
280 
X 
X 
X 
X 
X 
 
285 
X 
X 
 
 
 
 
290 
X 
X 
X 
X 
X 
 
295 
X 
X 
 
 
 
 
300 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Number  
28 
28 
23 
23 
2311 
Volume (ml) 
14 
56 
46 
46 
 
44 
 
Total blood loss = 252 ml