Conditions: Type2 Diabetes Cardiovascular Diseases
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 45
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of dapagliflozin, a FDA approved diabetes medication, on measures of nervous system function of the heart in patients with type 2 diabetes. The investigators will compare the effect of dapagliflozin with an active comparator, glimepiride (a different FDA approved diabetes medication) on measures of heart rate variability and assess whether dapagliflozin has modulating effects on measures of nervous system function of the heart. This is a crossover study design where all participants will receive both study medications equally (12-week intervention periods) in a certain order.

Detailed description:
Study rationale: Empagliflozin and dapagliflozin are sodium-glucose transporter-2 (SGLT-2) inhibitors which prevent the reabsorption of glucose via proximal renal tubules, and are the most recently approved class for treating hyperglycemia in type 2 diabetes. Besides effective glucose lowering effects as documented by \~ 0.7-1.2% HbA1c reduction, these agents also promote weight loss and reduce blood pressure (BP). Furthermore, recent data from the Empagliflozin Cardiovascular Outcome Trial in type 2 diabetes (EMPA-REG OUTCOME) reported significant reduction in main cardiovascular disease (CVD) outcomes and CVD death in patients with type 2 diabetes (T2D). The exact mechanism of the beneficial effects on cardiovascular outcomes is not yet understood, although their effects on body weight, glucose control and BP reduction were suggested. However, other classes of drugs with similar effects such as GLP-1 receptor agonist, thiazolidinedione did not clearly show the beneficial effects in CVD outcomes. The interesting observation is that improvement in BP with SGLT-2 inhibitors occurred without a compensatory increase in HR and that most benefit was obtained also in patients with some evidence of heart failure.

Thus, the investigators postulated the hypothesis that SGLT-2 may also have a modulatory effect on the sympathetic/parasympathetic balance, and this may contribute to the potential benefits on cardiovascular outcomes in patients with diabetes.

Study Design: The investigators plan to test this hypothesis in a randomized, double-blind, 2-period crossover clinical trial comparing 12-weeks of glycemic intervention with dapagliflozin versus glimepiride. The investigators include an active comparator with glimepiride which have a similar glucose lowering in patients with T2D, to account for the effects of reductions in blood glucose on measures of CAN, and will evaluate whether changes in measures of CAN are different among patients who are taking glimepiride or dapagliflozin. The two crossover periods will be separated by a 2-week wash-out period.

All subjects will be allocated and randomized to each treatment sequence. Participants will receive blindly either dapagliflozin 5 mg or glimepiride 2 mg 1 tablet daily initially for 4 weeks then titrating the dose based on blood glucose levels up to 2 tablets daily for 8 more weeks (total 12 weeks) followed by 2-week washout period and then they will receive the study drugs in reverse order to the first period during second crossover period for 12 weeks.

Study population: 45 patients with T2D on background metformin monotherapy who are not meeting ADA recommended glycemic target.

Primary outcomes: changes in measures of cardiovascular autonomic neuropathy such as heart rate variability (HRV) as defined by frequency domain measures of HRV: low frequency (LF) power (ms2); high frequency (HF) power (ms2) as measured as LF:HF ratio.

Secondary outcomes: (i) changes in measures of HRV as defined by time domain measures of HRV: standard deviation of the normal RR interval (SDNN) (msec) and root mean square of the differences of successive RR intervals (rmsSD) (msec); (ii) changes in cardiovascular autonomic reflex tests (CARTs) as defined by: expiration/inspiration (E/I) ratio, Valsalva ratio, and 30:15 ratio; (iii) changes in measures of systolic and diastolic function will be assessed by using stress echocardiogram and evaluate the following measures: i) LVEF, ii) LV end diastolic volume, iii) LV end systolic volume, iv) LV mass, v) cardiac output.

Arms:
arm 1: Participants will take open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. arm 2: Participants will take open-label glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose monitoring for a total of 12 weeks on glimepiride. Patients will then begin a 2 week washout period where they are not taking any study drugs. After the washout period, participants will receive open-label dapagliflozin 5 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg daily as needed based on their glucose monitoring for a total of 12 weeks on dapagliflozin.

Interventions: intervention 1: Dapagliflozin intervention 2: Glimepiride
Intervention descriptions: intervention 1: Dapagliflozin is a sodium glucose transporter-2 (SGLT-2) inhibitor, a new class of glucose lowering agent that reduces hyperglycemia in patients with T2D by reducing renal glucose reabsorption. intervention 2: Glimepiride is a sulfonylurea agent that reduces hyperglycemia in patients with T2D by stimulating insulin release from the pancreatic beta cells and reduction of glucose output from the liver.

Protocol document:
Prot_SAP_000.pdf: 
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Drug Substance 
Dapagliflozin 
Study Number 
ISS Number ESR-15-11724 
Version Number 
3.3 
Date 
Day Month Year  
10/03/2017 
Study Title: Dapagliflozin and Measures of Cardiovascular Autonomic 
Function in Patients with Type 2 Diabetes (T2D) 
Sponsor: AstraZeneca 
NCT02973477 
 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 6 
1. 
INTRODUCTION ................................................................................................... 9 
1.1 
Background .............................................................................................................. 9 
1.2 
Research hypothesis ............................................................................................... 10 
1.3 
Rationale for conducting this study ....................................................................... 10 
1.4 
Benefit/risk and ethical assessment........................................................................ 11 
2. 
STUDY OBJECTIVES .......................................................................................... 13 
2.1 
Primary objective ................................................................................................... 13 
2.2 
Secondary objectives ............................................................................................. 13 
2.3 
Safety objective ...................................................................................................... 13 
2.4 
Exploratory objectives ........................................................................................... 14 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 14 
3.1 
Overall study design and flow chart ...................................................................... 14 
3.2 
Rationale for study design, doses and control groups ............................................ 17 
4. 
SUBJECT SELECTION CRITERIA .................................................................... 17 
4.1 
Inclusion criteria .................................................................................................... 17 
4.2 
Exclusion criteria ................................................................................................... 18 
5. 
STUDY CONDUCT .............................................................................................. 19 
5.1 
Restrictions during the study ................................................................................. 19 
5.2 
Subject enrollment and randomization and initiation of investigational 
product ................................................................................................................... 19 
5.2.1 
Procedures for randomization ................................................................................ 19           
5.2.2        Study Visits ............................................................................................................ 20 
5.2.3        Assessments  ........................................................................................................... 23 
5.3 
Procedures for handling subjects incorrectly enrolled  or randomized or 
initiated on investigational product ........................................................................ 24 
5.4 
Blinding and procedures for unblinding the study ................................................. 25 
5.4.1 
Methods for ensuring blinding ............................................................................... 25 
5.4.2 
Methods for unblinding the study .......................................................................... 25 


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5.5 
Treatments .............................................................................................................. 25 
5.5.1 
Identity of investigational product(s) ..................................................................... 25 
5.5.2 
Doses and treatment regimens ............................................................................... 25 
5.5.3 
Additional study drug ............................................................................................ 25 
5.5.4 
Labeling ................................................................................................................. 26 
5.5.5 
Storage ................................................................................................................... 26 
5.6 
Concomitant and post-study treatment(s) .............................................................. 26 
5.7 
Treatment compliance ............................................................................................ 26 
5.7.1 
Accountability ........................................................................................................ 27 
5.8 
Discontinuation of investigational product ............................................................ 27 
5.8.1 
Procedures for discontinuation of a subject from investigational product ............ 27 
5.9 
Withdrawal from study .......................................................................................... 27 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 28 
6.1 
Recording of data ................................................................................................... 29 
6.2 
Data collection at enrollment and follow-up ......................................................... 29 
6.2.1 
Enrollment procedures ........................................................................................... 29 
6.2.2 
Follow-up procedures ............................................................................................ 30 
6.3 
Efficacy .................................................................................................................. 30 
6.3.1 
Efficacy variable .................................................................................................... 30 
6.4 
Safety ..................................................................................................................... 30 
6.4.1 
Definition of adverse events .................................................................................. 30 
6.4.2 
Definitions of serious adverse event ...................................................................... 31 
6.4.3 
Recording of adverse events .................................................................................. 31 
6.4.4 
Reporting of serious adverse events....................................................................... 33 
6.4.5 
Laboratory safety assessment ................................................................................ 34 
6.4.6 
Physical examination ............................................................................................. 34 
6.4.7 
ECG ........................................................................................................................ 34 
6.4.7.1 
Resting 12-lead ECG ............................................................................................. 35 
6.4.7.2 
Real time display (telemetry) ................................................................................. 35 
6.4.8 
Vital signs .............................................................................................................. 35 
6.4.8.1 
Pulse and blood pressure ........................................................................................ 35 
6.4.8.2 
Body temperature ................................................................................................... 35 
6.4.9 
Other safety assessments ........................................................................................ 35 
6.5 
Patient reported outcomes (PRO) .......................................................................... 35 
6.5.1.1 
Name of PRO method or questionnaire ................................................................. 35 
6.6 
Pharmacokinetics ................................................................................................... 35 
6.6.1 
Collection of samples ............................................................................................. 37 
6.6.2 
Determination of drug concentration ..................................................................... 37 
6.7 
Pharmacodynamics ................................................................................................ 37 
6.7.1 
Collection of pharmacodynamic markers .............................................................. 38 


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6.8 
Pharmacogenetics .................................................................................................. 38 
6.8.1 
Collection of pharmacogenetic samples ................................................................ 38 
6.9 
Health economics ................................................................................................... 38 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 38 
7.1 
Volume of blood .................................................................................................... 38 
7.2 
Handling, storage and destruction of biological samples ...................................... 38 
7.2.1 
Pharmacokinetic and/or pharmacodynamic samples ............................................. 39 
7.2.2 
Pharmacogenetic samples ...................................................................................... 39 
7.3 
Labeling and shipment of biohazard samples ........................................................ 39 
7.4 
Chain of custody of biological samples ................................................................. 39 
7.5 
Withdrawal of informed consent for donated biological samples ......................... 39 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 39 
8.1 
Ethical conduct of the study ................................................................................... 39 
8.2 
Ethics and regulatory review.................................................................................. 39 
8.3 
Informed consent ................................................................................................... 39 
8.4 
Changes to the protocol and informed consent form ............................................. 40 
8.5 
Audits and inspections ........................................................................................... 40 
9. 
STUDY MANAGEMENT .................................................................................... 40 
9.1 
Training of study site personnel ............................................................................. 40 
9.2 
Monitoring of the study ......................................................................................... 41 
9.2.1 
Source data ............................................................................................................. 41 
9.3 
Study timetable and end of study ........................................................................... 41 
10. 
DATA MANAGEMENT ....................................................................................... 41 
11. 
EVALUATION AND CALCULATION OF VARIABLES ................................. 42 
11.1 
Calculation or derivation of efficacy variable(s) ................................................... 42 
11.2 
Calculation or derivation of safety variable(s) ....................................................... 42 
11.2.1 
Other significant adverse events (OAE) ................................................................ 42 
11.3 
Calculation or derivation of patient reported outcome variables ........................... 42 
11.4 
Calculation or derivation of pharmacokinetic variables ........................................ 42 
11.5 
Calculation or derivation of pharmacodynamic variable(s) ................................... 42 
11.5.1 
Calculation or derivation of the relationship between pharmacokinetic and 
pharmacodynamic variables ................................................................................... 42 
11.5.2 
Population analysis of pharmacokinetic/pharmacodynamic variables .................. 42 
11.6 
Calculation or derivation of pharmacogenetic variables........................................ 43 


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11.7 
Calculation or derivation of health economic variables......................................... 43 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 43 
12.1 
Description of analysis sets .................................................................................... 43 
12.1.1 
Efficacy analysis set ............................................................................................... 43 
12.1.2 
Safety analysis set .................................................................................................. 43 
12.2 
Methods of statistical analyses ............................................................................... 43 
12.2.1 
Interim analyses ..................................................................................................... 44 
12.3 
Determination of sample size ................................................................................. 44 
12.4 
Data monitoring committee ................................................................................... 45 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 46 
13.1 
Overdose ................................................................................................................ 46 
13.2 
Pregnancy ............................................................................................................... 47 
13.2.1 
Maternal exposure .................................................................................................. 47 
13.2.2 
Paternal exposure ................................................................................................... 47 
14. 
LIST OF REFERENCES ....................................................................................... 48 
 
LIST OF TABLES 
Table 1: Proposed scheduled visits 
LIST OF FIGURES 
Figure 1: Study Design 
LIST OF APPENDICES 
 Appendix: Case report forms (Medical History and Physical Examination, Concomitant 
Medications Worksheet, Cardiovascular Autonomic Neuropathy Testing Worksheet, Heart 
Rate Variability Test Report, Adverse Events Reporting Form, Instructions for Patients for 
Heart Rate Variability Testing, Routine Visit Case Report Form, ECG Report, and 
Glucometer Download Data) 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term  
                            Explanation 
 
 


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Abbreviation or 
special term  
                            Explanation 
T1D 
T2D 
CAN 
CVD 
DDP-4 
SGLT-2 
CV  
FDA 
HR 
BP 
RR 
AE 
HRV 
CARTs 
IRB 
LV 
BNP 
ADA 
ULN 
PAD 
MI 
BMI 
SBP 
DBP 
CBCP 
CMP 
HbA1c 
TSH 
ECHO 
ESC 
ECG 
AST 
ALT 
CRF 
MEND 
LF 
HF 
E/I ratio 
 
Type 1 diabetes 
Type 2 diabetes 
Cardiovascular autonomic neuropathy 
Cardiovascular disease 
Dipeptidyl-peptidase-4  
Sodium-glucose transporter-2  
Cardiovascular  
Food and drug administration  
Heart rate 
Blood pressure 
Relative risk 
Adverse event 
Heart rate variability 
Cardiovascular autonomic reflex tests 
Institutional review board 
Left ventricle 
B type natriuretic peptide 
American Diabetes Association 
Upper limit of normal 
Peripheral arterial disease 
Myocardial infarct 
Body mass index 
Systolic blood pressure 
Diastolic blood pressure 
Complete blood count with platelet 
Complete metabolic panel 
Hemoglobin A1c 
Thyroid stimulating hormone 
Echocardiogram 
Electrochemical skin conductance 
Electrocardiography 
Aspartate aminotransferase 
Alanine aminotransferase 
Case report form 
Metabolism, Endocrinology and Diabetes Division 
Low frequency 
High frequency 
Expiration/ inspiration ratio 
 


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Abbreviation or 
special term  
                            Explanation 
SDNN 
rmsSD 
EDV 
ESV 
CO 
TNFα 
IL1β 
IL6 
MCP-1 
IL8 
IL17 
m-CSF 
sVCAM-1 
s-ICAM-1 
IL10 
SAE 
Standard deviation of the normal RR interval  
Root mean square of the differences of successive RR intervals  
End diastolic volume 
End systolic volume  
Cardiac output 
Tumor necrotic factor-alpha 
Interleukin 1 beta 
Interleukin 6 
Monocyte chemoattractant protein-1 
Interleukin 8 
Interleukin 17 
Macrophage colony-stimulating factor  
Soluble vascular cell adhesion molecule-1 
Soluble intercellular adhesion molecule-1 
Interleukin 10 
Serious adverse event 
HDL 
LDL 
ID 
RCR 
MICHR 
High-density lipoprotein 
Low-density lipoprotein 
Identification  
Responsible conduct of research 
Michigan Institutes for clinical and Heath research  
RHR 
FBG 
CGM 
Resting heart rate 
Fasting blood glucose 
Continuous glucose monitoring  
MACE 
CV 
SD 
LBGI 
AUC 
Mean amplitude of glycemic excursions  
Coefficient of variation  
Standard deviation 
Low blood glucose index  
Area under the curve 
 


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1. 
INTRODUCTION 
1.1 
Background 
Diabetes mellitus contributes substantially to the global burden of disease, with an 
estimated 415 million people affected worldwide in 2015, and expected to increase to 642 
million by 2040 (http://www.diabetesatlas.org/). The majority of these cases are due to type 2 
diabetes (T2D). The burden of T2D is driven by health care costs associated with disease 
management, its progressive course, the high prevalence and risks of chronic complications 
including diabetic kidney disease, retinopathy, neuropathy and cardiovascular disease (CVD) 
(http://www.diabetesatlas.org/), and the overall impact on patients’ quality of life [1].  
Currently, there are multiple FDA-approved agents to treat hyperglycemia in patients 
with T2D, that include metformin, sulfonylureas, dipeptidyl-peptidase-4 (DPP-4) inhibitors, 
glinides, thiazolidinediones, insulin, glucagon like peptide receptor agonists, and most 
recently the sodium-glucose transporter-2 (SGLT-2) inhibitors. These all have been shown to 
have various degrees of effectiveness in promoting glucose lowering in T2D [2-6].  
The SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) reduce 
hyperglycemia by selective inhibition of glucose reabsorption in renal proximal tubules via 
sodium-glucose co-transporter 2, and have been approved by FDA as a monotherapy or in 
combination with other glucose lowering agents in patients with T2D for improvement of 
glycemic control with a low risk of hypoglycemia 
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204629s000lbl.pdf; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204042s002lbl.pdf; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s003lbl.pdf ) [3-6],while 
also promoting reductions in body weight and blood pressure (BP) [7, 8]. Potential 
mechanisms for BP reduction involve several pathways including a modest diuretic effect and 
weight reduction [9, 10]. In addition, recently reported human data suggest that the BP 
reduction with the SGLT-2 inhibitors may also be associated with an improvement in arterial 
stiffness via reductions in insulin dose and improved arterial compliance, a direct effects on 
vascular smooth muscle relaxation after induction of a negative sodium balance, and a 
suppression of markers of inflammation and fibrosis, including nuclear factor κβ and collagen 
IV expression [11].  One interesting observation is that reduction in systolic and diastolic BP 
with SGLT-2 inhibitors occurred without a compensatory increase in HR [3, 11, 12] and that 
most benefit was obtained also in patients with some evidence of heart failure [12]. 
Tighter glucose control has been shown to effectively prevent chronic complications 
(nephropathy, retinopathy, neuropathy)[13, 14] and CVD in patients with an early course of 
T2D on metformin treatment arm [15, 16]. However, in patients with more advanced disease, 
the effects of tight glucose control on preventing CVD were inconsistent [17-19]. In addition, 
the effects of the specific agents used to treat hyperglycemia on the chronic complications and 
especially on CVD events in T2D remain uncertain, with some agents showing some potential 
benefit [15, 20] while most had been neutral [13, 21-23].  


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However, most recently beneficial effects on CVD events were reported with a SGLT-
2 inhibitor, empagliflozin, in patients with T2D at high risk of CVD events [12]. The 
Empagliflozin: Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients 
(EMPA-REG OUTCOME) trial, a randomized double-blind placebo-controlled trial, reported 
significant reduction of death from cardiovascular cause (38% RR), all-cause mortality (32% 
RR) and hospitalization for heart failure (35% RR) in patients with T2D in empagliflozin 
treatment arms [12].  
The exact mechanisms of the beneficial effects on cardiovascular outcomes is not yet 
understood, although their effects on body weight, glucose control and blood pressure (BP) 
reduction were suggested [7, 10, 12]. 
1.2 
Research hypothesis 
We hypothesize that the potential benefits of SGLT-2 inhibitors on cardiovascular 
outcomes in patients with T2D are due to modulatory effects on the 
sympathetic/parasympathetic imbalance, and cardiovascular autonomic neuropathy (CAN) as 
suggested by a blunting in the expected compensatory increase in HR associated with BP 
lowering. 
1.3 
Rationale for conducting this study 
As mentioned above reduction in systolic and diastolic BP with SGLT-2 inhibitors 
occur without a compensatory increase in HR [3, 11, 12]. In addition, in the EMPA-REG trial 
the CVD outcome was driven by a reduction in CVD related death and most benefit was 
observed  in patients with evidence of heart failure [12]. Although glucose control, reduction 
in BP and weight loss have all been considered for beneficial effects onCVD, other classes of 
above agents also reduce glucose, BP, and some body weight, while similar effects on CVD 
were not reported [23], except for the recent report of Liraglutide and Cardiovascular 
Outcomes in Type 2 Diabetes [24]. 
Thus, to test the above hypothesis we plan to evaluate potential mechanisms that could 
explain the CVD benefits with SGLT-2 inhibitors. We plan to specifically test in this study 
whether these benefits may be due to changes in the sympathetic/parasympathetic function 
and thus protect against arrhythmia and /or progression of myocardial dysfunction. We plan to 
perform a randomized, single-blinded to the investigators, open-label, 2-period crossover 
phase IV clinical trial comparing 12-weeks of glycemic intervention with a SGLT2 inhibitor, 
dapagliflozin versus a sulfonylurea, glimepiride on measures of heart rate variability (HRV). 
The rationale for using an active comparator is to maintain similar levels of glucose control 
with the interventions and thus account for the effects of reduction in blood glucose on 
measures of CAN, and the current evidence demonstrates similar glucose lowering effects 
between SGLT2 inhibitors and sulfonylureas [25]. In addition, sulfonylureas are very 
commonly used in treating T2D in clinical practice. Given some potential detrimental CVD 
effects described with glyburide or glipizide [26, 27], we have elected to use glimepiride in 
this study to evaluate the changes in measures of CAN during these different interventions. 


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We also plan to evaluate the indices of glucose variability and its association with 
changes in CAN parameters in patients with type 2 diabetes during each dapagliflozin and 
glimepiride treatment period. Glucose variability is also associated with an increased risk of 
hypoglycemia, which is an important barrier in sustaining intensive treatment in patients with 
diabetes [28, 29]. Recurrent severe hypoglycemia, besides inducing alterations in cardiac 
electrical stability and QT interval prolongation, may contribute to alter the cardiac autonomic 
function and the cardiovagal balance, increasing the risk of cardiac arrhythmia in patients with 
diabetes [30, 31] Theoretically, given the higher propensity for hypoglycemia, sulfonylurea 
may induce more glycemic variability than SGLT-2 inhibitors. Currently no studies evaluated 
directly the changes in daily glucose excursions with these commonly prescribed agents were 
done. Thus, adding a component continuous glucose monitoring with the Abbott’s Freestyle 
Libre Pro for 2 weeks during each sulfonylurea and SGLT-2 inhibitor intervention phase in 
this T2D cohort, will enable performing additional analyses linking effects of medications on 
daily glucose profiles with measures of heart rate variability and heart function, that could 
unveil important data on CVD risk with a minimal additional cost.  
.  
 
 
1.4 
Benefit/risk and ethical assessment 
 
1.4.1 Risks Associated with Study Participation 
Risks associated with study participation in general are related to the time commitment 
for the study, and risk for loss of privacy. There will be nine “in-person” visits required for the 
study. The study staff will try to minimize the burden of the visits to the extent practical by 
scheduling on days and at times that are most convenient for the patient. Privacy risks will be 
reduced by maintaining a separate research record that uses a coded identifier, rather than 
personal identities. Links to the coded identifier and personal identity shall be maintained in a 
secure electronic file by the study coordinator and the links will ultimately be destroyed.  
Destruction of the links will occur no sooner than 2 years after the study has been 
acknowledged as terminated by the University of Michigan Institutional Review Board (UM 
IRB). 
1.4.2 Risks Associated with Blood Collection 
Risks associated with blood collection are pain, discomfort, bleeding, bruising or 
infection. There is also the risk of dizziness, light-headedness, nausea or even fainting.   Blood 
sampling will be performed by staff with skill and experience in venipuncture. 
1.4.3 Risks Associated with Study Medications 
The study medications, dapagliflozin and glimepiride, are very effective in glucose 
lowering. However, because of glucose lowering agents, they are also associated with 
hypoglycemia in general. However, because of the mechanism of action of dapagliflozin 


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(SGLT-2 inhibitor), the risk of hypoglycemic episodes is considered to be low. The 
recommended starting dose of dapagliflozin is 5 mg daily and glimepiride 1-2 mg daily. 
Therefore, we will start with low dose and titrate it up to optimal dose (dapagliflozin 10 mg 
daily and glimepiride 4 mg daily) based on participants’ glucose monitoring and control to 
minimize hypoglycemic episodes. Symptoms attributed to hypoglycemia as well as glucose 
levels will be closely monitored in the trial.  
Other potential risks of dapagliflozin are volume depletion, diabetes ketoacidosis, 
urinary tract and genital infection and hypotension. Subjects will be advised to maintain 
adequate fluid intake and monitor BP closely during study periods. If the study participant 
develops any of the mentioned risks, he/she will be managed and monitored according to 
standard care.  
The common potential side effects of FDA approved glimepiride are hypersensitivity 
reaction and gastrointestinal reactions. All participants will be notified of risks of the study 
medications and are required to report to us as soon as they notice. The study personnel will 
report all directly observed adverse events and all adverse events spontaneously reported by 
the trial subject to University of Michigan IRB as adverse events (AE) and record those in 
CRF. All patients participating in this study will be treated in accordance to best standard of 
care per American Diabetes Association guidelines and recommendations.  
All the participants will receive both study medications equally (12-week intervention 
period) in certain order. Both the study medications are proved to be effective in lowering 
glucose. In addition, the patients taking part in the trial may derive general medical benefit 
from careful and close monitoring by medical personnel during the study. Safety will be 
ensured by monitoring the subjects for AEs both clinically and by laboratory testing and by 
the home blood glucose monitoring. Participation in the study is completely voluntary and the 
participant can withdraw anytime from the study if one does not want to continue study 
medications either due to adverse events or other reasons. The study will potentially benefit to 
the diabetes society as it will reveal the important information regarding the potential 
mechanism of dapagliflozin (SGLT-2 inhibitor) on sympathetic/parasympathetic tone, and this 
may further contribute to the potential benefits on cardiovascular outcomes in patients with 
diabetes.  
1.4.4 Risk Associated with Cardiovascular Autonomic Testing 
Participants will be asked to fast in preparation for testing and are therefore at risk for 
hypoglycemia. Testing will be scheduled in the morning to shorten the duration of fasting.  
The test itself has few risks associated with it, although some patients may become dizzy or 
lightheaded when moving from supine to standing, or after performing Valsalva maneuvers. 
Subjects will be reminded to report any dizziness or lightheadedness immediately to the 
examiner and will be instructed to return to a seated or lying position as needed to relieve 
symptoms.   
1.4.5 Risk Associated with Wearing Continuous Glucose Monitoring Device 


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Participants will be provided with a Freestyle Libre Pro CGM for monitoring of 
interstitial glucose every 5-minute interval for 14 days during each study intervention phase. 
There is a very low risk for developing a local skin infection at the site of the sensor needle 
placement. Itchiness, redness, bleeding, and bruising at the insertion site may occur as well as 
local tape allergies.  
 
During follow-up visit, the site where a CGM sensor has been worn will be carefully 
assessed by study personnel.  
2. 
STUDY OBJECTIVES    
   The main objective of this study is to evaluate the effects of dapagliflozin vs active 
comparator, glimepiride on measures of CAN, and indirectly on CVD outcomes in patients 
with T2D.   
2.1 
Primary objective 
  Evaluate the effects of 12-week treatment with dapagliflozin 5 mg daily escalating to 
10 mg daily on measures of CAN as assessed by changes in HRV, changes in cardiovascular 
autonomic reflex tests (CARTs) and resting heart rate (RHR) compared with 12-week 
treatment with glimepiride 2 mg daily escalating the dose to 4 mg (no more than 4 mg daily) 
as needed based on glucose monitoring and control.  
2.2 
Secondary objectives: 
              Evaluate the effects of 12-week glycemic interventions on glucose control, BP, and 
weight.  
2.3 
Safety objective:  
Evaluate the following parameters: 
1. Incidence of symptomatic and asymptomatic hypoglycemia, glucose ≤ 70 mg/dl, as 
defined by American Diabetes Association (ADA) 
2. Incidence of sever hypoglycemia as defined by hypoglycemia requiring assistance 
from another person. It is also characterized by cognitive impairment that may be 
recognized or unrecognized and can progress to loss of consciousness, seizure, coma, 
or death, and it is reversed by administration of glucose. 
 
3. UTIs 
4. Any other AEs (see Section 1.4) 


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2.4 
Exploratory objectives 
We will evaluate the effects of dapagliflozin on measures of cardiac function. We will 
assess the B type natriuretic peptide (BNP), a sensitive biomarker for left ventricle function 
and  prognosis and risk stratification [32, 33] at baselines and 12 weeks after each study drug 
(2 periods).  
We will use a 14-day continuous glucose monitoring (CGM) using Abbott’s Freestyle 
Libre Pro to evaluate and compare the indices of glucose variability [mean glucose, standard 
deviation (SD), coefficient of variation (CV), the mean amplitude of glycemic excursions 
(MAGE), low blood glucose index (LBGI) and area under the curve (AUC) for 
hypoglycemia] during each dapagliflozin and glimepiride intervention phase in patients with 
type 2 diabetes and also assess the association between the indices of glucose variability and 
changes in measures of HRV during each intervention period.  
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
This is a 26-week, single-center, randomized, single-blinded to the investigators, open-
label, 2-period crossover phase IV clinical trial comparing 12-weeks of glycemic intervention 
with dapagliflozin versus glimepiride on measures of HRV. The two periods will be separated 
by a 2-week wash-out period. All subjects will be allocated and randomized to each treatment 
sequence in a 1:1 fashion. Participants will receive either dapagliflozin 5 mg or glimepiride 2 
mg daily initially for 4 weeks then titrating the dose gradually up to dapagliflozin 10 mg daily 
or glimepiride 4 mg daily (no more than 4 mg daily) as needed based on glucose monitoring 
for 8 more weeks (total 12 weeks) followed by 2-week washout period. Then they will receive 
the study drugs in reverse order to the first period for another 12 weeks. Glucose variability 
will be also assessed using Abbott’s Freestyle Libre Pro CGM for 2-week during each 
intervention period. 
 
 
 
 
 
 
 
 


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Figure 1: Proposed study design 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1: Proposed visit schedule 
 
 
 
Period 1 
Wash
-out 
Period 2 
Visit Numbers 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit Description 
Screening 
Baseline 
Visit 
(Study 
Drug 1) 
Monitoring 
Monitorin
g 
End of 
Study 
Drug 1 
N/A 
Baseline 
Visit 
(Study 
Drug 2) 
Monitoring 
Monitoring 
End of 
Study 
Drug 2 
Time point 
Day -30 to 
0 
Day 0 
Week 4 
Week 8 
Week 
12 
Week 
13-14 
Week 15 
Week 19 
Week 23 
Week 26 
Visit window 
1 month 
± 7 days 
± 7 days 
± 7 days 
± 7 
days 
NA 
± 7 days 
± 7 days 
± 7 days 
± 7 days 
Informed consent 
and HIPPA1 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
X 
 
X 
 
 
X 
Physical exam2 
X 
 
 
 
X 
 
 
 
 
X 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
 
 
 
 
 
X 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
Urine analysis, 
urine β-HCG test in 
women of 
childbearing age 
X 
 
 
 
 
 
 
 
 
 
Venous blood A1C 
X 
 
 
 
X 
 
 
 
 
X 
CBCP, FBG, 
comprehensive 
metabolic profile, ,  
lipid profile, and 
urine albumin 
excretion  
X 
 
 
 
X 
 
 
 
 
X 
TSH 
X 
 
 
 
 
 
 
 
 
 
BNP  
X 
 
 
 
X 
 
X 
 
 
X 


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ECG 
X 
 
 
 
X 
 
X 
 
 
X 
HRV 
 
X 
 
 
X 
 
X 
 
 
X 
CARTs 
 
X 
 
 
X 
 
X 
 
 
X 
CGM 
 
 
 
2 weeks  
 
 
 
 
2 weeks  
 
Assess 
hypoglycemia 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Record Adverse 
Events (AEs), 
Serious Adverse 
Events (SAEs) 
 
X 
X 
X 
X 
 
 
X 
X 
X 
Assessment of 
compliance by 
counting pills 
 
 
X 
X 
X 
 
 
X 
X 
X 
1 The informed consent form must be signed before any study procedure is performed. 
2 Physical exams will include vital signs, height and weight measurements, as well as comprehensive systematic 
examination.   
 
3.2 
Rationale for study design, doses and control groups 
 See above (section 1.3) regarding overall study design and comparator group. 
The dose titration algorithm described above was selected to target equal glycemic 
lowering effects for avoiding confounding effects and for ethical considerations. To prevent 
hypoglycemic episodes, we will initiate a lower dose for both study medications 
(dapagliflozin 5 mg and glimepiride 2 mg), and will escalate the dose gradually up to 10 mg 
dapagliflozin and glimepiride 4 mg daily (no more than 4 mg daily) as needed based on daily 
glucose monitoring and profile of AEs 
(http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202293s003lbl.pdf).  
4. 
SUBJECT SELECTION CRITERIA 
   We plan to enroll 45 subjects with type 2 diabetes mellitus (T2D) in this study (see 
below power calculation) with the following eligibility criteria.  
 
4.1 
Inclusion criteria 
1. 
Patients with type 2 diabetes as defined [34] on background metformin monotherapy 
who are not meeting ADA standard of care recommended glucose target [34] 


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2. 
Age ≥18 years  
 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
History of recurrent urinary tract infections 
2. 
Patients with mycotic infections especially genital infection. 
3. 
Severely hypotensive patients   
4. 
History of unexplained microscopic or gross hematuria, or microscopic hematuria at 
visit 1, confirmed by a follow-up sample  
5. 
Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. 
anaphylaxis, angioedema, exfoliative skin conditions) 
6. 
Inability or refusal to comply with protocol 
7. 
Current participation or participation in an experimental drug study in previous 
three months 
8. 
Presence of history of diabetic ketoacidosis  
9. 
Planned cardiac surgery or angioplasty within 3 months 
10. 
Recent history of acute CV events such as MI, stroke, PAD within 3 months prior to 
enrollment 
11. 
Patients with severe renal impairment or unstable or rapidly progressing renal 
disease or end stage renal disease. 
12. 
Clinical conditions that could interfere with the cardiovascular autonomic function 
and heart rate variability (arrhythmias)  
13. 
Severe hepatic insufficiency and/or significant abnormal liver function (defined as 
aspartate aminotransferase >3× upper limit of normal (ULN) and/or alanine 
aminotransferase >3× ULN) or creatinine kinase >3× ULN.  
14. 
History of cancer other than basal cell carcinoma and or treatment for cancer within 
the last 5 years 
15. 
Women of child-bearing potential who may be pregnant or lactating. 
16. 
History of pancreas, kidney or liver transplant. 


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17. 
History of drug or alcohol abuse within 5 years 
18. 
History of allergy to sulfa drugs 
19. 
Presence of any condition that, in the opinion of the investigator would make it 
unlikely for the subject to complete the study. 
20. 
Congestive heart failure (CHF) defined as New York Heart Association class III 
and IV 
 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
 
All consented study patients are required to comply with the study protocol. 
Participation in other interventional research studies is completely restricted to participants. 
Glycemic intervention with additional antidiabetic medications other than metformin is 
prohibited. See above exclusion criteria in section 4.2. 
Medications that can interfere with the study procedures such as beta blockers, weight 
loss medications etc. are restricted during the study due to their influence on procedures for 
cardiovascular autonomic function. Systemic steroids are also prohibited due to the influence 
on glucose metabolism. 
Participants are also required to fast overnight the day before CAN testing and blood 
draw. Women of child-bearing potential must continue to practice an acceptable method of 
birth control throughout the study periods. 
5.2 
Subject enrollment and randomization and initiation of 
investigational product 
5.2.1 
Procedures for randomization 
 Subjects will be proceeded to visit 2-baseline visit (study drug 1) after they pass the 
screening visit (visit 1).   
Randomization to dapagliflozin or glimepiride: After signing informed consent, 
confirming eligibility and completion of baseline assessments (visit 2), subjects will be 
randomized in a 1:1 fashion to either open-label dapagliflozin 5 mg daily or open-label 
glimepiride 2 mg daily for 4 weeks and escalate the dose gradually up to dapagliflozin 10 mg 
daily or glimepiride 4 mg daily (no more than 4 mg daily) as needed based on their glucose 
monitoring. Patients will be asked to check glucose in the morning and before dinner. Fasting 
glucose should be between 80-130 mg/dl and daytime glucose should be in the range of 80-
160 mg/dl.  


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Procedure for Subject Treatment Assignment: Subjects will be randomized to 
treatment with either dapagliflozin or glimepiride. The procedures for randomization will be 
determined by the study biostatistician. The study drugs will be dispensed by the research 
pharmacy. 
5.2.2 
Study Visits 
 
The schedule of study visits is shown in Table 1. After obtaining informed consent, 
verifying eligibility at screening and completing all required baseline assessments, subjects 
will be randomized and provided with study medications. Patients will be also followed every 
4 weeks in each study drug period. The staff should query the subject regarding any changes 
to their health, changes to their medication regimen, and frequency and severity of 
hypoglycemia at each visit. 
Visit 1: Screening/Eligibility (Day -30 to 0)  
An eligibility visit will be scheduled for subjects who, based on preliminary screening 
(telephone, email, medical chart review), meet the general entry criteria (refer to inclusion 
criteria). At Visit 1 the investigator or her designee will obtain written informed consent, after 
which all required eligibility examinations will be performed. The eligibility examination will 
include the following laboratory assessments: Hemoglobin A1c (HbA1c), comprehensive 
metabolic panel (CMP) including FBG, complete blood count with platelets (CBCP), thyroid 
stimulating hormone (TSH), lipid profile, B type natriuretic peptide (BNP), urine albumin 
assessment, urine analysis and in all women of child bearing age and potential, a urine 
pregnancy test, even if an accepted method of contraception is being used. If any of the 
required laboratory measures are documented in the subject’s medical record as being 
completed in the prior 3 months (1 month for HbA1c, and 6 months for urine albumin), they 
will not need to be repeated at the screening visit.  
Weight, height and seated blood pressure and pulse will be obtained. A structured 
history and physical examination and electrocardiogram will be performed at the screening 
visit. All visit 1 measures are to be completed at one visit.  
Visit 2- Baseline Visit (Study Drug 1) (Day 0) 
This study will include CAN assessments (see section 5.2.3), meter download for 
evaluation of hypoglycemia at baseline and to initiate treatment with either dapagliflozin or 
glimepiride.  
Upon satisfactory completion of all eligibility and baseline visit (study drug 1) 
assessment, a 12-week supply of dapagliflozin 5 mg tablet or glimepiride 2 mg tablet will be 
provided, and written instructions for use of the medication reviewed with and provided to the 
subject. Subjects will be instructed to take dapagliflozin 5 mg daily or glimepiride 2 mg daily 
with or without food in the morning once daily for 4 weeks then escalating the dose up to 
dapagliflozin 10 mg daily or glimepiride 4 mg (no more than 4 mg daily) as needed based on 
glucose monitoring and control. Participants will be instructed to monitor glucose 2 times 


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daily, fasting glucose and before dinner with the goal of fasting glucose between 80-130 mg/dl 
and of pre-meal glucose between 80-180 mg/dl. Participants will be asked to record glucose 
data and the number of doses taken every day on a log that will be provided. Participants will 
be also asked to bring a glucometer with them for each visit. Subjects are to be reminded to 
return any unused study medication at their next visit. Adverse events will be recorded and 
reported as required. 
Study staff will contact the subject within one week of the Visit 2 to assess medication 
compliance and tolerance.  
All subjects in group A and B will be allocated and randomized to each treatment 
sequence in a 1:1 fashion. Participants will receive either dapagliflozin 5 mg or glimepiride 2 
mg daily initially for 4 weeks then titrating the dose based on blood glucose levels up to 
dapagliflozin 10 mg daily or glimepiride 4 mg (no more than 4 mg daily) for 8 more weeks 
(total 12 weeks) followed by a 2-week washout period. Participants will then receive the study 
drugs in reverse order to the first study drug period during second crossover period for another 
12 weeks.  
Visit 3: Safety Monitoring (Study Drug 1) (Week 4) 
At this visit, the study staff will obtain vital signs (weight, blood pressure, resting heart 
rate) and will ask the subject about any changes in health status or physical symptoms and 
record the findings in the source documents. Glucometers will be downloaded and incidence 
of hypoglycemia will be evaluated. The staff will assess compliance with study drug and 
tolerance. Adverse events will be recorded and reported as required.  
Visit 4: Safety Monitoring (Study Drug 1) (Week 8)  
At this visit, the study staff will obtain vital signs (weight, blood pressure, resting heart 
rate) and will ask the subject about any changes in health status or physical symptoms and 
record the findings in the source documents. Glucometers will be downloaded and incidence 
of hypoglycemia will be evaluated. The staff will assess compliance with study drug and 
tolerance. Adverse events will be recorded and reported as required. Urine pregnancy testing 
may be performed at the discretion of the investigator for all women of childbearing potential.   
Participants will be provided with a Freestyle Libre Pro CGM to collect glucose data 
for 2 weeks following this visit. Libre Pro CGM will be placed on the participants by trained 
study personnel during this visit. Freestyle Libre Pro CGM is very simple to use and does not 
require glucose calibration or participant’s operation. Then participants will also be asked 
either to mail the CGM or to bring the CGM with them in next visit.  
Visit 5: End of Study Drug 1 (Week 12) 
At this visit, the following will be performed: vital signs (weight, blood pressure, 
resting heart rate), a structured history and physical examination, electrocardiogram, 
information about any adverse events, all CAN assessments (see section 5.2.3), meter 


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download for evaluation of hypoglycemia, blood draw for HbA1c, BNP, and safety laboratory 
assessments (CMP including FBG, CBCP, urine albumin assessment and lipid profile). The 
study staff will collect any unused study medication. The number of unused dapagliflozin or 
glimepiride tablets will be recorded in the source document and unused medication secured 
until returned for final drug disposition. During this visit, the site where a CGM sensor has 
been worn will be carefully assessed by study personnel.  
Wash-out period  
 
A 2-week wash-out period will be followed after first study drug period.  
Visit 6: Baseline Visit (Study Drug 2) (Week 15) 
At this visit, the following will be performed: vital signs (weight, blood pressure, 
resting heart rate), a structured history, information about any adverse events, 
electrocardiogram, all CAN assessments (see section 5.2.3), meter download for evaluation of 
hypoglycemia and blood draw for BNP. The key activity of this visit is to re-initiate treatment 
with either dapagliflozin or glimepiride. After a 2-week wash-out period, visit 6-baseline visit 
(study drug 2) will be initiated. Participants will again receive study drugs (dapagliflozin or 
glimepiride) in a reverse order to the first study drug period for another 12 weeks. Urine 
pregnancy testing may be performed at the discretion of the investigator for all women of 
childbearing potential.   
A 12-week supply of dapagliflozin 5 mg tablet or glimepiride 2 mg tablet will be 
provided, and written instructions for use of the medication reviewed with and provided to the 
subject. Subjects will be instructed to take dapagliflozin 5 mg or glimepiride 2 mg with or 
without food in the morning daily for 4 weeks then escalating to dapagliflozin 10 mg daily or 
glimepiride 4 mg (no more than 4 mg daily) as needed based on glucose monitoring and 
control. Participants will be asked to record the number of doses taken every day on a log that 
will be provided. Subjects are to be reminded to return any unused study medication at their 
next visit.  
Study staff will contact the subject within one week of the Visit 6 to assess medication 
compliance and tolerance.  
Visit 7: Safety Monitoring (Study Drug 2) (Week 19) 
At this visit, the study staff will obtain vital signs (weight, blood pressure, resting heart 
rate) and will ask the subject about any changes in health status or physical symptoms and 
record the findings in the source documents. Glucometers will be downloaded and incidence 
of hypoglycemia will be evaluated. The staff will assess compliance with study drug and 
tolerance. Adverse events will be recorded and reported as required. 
Visit 8: Safety Monitoring (Study Drug 2) (Week 23) 


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At this visit, the study staff will obtain vital signs (weight, blood pressure, resting heart 
rate) and will ask the subject about any changes in health status or physical symptoms and 
record the findings in the source documents. Glucometers will be downloaded and incidence 
of hypoglycemia will be evaluated. The staff will assess compliance with study drug and 
tolerance. Adverse events will be recorded and reported as required. Urine pregnancy testing 
may be performed at the discretion of the investigator for all women of childbearing potential. 
 Participants will be provided with a Freestyle Libre Pro CGM to collect glucose data 
for 2 weeks following this visit. A Libre Pro CGM will be placed on the participants by 
trained study personnel during this visit. Freestyle Libre Pro CGM is very simple to use and 
does not require glucose calibration or participant’s operation. Then participants will also be 
asked either to mail the CGM or to bring the CGM with them in next visit.  
Visit 9: End of Study Drug 2 (Week 26) or Final Visit 
At this visit, the following will be performed: vital signs (weight, blood pressure, 
resting heart rate), a structured history and physical examination, information about any 
adverse events, electrocardiogram, all CAN assessments (see section 5.2.3), meter download 
for evaluation of hypoglycemia, blood draw for HbA1c, BNP, and safety laboratory 
assessments (CMP including FBG, CBCP, urine albumin assessment and lipid profile). The 
study staff will collect any unused study medication. The number of unused dapagliflozin or 
glimepiride tablets will be recorded in the source document and unused medication secured 
until returned for final drug disposition.  
The study staff will collect any unused study medication. The number of unused 
dapagliflozin or glimepiride tablets will be recorded in the source document and unused 
medication secured until returned for final drug disposition. The subjects will be again 
assessed for adverse events.  
During this visit, the site where a CGM sensor has been worn will be carefully 
assessed by study personnel.  
Within 1 week of the final visit, the study staff will contact the subject by phone or 
email to inquire about any changes in health status.  
5.2.3 
Assessments 
CAN 
A. Heart rate variability (HRV) studies: low and high frequency power (LF,HF), and time 
domain measures of HRV, standard deviation of normal RR interval(SDNN), root mean 
square of successive RR intervals (RMSSD) are analyzed from continuous ECG recordings 
using the ANX 3.1 software (ANSAR Inc., Philadelphia , PA) as described [35, 36]. 
B. Cardiovascular reflex tests will include: 1) changes in R-R interval with deep breathing, 
a measure of sinus arrhythmia during quiet respiration reflecting primarily parasympathetic 
function; 2) the R-R response to standing, inducing reflex tachycardia followed by 


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bradycardia which is jointly vagal and baroreflex-mediated; 3) the Valsalva ratio which 
evaluates cardiovagal function in response to a standardized increase in intrathoracic pressure 
(Valsalva Maneuver); and  4) orthostatic changes in BP.  These tests are reproducible and 
considered as gold-standard [36, 37]. 
C. Resting heart rate 
Subjects will be asked to avoid food, caffeine and tobacco products for at least 8 hours 
prior to testing, and hold any medication until testing was completed. Subjects who 
experienced a hypoglycemic episode after midnight [blood glucose ≤ 50mg/dl (2.77mmol/l)] 
prior to the testing were rescheduled.     
Cardiac function 
We will measure serum BNP, by Chemiluminescent Immunoassay (CLIA) (Siemens, 
Erlangen, Germany) and will evaluate changes in BNP, as a biomarker for LV function. The 
blood draw will be performed at baseline and end of each study drug period. 
Assessment of glucose variability 
 
 We will use a 14-day continuous glucose monitoring (CGM) using Abbott’s Freestyle 
Libre Pro to evaluate and compare the indices of glucose variability [mean glucose, standard 
deviation (SD), coefficient of variation (CV), the mean amplitude of glycemic excursions 
(MAGE), low blood glucose index (LBGI) and area under the curve (AUC) for 
hypoglycemia] during each dapagliflozin and glimepiride intervention phase in patients with 
type 2 diabetes and also assess the association between the indices of glucose variability and 
changes in measures of HRV during each intervention period.  
 
5.3 
Procedures for handling subjects incorrectly enrolled or 
randomized or initiated on investigational product 
 
The data management plan for this project is based on the randomization of 45 
participants, with randomization occurring at the time of Visit 2. All candidates who complete 
the informed consent process will be assigned a study identification number (ID) at the time of 
Visit 1. Unless otherwise stipulated by the sponsor-investigator, the ID numbers are patient-
specific and will be retained and associated with candidates who fail screening or are found to 
be ineligible, and/or drop-out prior to randomization. Follow-up will not be continued for 
candidates who do not proceed to randomization.  Follow-up and research activities will be 
pursued on all randomized participants, even those candidates who may for some reason stop 
research medications.   


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5.4 
Blinding and procedures for unblinding the study 
5.4.1 
Methods for ensuring blinding 
The investigators will be blinded to the study drugs. The research pharmacy and 
participants will know the study drugs that participants will be on. The research pharmacy will 
be dispensing the study medications per the randomization schedule that will be provided by 
the study biostatistician.  
5.4.2 
Methods for unblinding the study 
 
In the event of an emergency and a need to know study medications, the investigator 
will contact the Research Pharmacist and request identification of subject’s test article 
assignment. The Research Pharmacist will indicate that the blind was broken on the Pharmacy 
Randomization Log and will document the date of the request, the name of the research 
personnel making the request, and the pharmacist’s signature. The research coordinator will 
report the emergent event on the Adverse Event CRF and the unmasking event on the 
Unmasking Report CRF and then signed by the investigator.   
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
 
Dapagliflozin 5 mg tablet 
Dapagliflozin is a sodium glucose trasporter-2 (SGLT-2) inhibitor, a new class of 
glucose lowering agent that reduces hyperglycemia in patients with T2D by reducing renal 
glucose reabsorption.  
Investigational product 
Dosage form and strength 
Manufacturer 
Dapagliflozin 
Glimepiride  
5 mg tablet 
1 mg tablet  
AstraZeneca 
Sanofi Aventis  
 
 
 
 
5.5.2 
Doses and treatment regimens 
  
Participants will receive either open-label dapagliflozin 5 mg or open-label glimepiride 
2 mg daily initially for 4 weeks then titrating the dose based on blood glucose levels up to 
dapagliflozin 10 mg daily or glimepiride 4 mg (no more than 4 mg daily) daily for 8 more 
weeks (total 12 weeks) followed by a 2-week washout period and then participants will 
receive the study drugs in reverse order to the first period for another 12 weeks. 
5.5.3 
Additional study drug 
 
Glimepiride 2 mg tablet 


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Glimepiride is a sulfonylurea agent that reduces hyperglycemia in patients with T2D 
by stimulating insulin release from the pancreatic beta cells and reduction of glucose output 
from the liver. 
5.5.4 
Labeling 
The label will include the following information: trial number, medication number.  
Each medication box will contain an appropriate amount of dapagliflozin or 
glimepiride tablets, plus some reserve, for dosing until the next scheduled visit. Study drug 
will be supplied on a per Visit basis. Supply will be managed by University of Michigan 
Health System (UMHS) research pharmacy.  
 
5.5.5 
Storage 
 Dapagliflozin film-coated tablets and glimepiride tablets should be stored at 15° to 
25°C (59° to 77°F) in a tightly closed container. The minimum/ maximum storage temperature 
must be measured and documented at least weekly by investigational drug store manager or 
pharmacist. All study medications will be contained in medication boxes identified with the 
trial number and medication number.   
 
5.6 
Concomitant and post-study treatment(s) 
 
The research staff will record all concomitant drugs used by the subject in the source 
documents. This is to include prescription, non-prescription, homeopathic medications and 
dietary/vitamin supplements.  At the screening visit, medication use is to be carefully 
reviewed to ensure that no contraindicated medications as described in the protocol are being 
used (e.g., beta blocker agents, phentermine).  At all subsequent visits, subjects will be asked 
to report any changes to their reported medication use and the source document updated 
accordingly.  Queries regarding medication exclusions and contraindications are directed to 
the study principle investigator.  
5.7 
Treatment compliance 
 Study staff will contact the subject within one week of initiating study medications to 
assess medication compliance and tolerance. All patients will be asked to bring their study 
medications with them to each study visit. The study staff will assess medication compliance 
and tolerance at each visit.  Patients will be reminded about purpose of the study and 
importance of compliance with the study medications at each visit. Adverse events will be 
similarly recorded and reported as required. The study staff will also collect any unused study 
medication at the end of each intervention period. The number of unused dapagliflozin or 
glimepiride tablets will be recorded in the source document and unused medication secured 
until returned for final drug disposition.  


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5.7.1 
Accountability 
 
 The pharmacist / investigational drug storage manager must maintain records of the 
trial medication’s delivery to the trial site, the inventory at the site, the use by each patient, 
and destruction of unused medication. Proof of destruction will be provided to AstraZeneca at 
the end of the study. These records will include dates, quantities, batch/serial numbers, expiry 
(‘use by’) dates, and the unique code numbers assigned to the investigational product and trial 
patients. The pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the study protocol 
and reconcile all investigational products.  
5.8 
Discontinuation of investigational product 
  The study drugs will be discontinued in the following conditions: 
1. Study patient withdraws consent. 
2. Study patient fails to comply with the study protocol. 
3. Study subject becomes pregnant. 
4. If the study patient will need to be on concomitant drugs that may interfere with the 
study findings or study medications that may lead to higher risk of hypoglycemia, the 
study medication can be discontinued. 
5. If the study patient develops persistent or recurrent serious side effects as described 
above (Section 1.4, 6.4.2 and 6.4.4), study drugs will be discontinued permanently. 
 
5.8.1 
Procedures for discontinuation of a subject from investigational product  
  If the study patient withdraws consent or who fails to comply with the study protocol 
or becomes pregnant, participation in the study will end and the study medication will be 
stopped. No further evaluation will be performed and no attempts should be made to collect 
additional data.  
 
If a patient develops UTI or genital infection, we will manage the infection according 
to standard of care. However, a patient with persistent or recurrent UTI or genital infection 
despite standard of care, study medications will be hold temporarily until infections resolve. If 
a patient develops persistent serious adverse effects from study drugs (section 6.4.2 and 6.4.4), 
study medications will be discontinued permanently. And patients will be followed up until 
their serious adverse effects are completely resolved. 
5.9 
Withdrawal from study 
  A subject may withdraw from the trial at any time at their own request, or they may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, or 


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administrative reasons.  If a subject does not return for a scheduled visit, every effort should 
be made to contact the subject.  In any circumstance, every effort should be made to document 
subject outcome, if possible.   
If the subject withdraws consent, no further evaluations should be performed and no 
attempts should be made to collect additional data; however, they may be questioned 
regarding their reason for withdrawal and asked to return all unused investigational products. 
Patients who withdraw or discontinue from the trial after randomization will not be 
replaced. 
6. 
COLLECTION OF STUDY VARIABLES 
   
We will collect the following variables for primary and secondary endpoints: 
Primary Endpoints:  
Changes in measures of HRV as defined by: Frequency domain measures of HRV 
(continuous variables): high frequency (HF) power (0.04-0.15 Hz) (ms2); low frequency (LF) 
power (0.15-0.4 Hz) (ms2) as measured by the LF:HF ratio. The primary outcome will be the 
difference of the LF:HF ratio from baseline to 12 weeks between the two drugs (periods). 
 
Secondary Endpoints:  
1) Changes in measures of HRV as defined by: Time domain measures of HRV (continuous 
variables): (i) standard deviation of the normal RR interval (SDNN) (msec) and (ii) root mean 
square of the differences of successive RR intervals (rmsSD) (msec) 
2) Changes in CARTs as defined by: i) expiration/inspiration (E/I) ratio, ii) Valsalva ratio and 
iii) 30:15 ratio 
3) Changes in BNP with each intervention as a measure LV function 
 
Exploratory Endpoints:  
1) Evaluate the indices of glucose variability (mean, SD, CV, MACE, LBGI, AUC for 
hypoglycemia) during each intervention period 
2) Assess the association between the indices of glucose variability and changes in measures 
of CAN parameters during each intervention phase 
 


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6.1 
Recording of data 
  Case Report Forms (CRFs) for individual patients will be developed by the 
investigators and served as the source document. Source documents provide evidence for the 
existence of the patient and substantiate the integrity of the data collected. The study staff will 
record all medical history, physical examination, safety laboratory assessment and all 
procedures involved during the study in CRF. Principle investigator will review, sign and date 
the results. The study staff will communicate with the patients regarding their results and 
appropriate follow-up and management.  It is the sponsor- investigator's responsibility to 
ensure accuracy, completeness, legibility, and timeliness of the data reported.  Data reported 
in the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies will be explained by the study staff. Any change or correction 
to a CRF will be dated, initialled, and explained by the study staff.  
6.2 
Data collection at enrollment and follow-up 
  The following data will be collected at enrollment periods (for each study drug 
period): 
1. Vital signs: BP, weight, BMI, HR 
2. Blood sample for safety laboratory assessments, glucose control and biomarker for cardiac 
function (CBCP, CMP including FBG, HbA1c, lipid panel and urine albumin assessment, 
BNP) (See Table 1) 
3. ECGs for heart rate variability studies (LF, HF, LF/HF ratio, SDNN and RMSSD), 
cardiovascular autonomic reflex tests (E/I ration, Valsalva ratio, 30:15 and orthostatic BP) and 
RHR 
4. Assessment of hypoglycemia by evaluating symptoms and downloading glucometers and 
glucose log sheets 
         During follow-up monitoring visits, we will assess hypoglycemia (symptoms, 
recordings) vital signs, any changes in their medication list, recording of adverse events, 
serious adverse events and compliance and tolerability of study medications.  
         At the end of each intervention period, we will repeat the same measures and procedures 
to obtain primary and secondary endpoints. Those include blood sample for biomarkers, HRV, 
and CARTs. 
          We will also evaluate the indices of glucose variability by using Freestyle Libre Pro 
CGM during each intervention phase in this cohort.  
6.2.1 
Enrollment procedures 
  
All candidates will be selected from University of Michigan Health System (UMHS), 
which has a unified electronic medical records system (EPIC) that allows screening in real 
time for all patients seen at UMHS via best practice alerts. Currently there are ~ 25,000 


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patients with type 2 diabetes that are being seen in our system. In addition, we have access to 
the Diabetes Registry, an IRB approved registry of patients with diabetes who provided 
written consent to have their medical records screened to determine eligibility and to be 
contacted directly should they be eligible. 
 
Once identified, the candidates will be contacted via phone or email and provided the 
information regarding the study. Following their review of the study, candidates who express 
interest in participation will be scheduled for a screening visit (visit 1) in the dedicated 
research space either within the outpatient clinics of the Division of Metabolism, 
Endocrinology and Diabetes (MEND) or at the Michigan Clinical Research Unit. (MCRU) 
(http://www.michr.umich.edu/services/mcru) depending on subjects preferences. 
 
Once eligibility is confirmed, candidates will proceed to Visit 2-baseline visit within 4 
weeks for randomization and dispensing study medication. Written instructions for use of the 
medication will be reviewed with and provided to the subject.  All participants will be asked 
to monitor glucose in the morning and before dinner and record in the log book and meter.   
6.2.2 
Follow-up procedures  
 
Follow-up monitoring visit will be scheduled every 4 weeks during intervention 
period. After randomization visit (Visit 2), the study staff will contact the subject within one 
week via phone to assess medication compliance and tolerance. Participants will be asked to 
record the number of doses taken every day on a log that will be provided. All participants 
will also be asked to monitor glucose in the morning and before dinner, and record those in 
the log book. Participants will be advised to bring the study medications, glucometers and 
glucose log books at each follow-up visit. Depending on glucose monitoring and their 
tolerability, the dose of study medications will be doubled in following visit (Visit 3). Subjects 
are to be reminded to return any unused study medication at their next visit.  
6.3 
Efficacy: NA 
 
6.3.1 
Efficacy variable:  NA 
 
6.4 
Safety 
 
The Principal Investigator is responsible for ensuring that all staff involved in the 
study is familiar with the content of this section. 
6.4.1 
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.  An 
undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., 


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tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory 
findings, electrocardiogram).  In clinical studies, an AE can include an undesirable medical 
condition occurring at any time, including washout period, even if no study treatment has been 
administered. 
The term AE is used to include both serious and non-serious AEs. 
6.4.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., 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/procedures) will be 
assessed by the investigator(s) and communicated to AstraZeneca. 
6.4.3 
Recording of adverse events 
 
The investigators are responsible to perform periodic and special assessments for 
adverse events.  All adverse events will be summarized and reported to the Institutional 
Review Board.  The investigator and research staff will note all AEs reported by the subject 
after administration of dapagliflozin or glimepiride.  All clinical complaints volunteered by, or 
elicited from, the subject during the study will be recorded in the appropriate section of the 
case report form for the study period indicated.  AEs may include events that occur as a result 
of protocol-mandated procedures (e.g., events due to invasive procedures). We will only 
include non-invasive procedures such as HRV and CARTs for assessment of cardiovascular 
autonomic function. Therefore, AEs from protocol-mandated procedures are not likely 
expected other than minor skin irritation from electrodes. If any AE occurs, the subject will 
receive appropriate treatment and medical supervision and will be followed until the AE is 
stabilized or to a point where it is no longer clinically significant.  As previously noted, all 
medical conditions and abnormal findings present before administration of the first dose of 
dapagliflozin or glimepiride will be recorded as concurrent illnesses or baseline symptoms. 


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Follow-up of unresolved adverse events: All AEs judged to be clinically significant, 
including clinically significant laboratory abnormalities, will be followed until resolution. 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 (that is, the intensity – mild, moderate or severe) 
 Investigator causality rating against the Investigational Product or procedures 
(unlikely, possibly, probably, definitely) 
 Action taken with regard to investigational product/procedure 
 Adverse event caused subject’s withdrawal from study (yes or no) 
 Outcome (recovered, recovering, ongoing, fatal – see SAE). 
In addition, the following variables will be collected for serious adverse events: 
 Date AE met criteria for serious AE 
 Date Investigator became aware of serious AE 
 AE is serious due to: 
 Date of hospitalization 
 Date of discharge 
 Probable cause of death 
 Date of death 
 Autopsy performed 
 Causality assessment in relation to study procedure(s) 
 Causality assessment in relation to other medication 
 Causality assessment in relation to additional study drug 
 Description of AE. 
 Date reported to IRB 


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It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
 
Adverse Events based on signs and symptoms: When collecting AEs, the recording 
of diagnoses is preferred (when possible) to recording a list of signs and symptoms.  However, 
if a diagnosis is known and there are other signs or symptoms that are not generally part of the 
diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
 
Adverse Events based on examinations and tests: Deterioration as compared to 
baseline in protocol-mandated glucose values and/or blood pressure values should therefore 
only be reported as AEs if they fulfil any of the SAE criteria or are the reason for 
discontinuation of treatment with the investigational product. 
If deterioration in glucose concentration and/or blood pressure is associated with 
clinical signs and symptoms, the sign or symptom will be reported as an AE and the 
associated laboratory result/vital sign will be considered as additional information.  Wherever 
possible the reporting investigator uses the clinical, rather than the laboratory term (e.g., 
anemia versus low hemoglobin value). In the absence of clinical signs or symptoms, clinically 
relevant deteriorations in non-mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE. 
 
Reporting of serious adverse events: Investigators must inform the FDA, via a Med 
Watch/AdEERs form, of any serious or unexpected adverse events that occur in accordance 
with the reporting obligations of 21 CFR 312.32, and will concurrently forward all such 
reports to AstraZeneca within 24 hours of events.  A copy of the Med Watch/AdEERs report 
must be faxed to AstraZeneca 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 AstraZeneca at the same time. 
When reporting to AstraZeneca, a cover page should accompany the Med Watch/AdEERs 
form indicating the following: 
 Investigator Sponsored Study (ISS) 
 The investigator’s name and address 
 The trial name/title and AstraZeneca ISS reference number 


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Investigative site must also indicate, either in the SAE report or 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 principal investigator. 
The study staff will send SAE report and accompanying cover page by way of fax to 
AstraZeneca’s designated fax line: 1-1-302-886-4114 or email 
AEMailboxClinicalTrialTCS@astrazeneca.com within 24 hours of events. 
Serious adverse events that do not require expedited reporting to the FDA need to be 
reported to AstraZeneca preferably using the MedDRA coding language for serious adverse 
events.   
The investigator will contact the research pharmacist and request a copy of the 
randomization code to identify the subject with SAE for expedited reporting to IRB. The 
research pharmacist will indicate that the blind was broken on the Pharmacy Randomization 
Log and will document the date of the request, the name of the research personnel making the 
request, and the pharmacist’s signature. The research coordinator will report the emergent 
event on the Adverse Event CRF and the unmasking event on the Unmasking Report CRF and 
then signed by the investigator.   
All SAEs will also be reported to AstraZeneca within 24 hours, whether or not 
considered causally related to the investigational product.  All SAEs will be documented.  The 
investigator is responsible for informing the IRB and/or the regulatory authority (FDA) of the 
SAE.  
6.4.4 
Laboratory safety assessment 
 
We will obtain the following safety laboratory samples at the screening visit before 
initiating of study medications and at the end of each study drug period:  comprehensive 
metabolic panel including fasting blood glucose and CBC and platelets, urine albumin 
assessment and lipid profile.  
At the screening visit (Visit 1), we will also obtain thyroid function test (TSH), urine 
pregnancy test and urine analysis. 
For blood volume see Section 7.1. 
6.4.5 
Physical examination 
 
Complete physical examination will be performed by either principle investigator or 
co-investigators. It will include general appearance, vital signs, and comprehensive systematic 
examinations including head and neck, cardiovascular exam, respiratory exam, 
gastroenterology exam, extremities, skin and neurology exam.  
6.4.6 
ECG 
 
We will record baseline ECG while lying in all participants by using standard ECG 
monitoring device (Mortara Instrument, ELI 250).   


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6.4.6.1 
Resting 12-lead ECG 
  12-lead ECG including I, II, III, aVR, aVL, aVF, V1 - V6 will be recorded with 
standardized devices and stored at the research facility. Morphology of waves at various leads, 
RR interval, corrected QT interval, and ST depression will be evaluated by the study 
investigators and recorded in the flow chart. 
6.4.6.2 
Real time display (telemetry): NA 
6.4.7 
Vital signs  
 It will include temperature, resting blood pressure, heart rate, weight in kg, height in 
cm, and calculated BMI. 
6.4.7.1 
Pulse and blood pressure 
 Systolic and diastolic blood pressure as well as pulse rate (electronically or by 
palpation, count for 1 minute) will be measured after approximately 5 minutes of rest in the 
seated position. The blood pressure measurement should be performed three times at each 
time point and the mean value of these measurements will be entered in the CRF. 
6.4.7.2 
Body temperature 
 All participants’ body temperature will be recorded in CRF by using standard Welch 
Allyn Sure Temp Plus device.  
6.4.8 
Other safety assessments 
 
Home Blood Glucose Monitoring 
All patients will be provided with a glucometer for home blood glucose monitoring 
and supplies for use at home during 12-week intervention periods and wash-out period. 
Instruction on the proper use of the glucometer will be provided by the study staff. The patient 
will be asked to monitor glucose 2 times daily, in the morning and before dinner and to record 
the results of the glucose log book that will be included in the patient source document file.  
6.5 
Patient reported outcomes (PRO):  
 
NA 
6.5.1.1 
<<Name of PRO method or questionnaire>>  
 NA 
6.6 
Pharmacokinetics 
 Blood samples for pharmacokinetic evaluation will not be collected before and after 
initiating of study medications in this crossover study. Primary outcomes include changes in 
measures of cardiovascular autonomic neuropathy among patients taking glimepiride or 
dapagliflozin.   


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The followings are the pharmacokinetic activities of FDA approved dapagliflozin and 
glimepiride.  
 
Dapagliflozin 
Absorption 
Dapagliflozin is rapidly and well absorbed after oral administration and can be 
administered with or without food. Maximum dapagliflozin plasma concentrations (Cmax) are 
usually attained within 2 hours after administration in the fasted state. The Cmax and AUC 
values increase proportionally to the increment in dapagliflozin dose. The absolute oral 
bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Food has 
relatively modest effects on the pharmacokinetics of dapagliflozin in healthy subjects. 
Administration with a high-fat meal decreases dapagliflozin Cmax by up to 50% and 
prolonged 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. 
Distribution 
Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in 
various disease states (e.g., renal or hepatic impairment). 
Metabolism 
Dapagliflozin is a C-linked glucoside, meaning the aglycone component is attached to 
glucose by a carbon-carbon bond, thereby conferring stability against glucosidase enzymes. 
The mean plasma terminal half-life (t1/2) for dapagliflozin is 12.9 hours following a single 
oral dose of dapagliflozin 10 mg to healthy subjects. Dapagliflozin is extensively metabolized, 
primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. 
Dapagliflozin 3-Oglucuronide accounted for 61% of a 50 mg [14C]-dapagliflozin dose and is 
the predominant drug-related component in human plasma, accounting for 42% (based on 
AUC [0-12 hour]) of total plasma radioactivity, similar to the 39% contribution by parent 
drug. Based on AUC, no other metabolite accounts for >5% of the total plasma radioactivity. 
Dapagliflozin 3-Oglucuronide or other metabolites do not contribute to the glucose-lowering 
effects. The formation of dapagliflozin 3-O-glucuronide is mediated by UGT1A9, an enzyme 
present in the liver and kidney, and CYP-mediated metabolism is a minor clearance pathway 
in humans. 
Elimination 
Dapagliflozin and related metabolites are primarily eliminated via urinary excretion, of 
which less than 2% is unchanged dapagliflozin. After administration of 50 mg [14C]-
dapagliflozin dose, 96% is recovered; 75% in urine and 21% in feces. In feces, approximately 
15% of the dose is excreted as parent drug. 
 
Glimepiride 


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Absorption 
Studies with single oral doses of glimepiride in healthy subjects and with multiple oral 
doses in patients with type 2 diabetes showed peak drug concentrations (Cmax) 2 to 3 hours 
post-dose. When glimepiride was given with meals, the mean Cmax and AUC (area under the 
curve) were decreased by 8% and 9%, respectively. Glimepiride does not accumulate in serum 
following multiple dosing. The pharmacokinetics of glimepiride does not differ between 
healthy subjects and patients with type 2 diabetes. Clearance of glimepiride after oral 
administration does not change over the 1 mg to 8 mg dose range, indicating linear 
pharmacokinetics. In healthy subjects, the intra- and inter-individual variabilities of 
glimepiride pharmacokinetic parameters were 15-23% and 24-29%, respectively. 
Distribution 
After intravenous dosing in healthy subjects, the volume of distribution (Vd) was 
8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was 
greater than 99.5%. 
Metabolism 
Glimepiride is completely metabolized by oxidative biotransformation after either an 
intravenous or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative 
(M1) and the carboxyl derivative (M2). Cytochrome P450 2C9 is involved in the 
biotransformation of glimepiride to M1. M1 is further metabolized to M2 by one or several 
cytosolic enzymes. M2 is inactive. In animals, M1 possesses about one-third of the 
pharmacological activity of glimepiride, but it is unclear whether M1 results in clinically 
meaningful effects on blood glucose in humans. 
Excretion 
When 14C-glimepiride was given orally to 3 healthy male subjects, approximately 
60% of the total radioactivity was recovered in the urine in 7 days. M1 and M2 accounted for 
80-90% of the radioactivity recovered in the urine. The ratio of M1 to M2 in the urine was 
approximately 3:2 in two subjects and 4:1 in one subject. Approximately 40% of the total 
radioactivity was recovered in feces. M1 and M2 accounted for about 70% (ratio of M1 to M2 
was 1:3) of the radioactivity recovered in feces. No parent drug was recovered from urine or 
feces. After intravenous dosing in patients, no significant biliary excretion of glimepiride or its 
M1 metabolite was observed. 
 
6.6.1 
Collection of samples   
 
NA 
6.6.2 
Determination of drug concentration: NA 
 Determination of drug concentration will not be investigated in this study.  
6.7 
Pharmacodynamics 
 
No pharmacodynamics parameters will be determined in this study. 


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6.7.1 
Collection of pharmacodynamics markers:  
 
NA 
6.8 
Pharmacogenetics: NA 
 No pharmacogenetic samples will be investigated in this study. 
6.8.1 
Collection of pharmacogenetic samples: NA 
 
6.9 
Health economics 
  
This study is a pilot crossover clinical trial comparing 12 weeks of glycemic 
intervention on measures of cardiovascular autonomic neuropathy in patients with type 2 
diabetes. The duration of the study is quite short. Therefore, it is likely that this study won’t be 
able to offer health economics parameters. However, we may consider performing analysis of 
glucose control and risk of hypoglycemic in study patients.  
7. 
BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
   
The study staff will collect 4 tubes of blood samples in screening visit (visit 1), visit 5, 
and visit 9. We will also collect 1 tube of blood sample at visit 6. Each tube contains 6ml 
blood sample (each tube 6 ml = 1 teaspoon). A total of 78 ml (13 teaspoons) of blood per 
subject will be taken for the entire study.  
7.2 
Handling, storage and destruction of biological samples 
  We will obtain all safety laboratory samples after overnight fasting at screening visit 
before initiating of study medications and at the end of each intervention period. Sample 
will be marked using subject unique study ID number. Study coordinator will keep separate 
list that links personal identity to ID number until all data have been analyzed and verified. 
All safety laboratory including HbA1c, liver transaminases (AST, ALT), alkaline 
phosphatase, serum creatinine, hematocrit, hemoglobin, red blood cell count, white blood 
cell count, platelet count, electrolytes (sodium, potassium, chloride, bicarbonate, Chloride, 
Calcium, bilirubin, Urea, total protein, albumin, FBG), lipid panel (Total cholesterol, 
Triglycerides, HDL, LDL) will be processed immediately after collection. Then we will 
dispose those blood samples to the container labeled as Biohazard through Hazardous 
Materials Management (HMM) for the collection of liquid biohazardous waste.  
 


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7.2.1 
Pharmacokinetic and/or pharmacodynamics samples 
  
No pharmacokinetic and pharmacodynamics samples will be collected during the 
study 
7.2.2 
Pharmacogenetic samples:   
No pharmacogenetics samples will be collected during the study 
7.3 
Labeling and shipment of biohazard samples 
 
NA 
7.4 
Chain of custody of biological samples 
 
NA 
7.5 
Withdrawal of informed consent for donated biological samples 
A subject may withdraw from the trial at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, 
or administrative reasons.  If the subject withdraws consent, no further evaluations should 
be performed and no attempts should be made to collect additional data. We will not 
process stored biological samples of such particular subject. It will be disposed safely 
through HMM.  
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
  
The trial will be performed in accordance with the protocol, International Conference 
on Harmonization Good Clinical Practice guidelines, and applicable local regulatory 
requirements and laws. 
8.2 
Ethics and regulatory review 
 
 Institutional Review Board (IRB)  
It is the responsibility of the investigator to obtain prospective approval of the trial 
protocol, protocol amendments, informed consent forms, and other relevant documents, e.g., 
advertisements, if applicable, from the IRB.  All correspondence with the IRB should be 
retained in the Investigator File. 
8.3 
Informed consent 
 
The informed consent form must be agreed to by the Protocol Committee and the IRB 
and must be in compliance with ICH Good Clinical Practice Guidelines, local regulatory 
requirements, and legal requirements. 


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The investigator must ensure that each trial subject, or her legally acceptable 
representative, is fully informed about the nature and objectives of the trial and possible risks 
associated with participation.  The investigator will obtain written informed consent from each 
subject or the subject's legally acceptable representative before any study-specific activity is 
performed.  The informed consent form used in this trial, and any changes made during the 
course of the trial, must be prospectively approved by the IRB before use.  The investigator 
will retain a copy of each subject's signed consent form. 
Study records with the study participant’s information for internal use at the clinical 
sites will be secured at the study site during the study. At the end of the study, all records will 
continue to be kept in a secure location. There are no plans to destroy the records.  
Study participant data, which is for reporting purposes, will be stored at the 
Coordinating Center. Data will identify participants by the unique study identification number. 
The study data entry and study management systems used by clinical sites and by 
Coordinating Center research staff will be a secured, password protected computer. 
8.4 
Changes to the protocol and informed consent form 
 NA 
8.5 
Audits and inspections 
  
Audits and inspections may be pursued by the Michigan Institute of Clinical Research 
as part of implementing quality assurance of the study trial and the time interval of audits will 
be scheduled based on discretion of these parties.  
9. 
STUDY MANAGEMENT 
 
The principle investigator and co-investigators will be responsible for oversight of all 
aspects of the study. The study will be conducted according to ICH Good Clinical Practice 
Guidelines and in accordance with University of Michigan Health System (UMHS) policies. 
9.1 
Training of study site personnel 
 
A delegation log of research personnel will be generated. The study staff will be 
trained for the following study procedures and certified by principle investigator: 
 Heart rate variability (HRV) studies,  
 Cardiovascular reflex tests (CARTs)  
 Freestyle Libre Pro CGM 
The efficiency of training of study staff will be periodically assessed by principle 
investigator. All study staff should be certified for Program for Education and Evaluation in 
Responsible Research and Scholarship (PEERRS) as part of regulation by Michigan Institutes 


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for clinical and Heath research (MICHR). These courses provide training required per 
university, state, and federal regulations regarding responsible conduct of research (RCR). 
The study staff will be also trained to report all un-anticipated events, deviations, and AEs to 
IRBMED.  
9.2 
 Monitoring of the study 
9.2.1 
Source data 
 
Protocol for Case Report Form (CRF) will be developed and served as the source 
document. Source documents provide evidence for the existence of the patient and 
substantiate the integrity of the data collected. We will record all medical history, physical 
examination, safety laboratory assessment and all procedures involved during the study in 
CRF. It is the investigator's responsibility to ensure completion and to review and approve all 
CRFs.  Additional source data will be in patients’ medical record in electronic medical record 
aka Michart. Michart will also be used as source document. Outside medical record may also 
be requested for source document.  
9.3 
Study timetable and end of study 
 
Projected study timelines are as the following: 
Research Agreement executed: Oct 30, 2016 
Projected IRB/IEC approval: Nov 30, 2016 
First Subject In: Dec 30, 2016 
50% Enrollment: Sep 30, 2017 
Last Subject In (100% enrollment): Jun 30, 2018  
Last Subject Last Visit (Treatment end): Dec 30, 2018  
Publication: Mar 30, 2019 
10. 
DATA MANAGEMENT 
 
Case Report Forms / Electronic Data Record 
As used in this protocol, the term case report form (CRF) should be understood to refer 
to either a paper form or an electronic data record or both, depending on the data collection 
method used in this trial. 
A CRF is required and should be completed for each included subject.  It is the 
investigator's responsibility to ensure completion and to review and approve all CRFs.  CRFs 
must be signed by the investigator or by an authorized staff member.  These signatures serve 


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to attest that the information contained on the CRFs is true.  At all times, the investigator has 
final personal responsibility for the accuracy and authenticity of all clinical and laboratory 
data entered on the CRFs.  Subject source documents are the physician's subject records 
maintained at the trial site.  In most cases, the source documents will be the hospital's or the 
physician's chart.  In cases where the source documents are the hospital or the physician's 
chart, the information collected on the CRFs must match those charts.  
In some cases, the CRF may also serve as the source document.  In these cases, the 
investigator must prospectively document which items will be recorded in the source 
documents and for which items the CRF will stand as the source document. 
11. 
EVALUATION AND CALCULATION OF 
VARIABLES 
      NA 
11.1 
Calculation or derivation of efficacy variable(s) 
 NA 
11.2 
Calculation or derivation of safety variable(s) 
 NA 
11.2.1 
Other significant adverse events (OAE) 
 NA 
11.3 
Calculation or derivation of patient reported outcome variables 
 NA 
11.4 
Calculation or derivation of pharmacokinetic variables 
 NA 
11.5 
Calculation or derivation of pharmacodynamic variable(s) 
 NA 
11.5.1 
Calculation or derivation of the relationship between pharmacokinetic and 
pharmacodynamic variables  
 NA 
11.5.2 
Population analysis of pharmacokinetic/pharmacodynamic variables  
 NA 


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11.6 
Calculation or derivation of pharmacogenetic variables 
 NA 
11.7 
Calculation or derivation of health economic variables 
 NA 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1 
Description of analysis sets 
12.1.1 
Efficacy analysis set 
 
The primary efficacy analysis set will be based on a pharmacodynamic set such that 
subjects must have non-missing observations of study endpoints in both periods. A secondary 
analysis will be performed on the intent-to-treat (ITT) set which includes all patients who 
receive at least 1 dose of treatment. 
12.1.2 
Safety analysis set 
 
All patients will be evaluable for toxicity from the time of their first treatment.  All 
safety laboratory measurements (see section 6.4.5) and any reported or observed AEs (see 
section 6.4.3) will be documented in source document.  
12.2 
Methods of statistical analyses 
 
The primary objective of this trial is to compare the change in the LF: HF ratio from 
baseline to 12 weeks for patients on dapaglifozin versus glimepiride. 
The mean change in LF: HF ratio for each drug from baseline to 12 weeks will be 
reported with the corresponding 95% confidence interval. The mean difference between drugs 
of changes from baseline to 12 weeks and the corresponding 95% confidence interval will also 
be reported. The change from baseline to 12 weeks within each period (between drugs) will be 
compared within patients using a two-sided t-test (applying transformations where 
appropriate; using the pharmacodynamics set of subjects). This analysis will be repeated using 
the ITT set of subjects.  If there is chance within-subject or between-subject imbalance in 
baseline measures (such as glucose control, BMI and age), we will use the ANCOVA method 
including those unbalanced covariates to improve precision (Metcalfe, Statistics in Medicine, 
The analysis of cross-over trials with baseline measurements, 2010). 
A corresponding primary analysis to the t-test controlling for possible sequence and 
period effects includes a linear mixed effects model (also known as random effects model; 
applying transformations where appropriate) with outcome of the change in LF: HF ratio from 
baseline to 12 weeks. This model assesses the difference between drugs by accounting for a 


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random effect for subject (nested within sequence) and fixed effects for treatment, sequence, 
and period.   
We will additionally explore differences between the drugs over time using all of the 
data measured at baseline, 4, 8 and 12 weeks with a linear mixed model. The outcome will be 
the change from baseline at 4, 8 and 12 weeks. The model will include a random term for 
subject nested within sequence and fixed effects for treatment, sequence, visit, period, and 
interaction terms for visit by treatment. The interaction terms for visit by treatment provide 
estimates of treatment effects at each visit. An unstructured variance/covariance matrix will be 
used. 
 All secondary endpoints will be similarly compared where each endpoint for each 
drug will be measured at baseline and 12 weeks and the difference within each drug will be 
compared within patients using a two-sided t-test (applying transformations where 
appropriate). Similar to the analysis for the main outcome, linear mixed effect models with an 
unstructured variance/covariance matrix and outcomes of changes from baseline at 4, 8, and 
12 weeks will assess changes over time for each outcome. The mixed effects models will 
include a random effect for patients nested within sequence and fixed effects for treatment, 
sequence, visit, period and the interaction between treatment and visit. 
Associations between the indices of glucose variability and changes in measures of 
HRV during each intervention will be analyzed using paired t-tests or Wilcoxon signed rank 
test (if normality assumption is violated). Effect sizes will be estimated with 95% confidence 
intervals of the associations between glucose variability and changes in measures of HRV 
within each intervention using linear regression (applying transformations when necessary). If 
period effects are found from our primary analysis, we will control for the period in which the 
drug was given within the model. The interaction between drug and glucose variability on the 
changes in measures of HRV will be explored using a generalized estimating equations (using 
an unstructured working correlation matrix since we only have 2 observations per person). We 
will not control for multiple comparisons and expect results to be validated in a future 
independent cohort. 
12.2.1 
Interim analyses 
 
No interim analysis is planned. The study medications, dapagliflozin and glimepiride, 
are FDA approved drugs for treatment of type 2 diabetes. They are very effective in lowering 
glucose. There is no harm in continuing treatment for the entire study period due to their 
safety profile as mentioned above (see section 1.4 and 13).  
12.3 
Determination of sample size 
 
We assume there are no carryover effect and no interactions between patients, 
treatments, and time period.  For each patient in each period (on each drug), the LF: HF ratio 
will be measured at baseline and at 12 weeks. The primary outcome will be the difference 
between periods (drugs) in the differences from baseline to 12 weeks of the LF: HF ratio (i.e. 
[LF: HF sulfonylurea, week12 – LF: HF sulfonylurea, baseline] – [LF: HF dapagliflozin, 


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week12 – LF: HF dapagliflozin, baseline]). Based on previous studies, we have found the LF: 
HF ratio to have a mean of 3.4 (SD=2.1) for those with T2D. Assuming a similar within 
person standard deviation (2.1) of the difference of the differences in the LF: HF ratio from 
baseline to 12 weeks, we have 80% power with 38 patients to find a difference between the 
two drugs in the differences in LF: HF ratios of 1.4 using a two-sided (paired) t-test at the 0.05 
significance level (sample size from applet available at 
http://hedwig.mgh.harvard.edu/sample_size/js/js_crossover_quant.html). Expecting 10% of 
the subjects to not complete the entire study, we plan to enroll 45 patients.  
12.4 
Data monitoring committee  
 
A Data and Safety Monitoring Board (DSMB) will oversee this study.  This is the 
single center cross-over pilot study using on-label study medications. Therefore, we feel that 
composing DSMB with an endocrinologist and a biostatistician would be appropriate to 
monitor the study. Members of the DSMB are independent of the study investigators and 
study biostatistician.   The DSMB will meet every six months.  During the DMSB’s meetings, 
the team will discuss matters related to: enrollment rate relative to expectations; 
characteristics of participants; safety of study participants (SAE and AE reporting); adherence 
to protocol (protocol deviations); completeness, validity and integrity of study data; and 
retention of study participants.  


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13. 
IMPORTANT MEDICAL PROCEDURES TO BE 
FOLLOWED BY THE INVESTIGATOR 
  Given the mechanistic nature of the study drug, dapagliflozin, the common side 
effects are urinary tract infection (UTI) and genital mycotic infection. Those patients who 
developed infections will be managed according to standard care and guidelines. Baseline 
urinary analysis (UA) will be collected before starting any study medications. In any case of 
suspect UTI, UA will be collected. If positive urine analysis, then we will proceed with urine 
culture and treat the patient accordingly to bacterial growth in the urine culture. If negative 
UA, we will not proceed with midstream urine culture.  
 
If the patient has abnormal ECG, the study investigator will ask the prior documented 
ECG report from patient’s primary care provider or endocrinologist and repeat the ECG. If the 
patient is symptomatic, then patient will be sent to emergency department for further urgent 
evaluation of coronary artery disease. The study medication will be discontinued. If 
asymptomatic, then the investigators will ask the prior ECG report and repeat ECG in the 
same visit. If similar findings compared to the old one, then he will be monitored 
conservatively. If significant changes from prior ECG, then he will be referred to the 
cardiologist for further evaluation upon the investigator’s discretion.  
13.1 
Overdose  
Orally administrated dapagliflozin has been shown to be safe and well tolerated in 
healthy subjects at single doses up to 500 mg [50 times the maximum recommended human 
dose (MRHD)]. These subjects had detectable glucose in the urine for a dose-related period of 
time (at least 5 days for the 500 mg dose) with no reports of dehydration, hypotension, or 
electrolyte imbalance, and with no clinically meaningful effect on QTc interval. In clinical 
studies where once-daily doses of up to 100 mg (10 times the MRHD) of dapagliflozin were 
administered for 2 weeks in healthy subjects and type 2 diabetes patients, the incidence of 
hypoglycemia for subjects administered dapagliflozin was slightly higher than placebo and 
was not dose related. Rates of adverse events including dehydration or hypotension for 
patients treated with dapagliflozin were similar to placebo, and there were no clinically 
meaningful dose-related changes in laboratory parameters including serum electrolytes and 
biomarkers of renal function. In the event of an overdose, appropriate supportive treatment 
should be initiated as dictated by the patient’s clinical status. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
sponsor or other site personnel inform appropriate AstraZeneca representatives within one 
day, i.e., immediately but no later than the end of the next business day of when he or she 
becomes aware of it. 
 
An over dosage of glimepiride, as with other sulfonylureas, can produce severe 
hypoglycemia. Mild episodes of hypoglycemia can be treated with oral glucose. Severe 
hypoglycemic reactions constitute medical emergencies requiring immediate treatment. 
Severe hypoglycemia with coma, seizure, or neurological impairment can be treated with 


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glucagon or intravenous glucose. Continued observation and additional carbohydrate intake 
may be necessary because hypoglycemia may recur after apparent clinical recovery. 
 
The designated AstraZeneca representative works with the sponsor to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
13.2 
Pregnancy 
 
All female reproductive aged participants will be asked to use a definitive form of 
contraception before enrolling in the study. However, pregnancy might occur in the study 
period. Once a female subject has been enrolled into the clinical trial, after having taken study 
medication, the investigator must report immediately any drug exposure during pregnancy and 
stop the study medication. The outcome of the pregnancy associated with the drug exposure 
during pregnancy must be followed up. All outcomes of pregnancy should be reported to 
AstraZeneca.  
13.2.1 
Maternal exposure 
Dapagliflozin is pregnancy category drug C. Based on the results of reproductive and 
developmental toxicity studies in animals, dapagliflozin doses > 137 MRHD may affect renal 
development and skeletal malformation and maturation.  
Glimepiride is pregnancy category drug C. There are no adequate and well-controlled 
studies in pregnant women. In animal studies there was no increase in congenital anomalies, 
but an increase in fetal deaths occurred in rats and rabbits at glimepiride doses 50 times (rats) 
and 0.1 times (rabbits) the maximum recommended human dose (based on body surface area). 
As soon as we learn that a female subject has been pregnant, we will stop the study 
medication immediately. We will report this to AstraZeneca and IRBMED immediately. 
Patient will be asked to follow with her Obstetrician closely. We will also follow the 
pregnancy outcomes and report this to AstraZeneca. 
13.2.2 
Paternal exposure 
 
Dapagliflozin had no effects on mating, fertility, or early embryonic development in 
treated male or female rats at exposure multiples ≤1708 times and 998 times the maximum 
recommended human dose in males and females, respectively.  
There was no effect of glimepiride on male mouse fertility in animals exposed up to 
2500 mg/kg body weight (>1,700 times the maximum recommended human dose based on 
surface area). Glimepiride had no effect on the fertility of male and female rats administered 
up to 4000 mg/kg body weight (approximately 4,000 times the maximum recommended 
human dose based on surface area).  
Therefore, male subjects may have children while on study medications.  


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14. 
LIST OF REFERENCES 
1. 
Sloan, F.A., et al., THe growing burden of diabetes mellitus in the us elderly 
population. Archives of Internal Medicine, 2008. 168(2): p. 192-199. 
2. 
Bennett, W.L., et al., Comparative Effectiveness and Safety of Medications for Type 2 
Diabetes: An Update Including New Drugs and 2-Drug Combinations. Annals of 
internal medicine, 2011. 154(9): p. 602-613. 
3. 
Häring, H.-U., et al., Empagliflozin as Add-On to Metformin in Patients With Type 2 
Diabetes: A 24-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Diabetes 
Care, 2014. 37(6): p. 1650-1659. 
4. 
Henry, R.R., et al., Dapagliflozin, metformin XR, or both: initial pharmacotherapy for 
type 2 diabetes, a randomised controlled trial. International Journal of Clinical 
Practice, 2012. 66(5): p. 446-456. 
5. 
Wilding, J.P.H., et al., A Study of Dapagliflozin in Patients With Type 2 Diabetes 
Receiving High Doses of Insulin Plus Insulin Sensitizers: Applicability of a novel 
insulin-independent treatment. Diabetes Care, 2009. 32(9): p. 1656-1662. 
6. 
Bailey, C.J., et al., Effect of dapagliflozin in patients with type 2 diabetes who have 
inadequate glycaemic control with metformin: a randomised, double-blind, placebo-
controlled trial. The Lancet. 375(9733): p. 2223-2233. 
7. 
Cefalu, W.T., et al., Dapagliflozin’s Effects on Glycemia and Cardiovascular Risk 
Factors in High-Risk Patients With Type 2 Diabetes: A 24-Week, Multicenter, 
Randomized, Double-Blind, Placebo-Controlled Study With a 28-Week Extension. 
Diabetes Care, 2015. 38(7): p. 1218-1227. 
8. 
Kovacs, C.S., et al., Empagliflozin improves glycaemic and weight control as add-on 
therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: 
a 24-week, randomized, placebo-controlled trial. Diabetes, Obesity and Metabolism, 
2014. 16(2): p. 147-158. 
9. 
Heerspink, H.J.L., et al., Dapagliflozin a glucose-regulating drug with diuretic 
properties in subjects with type 2 diabetes. Diabetes, Obesity & Metabolism, 2013. 
15(9): p. 853-862. 
10. 
Inzucchi, S.E., et al., SGLT-2 inhibitors and cardiovascular risk: Proposed pathways 
and review of ongoing outcome trials. Diabetes & Vascular Disease Research, 2015. 
12(2): p. 90-100. 
11. 
Cherney, D.Z.I., et al., The effect of empagliflozin on arterial stiffness and heart rate 
variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc 
Diabetol, 2014. 13: p. 28. 
12. 
Zinman, B., et al., Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 
Diabetes. New England Journal of Medicine. 0(0): p. null. 
13. 
Group, U.K.P.D.S., Intensive blood-glucose control with sulphonylureas or insulin 
compared with conventional treatment and risk of complications in patients with type 
2 diabetes (UKPDS 33). The Lancet, 1998. 352(9131): p. 837-853. 
14. 
Ohkubo, Y., et al., Intensive insulin therapy prevents the progression of diabetic 
microvascular complications in Japanese patients with non-insulin-dependent diabetes 
mellitus: a randomized prospective 6-year study. Diabetes Research and Clinical 
Practice, 1995. 28(2): p. 103-117. 


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15. 
Group, U.K.P.D.S., Effect of intensive blood-glucose control with metformin on 
complications in overweight patients with type 2 diabetes (UKPDS 34). The Lancet, 
1998. 352(9131): p. 854-865. 
16. 
Holman , R.R., et al., 10-Year Follow-up of Intensive Glucose Control in Type 2 
Diabetes. New England Journal of Medicine, 2008. 359(15): p. 1577-1589. 
17. 
The Action to Control Cardiovascular Risk in Diabetes Study, G., Effects of Intensive 
Glucose Lowering in Type 2 Diabetes. The New England journal of medicine, 2008. 
358(24): p. 2545-2559. 
18. 
Duckworth , W., et al., Glucose Control and Vascular Complications in Veterans with 
Type 2 Diabetes. New England Journal of Medicine, 2009. 360(2): p. 129-139. 
19. 
Group, T.A.C., Intensive Blood Glucose Control and Vascular Outcomes in Patients 
with Type 2 Diabetes. New England Journal of Medicine, 2008. 358(24): p. 2560-
2572. 
20. 
Erdmann, E., et al., PROactive 07: pioglitazone in the treatment of type 2 diabetes: 
results of the PROactive study. Vascular Health and Risk Management, 2007. 3(4): p. 
355-370. 
21. 
Kahn , S.E., et al., Glycemic Durability of Rosiglitazone, Metformin, or Glyburide 
Monotherapy. New England Journal of Medicine, 2006. 355(23): p. 2427-2443. 
22. 
Home, P.D., et al., Rosiglitazone evaluated for cardiovascular outcomes in oral agent 
combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-
label trial. The Lancet. 373(9681): p. 2125-2135. 
23. 
Ratner, R., et al., Cardiovascular safety of exenatide BID: an integrated analysis from 
controlled clinical trials in participants with type 2 diabetes. Cardiovascular 
Diabetology, 2011. 10: p. 22-22. 
24. 
Marso, S.P., et al., Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. New 
England Journal of Medicine. 0(0): p. null. 
25. 
Nauck, M.A., et al., Dapagliflozin Versus Glipizide as Add-on Therapy in Patients 
With Type 2 Diabetes Who Have Inadequate Glycemic Control With Metformin: A 
randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes 
Care, 2011. 34(9): p. 2015-2022. 
26. 
Jørgensen, C.H., et al., Glyburide increases risk in patients with diabetes mellitus after 
emergent percutaneous intervention for myocardial infarction — A nationwide study. 
International Journal of Cardiology, 2011. 152(3): p. 327-331. 
27. 
Pantalone, K.M., et al., The Risk of Overall Mortality in Patients With Type 2 Diabetes 
Receiving Glipizide, Glyburide, or Glimepiride Monotherapy: A retrospective 
analysis. Diabetes Care, 2010. 33(6): p. 1224-1229. 
28. 
Cryer, P., Hypoglycemia: Still the Limiting Factor in the Glycemic Management of 
Diabetes. Endocrine Practice, 2008. 14(6): p. 750-756. 
29. 
Cryer, P.E., S.N. Davis, and H. Shamoon, Hypoglycemia in Diabetes. Diabetes Care, 
2003. 26(6): p. 1902-1912. 
30. 
Limberg, J., et al., Autonomic control during acute hypoglycemia in type 1 diabetes 
mellitus. Clinical Autonomic Research, 2014. 24(6): p. 275-283. 
31. 
Robinson, R.T.C.E., et al., Mechanisms of Abnormal Cardiac Repolarization During 
Insulin-Induced Hypoglycemia. Diabetes, 2003. 52(6): p. 1469-1474. 
32. 
Maalouf, R. and S. Bailey, A review on B-type natriuretic peptide monitoring: assays 
and biosensors. Heart Failure Reviews, 2016: p. 1-12. 


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33. 
Maisel, A., B-Type Natriuretic Peptide Levels: Diagnostic and Prognostic in 
Congestive Heart Failure: What’s Next? Circulation, 2002. 105(20): p. 2328-2331. 
34. 
Professional Practice Committee. Diabetes Care, 2016. 39(Supplement 1): p. S3-S3. 
35. 
Jaiswal, M., et al., Association Between Impaired Cardiovascular Autonomic Function 
and Hypoglycemia in Patients With Type 1 Diabetes. Diabetes Care, 2014. 37(9): p. 
2616-2621. 
36. 
Pop-Busui, R., What Do We Know and We Do Not Know About Cardiovascular 
Autonomic Neuropathy in Diabetes. Journal of Cardiovascular Translational Research, 
2012. 5(4): p. 463-478. 
37. 
Vinik, A.I. and D. Ziegler, Diabetic Cardiovascular Autonomic Neuropathy. 
Circulation, 2007. 115(3): p. 387-397. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Documentation of the Informed Consent Process for Onsite Subject File 
 
Protocol No.:HUM00121107  
 
 
 
 
 
 
 
Study Title/PI: Dapagliflozin and Measures of Cardiovascular Autonomic Function in Patients 
with Type 2 Diabetes (T2D) 
Rodica Pop-Busui, Ph.D, M.D. 
Subject ID: 
 
 
 
 
 
 
 
 
 
 
 
Consent Obtained by:  
 
 
 
 
 
 
 
 
 
Date of Consent: 
 
 
 
 
 
 
 
 
 
 
 
15. 
CHECK ALL THAT APPLY 
 
The subject meets all eligibility requirements. 
 
Discussed, explained and reviewed the consent form with subject. 
 Verbal consent was obtained (per IRB approved consent process) 
 Surrogate consent was obtained (per IRB approved consent process) 
 
All of the subject’s questions were answered/concerns addressed.  (document 
multiple subject contacts below) 
 Subject did not have any questions/concerns 
 
Subject was given time to review the consent form and to discuss participation in 
this study with family members/others. 
 
The subject has agreed to participate in the study and signed/dated a valid consent 
form prior to the start of any study procedures. 
 The consent process was witnessed by a third party (if applicable).   
Witnessed by: 
 A copy of the signed and dated consent form was given to the subject. 
 A copy of the signed and dated consent form was placed in the medical record. 
 A copy of the signed and dated consent form was placed in the research record. 
Signature/Initials: 
Date: 


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MEDICAL HISTORY WORKSHEET  
DATE _____________ 
SUBJECT ID ____________________ 
 
STAFF INITIALS _______________ 
Record all past and/or concomitant medical conditions or surgeries. Record only one 
condition or surgery per line using the codes provided in the table. When recording a 
condition and surgery related to that condition use one line for the condition and one line for 
the surgery. 
 
01 Head, Eye, Ear, Nose, Throat  
02 Respiratory 
03 Cardiovascular 
04 Gastrointestinal 
05 Genitourinary 
06 Musculoskeletal 
07 Neurological 
08 Endocrine/Metabolic 
09 Blood/Lymphatic 
10 Dermatologic 
11 Psychiatric 
12 Allergy 
91 Other 
 
 
Code 
 
Condition/Disease 
(one item per line) 
Start Date 
dd/mmm/yyyy 
Current / 
Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 


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 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 Current 
 Resolved 
 
 
 
 
 
 
 
 
 
 
 
PHYSICAL EXAMINATION WORKSHEET  


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DATE __________ 
 
SUBJECT ID ___________________ 
 
STAFF INITIALS ___________ 
 
Please complete checklist and describe any abnormalities. 
 
 
 
 
Normal   Abnormal   Not done 
Eyes (including fundoscopy)    ⎕ 
     ⎕          ⎕       Retinopathy, macular degeneration 
 
Other  
 
 
 
 
      __________________________ 
Cardiovascular 
 
   ⎕ 
     ⎕          ⎕       Arrhythmia, murmur 
 
Other  
 
 
 
 
       ___________________________ 
Extremities 
 
 
   ⎕          ⎕           ⎕        Amputation, tenderness, edema 
            Pulses:  1+  / 2+ /  3+ / 4+ 
            Other                                                                      ___________________________ 
Lymph Nodes                          ⎕             ⎕          ⎕       Swelling 
             Other                                                                     ____________________________ 
Pulmonary                               ⎕           ⎕         ⎕      Decreased breath sounds 
           Other                                                                      ____________________________ 
Skin                                          ⎕           ⎕          ⎕      Red or purple painful rash, 
scar,eczema, 
                                                                                           psoriasis, ulcer, excessive bruising 
          Other                                                                       ______________________________ 
Gastrointestinal                      ⎕           ⎕          ⎕       Ascites, abdominal mass, 
                                                                                         Organomegaly, stoma 
          Other                                                                   ______________________________                      
Musculoskeletal                      ⎕           ⎕          ⎕       Joint pain stiffness or swelling,  
                                                                                          Muscle pain or weakness, difficulty   


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                                                                                         walking or moving                          
            Other                                                                   ______________________________               
Neurological                               ⎕             ⎕          ⎕     Abnormal reflexes (hypo/  
                                                                                            hyperreflexia), decreased sensation               
                                                                                            cranial nerves (abnormal –  specify) 
         Other                                                                        ______________________________          
Reflexes                                    ⎕             ⎕         ⎕     ______________________________ 
 
Other, specify: 
___________________________________________________________________________ 
Is participant having any side effects from study meds?  Yes ⎕   No ⎕ 
If yes, specify:  
___________________________________________________________________________ 
NOTE: If participant has side effects, complete AE worksheet and SAE worksheet (if 
necessary). 
If this is a screening Physical Exam, is participant eligible based in this exam? 
Yes  ⎕    No  ⎕   N/A ⎕ If no, explain:  
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________
___________________________________________________________________________ 
 
 
Physician’s Name (printed):__________________________________________________ 
 
Physician’s Signature:  ______________________________________________________                            
 
 
 
  
      


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Medical History Changes 
 
Subject ID: ____________________  
Date: __________________ 
 
Visit: ____________ 
Was there a change in your medical or surgical history?  
 
Yes   
No 
 
If yes, describe:__________________________________________________ 
____________________________________________________________________
____________________________________________________________________
____________________________________________________________________ 
 
Was there a change in your current medications? 
 
Yes   
No  
If yes, describe: ___________________________________________________ 
____________________________________________________________________
____________________________________________________________________
____________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Title:  _DAPA-CAN  HUM00121107 
Subject ID:    
 
 
 
 
CONCOMITANT MEDICATIONS WORKSHEET  
 
 
Is the participant taken any concomitant medications at 
screening or during the prior 3 months     
 No        
 Yes, Complete below 
Medication 
(Record 
Generic or  
trade name) 
Reason for use 
(Medical History 
diagnosis or other 
reason, e.g. 
Prophylaxis) 
Dose 
and 
units 
Frequency 
 
 
Route 
Start Date 
(DD/MMM/YYYY) 
Stop Date 
(DD//MMM
/YYY) 
Or tick if 
ongoing at 
Screening 
Visit 
1. 
 
 
 
 
____/_____/_____ 
 
____/_____/
_____ 
        
 
2. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
3. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
4. 
 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
5. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
6. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
7. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
8. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
       
 
9. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
 
10. 
 
 
 
 
____/_____/_____ 
____/_____/
_____ 
 
 
 
Staff Initials:   
 
_____________ 
 


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DATE _ _/_ _/_ _ _ _ 
              mo           day                    yr  
SUBJECT ID   
_ _ _   
 
STAFF INITIALS     _ _ _   
Cardiovascular Autonomic Neuropathy Testing Worksheet 
PREPAREDNESS FOR TESTING  
(If YES is answered to any of the questions below, patient is ineligible for CAN testing today.  
Reschedule the patient for testing another day and discard this form.) 
  
No       Yes 
1.        Any food since in the past 12 hours? 
(1)        (2) 
2.        Any liquids in the past 12 hours? (except water) 
(1)        (2) 
3.        Any caffeine in the past 12 hours? 
(1)        (2) 
4.        Any medication in the past 12 hours (excluding basal pump insulin)? 
(1)        (2) 
5.        Any over-the-counter drugs in the past 12 hours (aspirin, antihistamines, nasal 
spray, etc.) 
(1)        (2) 
6.        Any alcohol in the last 24 hours 
(1)        (2) 
7.        Any tobacco in the past 12 hours? 
(1)        (2) 
8.        Any vigorous exercise in the last 24 hours? (Any exercise not part of patient’s 
daily routine, i.e., routine jogging O.K., but marathon running is not.  NO exercise 
morning of test.) 
(1)        (2) 
9.     Any emotional upset in the last 24 hours” (Depression, crying episodes, anxiety 
from personal trauma 
(1)       (2) 
10.     Acute illness in last 48 hours? (cold, flu, measles, etc.).  
(1)        (2) 
11.     Any hypoglycemic episodes since midnight? 
(1)        (2) 
12 a) Fasting blood sugar value (finger stick method O.K.) 
___  ___ ___ 
mg/dl 
     b)  Below 50 or signs or symptoms of hypoglycemia? 
(1)       (2) 
VITAL SIGNS 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
59(91) 
1. 
Height 
2. 
Weight 
___ ___ ___ . 
___(cm)   
___ ___ ___ . 
___(kg) 
3. 
BP 
4. 
Pulse 
__ __ __ / __ 
__mmHg 
___ ___ ___ 
BPM 
List any medications taken in the last 48 hours: 
 
 
 
 
 
 
 
 
 
 
 
Form completed by:_________________________________________________________ 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
60(91) 
DATE _ _/_ _/_ _ _ _ 
          mo               day                     yr  
SUBJECT ID   
_ _ _   
 
STAFF INITIALS     _ _ _   
 
Heart Rate Variability Test Report 
 
 
Technician’s Signature:_________________________ 
Date:______________ 
Physician’s Signature:________________________ 
Date:______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
61(91) 
Adverse Event Monitoring 
 
Subject ID: ________________  
 
Date: ____________________ 
 
Visit: ____ 
 
Was there any new or worsening adverse events reported?  
Yes, new event(s) 
Yes, worsening event(s) 
Yes, both 
No 
Number of new or worsening adverse events: ________ 
 
Were any of the following events reported (check all that apply)? 
Urinary Tract Infection 
Genital Infection 
Hypotension 
Dehydration 
DKA 
Other 
If other, describe: 
__________________________________________________  
*If there was a new or worsening adverse event, fill out a corresponding AE 
form for each event.  
 
 
Completed By: __________________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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Adverse Event Form 
 
Subject ID: ___________________  
 
AE Number:  AE __ __ 
 
Description of AE: 
_____________________________________________________________ 
_____________________________________________________________ 
 
Date this Report Opened: _________________________ 
 
Date this Report Closed: _________________________ 
 
Most recently completed subject visit number (if event is reported in context of current 
visit, record today's visit number): _____________ 
Date Adverse Event Started: ____________________ 
(can be approximate or unsure) 
Date that the Study Staff Learned of the Event: ______________________ 
 
Date Adverse Event Abated: ________________________ 
 
(can be approximate or unsure, leave blank until abated)  
 
 
 
 
 
Check if ongoing at conclusion of study 
Indicate PI initial level of severity using the scale below:  
1 - Mild AE - No treatment needed 
2 - Moderate AE - Resolved with treatment 
3 - Severe AE - Inability to carry on normal activities, required professional 
medical attention. 
4 - Life-threatening or disabling AE 
5 - Fatal AE 
Indicate the final PI level of severity using the scale below:  
1 - Mild AE - No treatment needed 
2 - Moderate AE - Resolved with treatment 
3 - Severe AE - Inability to carry on normal activities, required 
professional medical attention. 
4 - Life-threatening or disabling AE 
5 - Fatal AE 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
63(91) 
 
Indicate the PI initially relation to study participation.  
 
Definite 
Probable 
Possible  
Unlikely 
Unrelated 
 
 
Indicate the PI final relation to study participation. 
 
Definite 
Probable 
Possible 
Unlikely 
Unrelated 
 
 
Was the event expected?        Yes 
 
No 
 
What action was taken for the event reported (check all that apply)? 
No action taken 
 
 
 
 
 
 
Medication Prescribed 
Non-Drug Treatment Prescribed (e.g., physical therapy) 
 
Study Medication Dose Reduced  
 
 
 
Study Medication Stopped 
Outpatient Medical Visit 
 
 
 
 
 
Urgent Care Visit 
 
 
Emergency Room Visit 
Hospitalization 
 
 
 
 
Other 
 
 
 
If other, describe: __________________________________________ 
 
Was medication stopped or reduced?           Yes          No 
 
Date dose was stopped or reduced: _______________________ 
 
Did the adverse event abate after stopping/reducing study medication? 
 
Yes  No 
 
If yes, has the study medication dose increased or restarted? 
 
Yes 
No 
Date medication was increased or restarted: _____________________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
64(91) 
 
 
Was AE submitted to UM IRB?  Yes 
     No  
Pending yearly submission  
 
Date of Submission: _________________________ 
 
Did this event meet the definition of a serious adverse event? 
Yes 
     No  
*If this adverse event meet the definition of a serious adverse event, complete a 
serious adverse event form.   
 
Comments:  
 
 
 
 
 
 
 
 
 
 
 
 
Complete By: _______________________________________ Date: ____________ 
 
Principal Investigator Signature: ____________________________ Date: _________ 
 


Clinical Study Protocol 
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Serious Adverse Event Form 
 
Subject ID: ______________________  
SAE Number: SAE __ __  
Description of Serious Adverse Event: _____________________________________ 
____________________________________________________________________ 
Date this Report Opened: ________________________ 
Date this Report Closed: _________________________ 
 
Most recently completed subject visit number (if event is reported in context of current 
visit, record today's visit number): _____________ 
Date Serious Adverse Event Occurred/Started: ____________________ 
Date that the Study Staff Learned of the Event: _______________________ 
Date Serious Adverse Event Abated: ________________________ 
 
(can be approximate or unsure, leave blank until abated)   
 
  
 
 
 
Check if ongoing at conclusion of study 
 
Is this a Death?  
Yes 
 
No 
Date of Death: ________________________ 
Location of Death: _______________________________________ 
Probable Cause of Death: _________________________________ 
Is this a Life-Threatening Event?  
Yes 
 
No 
Did the event result in inpatient hospitalization or prolongation of existing 
hospitalization? 
Yes 
 
No 
If yes, number of days in hospital: ___________ 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
66(91) 
Did the event result in persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions? 
 
Yes 
 
No 
Is the event a pregnancy resulting in a congenital anomaly or birth defect?  
Yes 
  
No 
Was this a serious event in the judgment of the investigator that required medical or 
surgical intervention to prevent death, hospitalization of life-threatening outcomes?
 
 
Yes 
 
No 
Was the event due to an overdose of study medication?  
Yes 
 
No 
Indicate the PI initially relation to study participation.  
 
Definite 
Probable 
Possible  
Unlikely 
Unrelated 
 
 
Indicate the PI final relation to study participation. 
 
Definite 
Probable 
Possible 
Unlikely 
Unrelated 
 
Was the Event Expected?      
 
Yes 
 
No 
Indicate PI initial level of severity using the scale below:  
1 - Mild AE - No treatment needed 
2 - Moderate AE - Resolved with treatment 
3 - Severe AE - Inability to carry on normal activities, required professional 
medical attention. 
4 - Life-threatening or disabling AE 
5 - Fatal AE 
Indicate the final PI level of severity using the scale below:  
1 - Mild AE - No treatment needed 
2 - Moderate AE - Resolved with treatment 
3 - Severe AE - Inability to carry on normal activities, required 
professional medical attention. 
4 - Life-threatening or disabling AE 
5 - Fatal AE 


Clinical Study Protocol 
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67(91) 
 
What action was taken for the event reported (check all that apply)? 
No action taken 
 
 
 
 
 
 
Medication Prescribed 
Non-Drug Treatment Prescribed (e.g., physical therapy) 
 
Study Medication Dose Reduced  
 
 
 
Study Medication Stopped 
Outpatient Medical Visit 
 
 
 
 
 
Urgent Care Visit 
 
 
Emergency Room Visit 
Hospitalization 
 
 
 
 
Other 
 
 
 
If other, describe: __________________________________________ 
 
Was medication stopped or reduced?           Yes          No 
 
Date dose was stopped or reduced: _______________________ 
 
Did the event abate after stopping/reducing study medication?  
 
Yes 
 
No 
 
If yes, has the study medication dose increased or restarted? 
Yes 
No 
Date medication was increased or restarted: _____________________ 
 
Was SAE submitted to UM IRB?    Yes      No  
 
Date of Submission: _________________________ 
 
 
 
Comments:  
 
Completed by: ________________________________________ Date: __________ 
Principal Investigator Signature: ______________________________ Date: _______ 


Clinical Study Protocol 
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DATE _ _/_ _/_ _ _ _ 
        
mo               day                     yr  
SUBJECT ID   
_ _ _   
 
STAFF INITIALS     _ _ _   
 
INSTRUCTIONS FOR HEART RATE VARIABILITY (HRV) TESTING 
CAN testing is done to evaluate the nerves that help to regulate heart rate and blood pressure.   
Many factors can affect CAN test results, so for accurate testing, we ask that you read and 
follow these instructions carefully and completely.  As always, if you have any questions or 
concerns about these, please contact us so that we can discuss them. 
1.  FAST FOR 12 HOURS PRIOR TO TESTING and NO CAFFEINE 12 HOURS prior to 
testing.  You should have nothing to eat or drink except water for at least 12 hours before your 
appointment.  Water is fine, but other beverages, even if they are decaffeinated, are to be 
avoided. 
2.  AVOID LOW BLOOD SUGAR.  Low blood sugar reactions can greatly affect CAN test 
results, so it is very important to avoid lows, even mild low blood sugar reactions in the 12 
hours before the test.  TAKE STEPS TO PREVENT LOW BLOOD SUGAR.  You may need 
to eat something before you go to bed, and / or reduce your evening or overnight insulin to 
prevent going low.  If you need help making insulin dose adjustments, please contact Dr. Pop-
Busui AT 734-647-9809 OR ASK OPERATOR (734-936-6267) TO PAGE HER. 
3.  DO NOT TAKE ANY MEDICATIONS for 12 hours prior to the test.  This includes 
prescription and over the counter medications.  Bring your medications (including your 
insulin) with you so that you can take them as soon as the testing is done.  IF YOU HAVE 
QUESTIONS ABOUT THIS, OR CONCERNS ABOUT SPECIFIC MEDICATIONS THAT 
YOU TAKE THAT ARE ON A VERY SPECIFIC SCHEDULE PLEASE CONTACT DR. 
POP-BUSUI PRIOR TO YOUR TEST.   
4.  NO ALCOHOL for 24 hours before the test.  Alcohol can interfere with the function of 
autonomic nerves, so any alcohol consumed in the 24 hours prior to your test may lead to 
invalid results. 
5.  NO VIGOROUS EXERCISE for 24 hours prior to the test AND NO EXERCISE ON 
MORNING OF TEST.  Exercise that is part of your daily routine is fine in the 24 hours prior 
to testing (for example – routine jogging is okay, but running a marathon the day before 
testing is not – unless you run marathons on a daily basis).   
6.  SIGNIFICANT EMOTIONAL UPSET within 24 hours of testing can also lead to invalid 
test results.  If something comes up the day before testing that is very upsetting, please call to 
discuss rescheduling the appointment. 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
69(91) 
7.  ANY ACUTE ILLNESS IN THE 48 HOURS PRIOR TO TESTING (such as colds, flu’s, 
dental work) may affect test results.  If you are sick or feeling unwell, please call and we can 
discuss whether or not we should reschedule this test. 
8.  NO SMOKING FOR AT LEAST 12 HOURS PRIOR TO TESTING.  If you do smoke, 
please do not have any cigarettes/cigars for at least the eight hours prior to testing. 
Finally, please bring your blood glucose monitor with you.  I will be asking you to check your 
blood sugar just before testing starts.  Thank you and please call or email if you have any 
questions about the CAN testing or these instructions.   
Dr. Rodica Pop-Busui: (734) 647-9809; rpbusui@umich.edu  
Dr. Lynn Ang: (734) 232-8058; angly@med.umich.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
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CASE REPORT FORM:  SCREENING VISIT (VISIT 1) 
SUBJECT ID: 
______________________ 
VISIT DATE: 
_____________________ 
CONSENT SIGNED: 
 
Eligibility Checklist: INCLUSION CRITERIA and EXCLUSION CRITERIA 
 
Inclusion Criteria – All must be 
checked to be in study 
EXCLUSION CRITERIA – If any are checked, cannot be in 
the study 
Type 2  diabetes 
History of recurrent urinary tract infections 
At least 18 Years of age 
Current participation or participation within the  
last three months in an experimental drug study. 
BMI ≤45 kg/m2 
Fungal infection, especially genital infections 
Background metformin 
monotherapy 
Severe low blood pressure 
Willing and able to take an 
oral (by mouth) medication 
once per day for 2 periods 
f 12
History of unexplained microscopic or gross 
hematuria (blood in your urine) (confirmed by 
follow-up) 
WOMEN using an 
appropriate method of 
contraception during the 
course of the study 
(hormonal, IUD, or 
diaphragm). 
Allergy to and/or have evidenced sensitivity (i.e. 
swelling, skin rashes) to the study medications (brand 
names: Farxiga and Amaryl) or other SGLT2 
 inhibitors (i.e. Jardiance, Invokana) 
 
History of diabetic ketoacidosis 
 
If you had a cardiovascular event (such as surgery, 
angioplasty, heart attack, stroke, peripheral artery 
disease) in the last three months. 
Severe kidney disease or rapidly progressing kidney 
disease 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
71(91) 
Any clinical conditions that could interfere with the 
cardiovascular autonomic function and heart rate 
variability testing (arrhythmias) 
Severe liver insufficiency and/or significant 
abnormal liver function 
 
History of cancer other than basal cell carcinoma 
and/or treatment for cancer within the last five years 
History of drug or alcohol abuse in prior 5 years. 
History of pancreas, kidney or liver transplant 
Allergy to sulfa drugs 
Class III or IV congestive heart failure 
 
 
 
 
 
 
 
Completed by: _______________________________________________________________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
72(91) 
Participant Information Survey 
HAS THE PATIENT PROVIDED SIGNED INFORMED CONSENT TO PARTICIPATE 
IN THIS RESEARCH STUDY?  
Yes   
No 
UMHS MRN: __________________________________  
Pronoun: _______ 
First Name: __________________________________  
Last Name: __________________________________  
Date of Birth: 
Gender at Birth:  
 Male   
Female 
Ethnicity:   
Hispanic or Latino       Not Hispanic or Latino         Unknown / Not 
Reported  
Race:              American Indian/Alaska 
 
 
Asian  
 
Native Hawaiian or Other Pacific Islander  
Black or African American  
White  
More than One Race  
Unknown / Not Reported  
Date of Diabetes Diagnosis: 
 
 
     (MM-YYYY)  
Address, Street, City, State, ZIP: 
________________________________________________  
Primary Phone Number: ______________________________  
Secondary Phone Number: _______________________________  
Email Address: __________________________________  
Secondary Email Address: __________________________________  
Completed By: _________________________________________ Date: _________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
73(91) 
 
Visit 1 Overview and Screening Disposition 
 
 
SUBJECT ID: ____________________________ 
 
Date: _________________________  
 
Weight (kgs): _____________________    Height (inches): _____________________ 
 
Pulse (seated): __________________    Blood Pressure (seated): __________________ 
 
 
 
Assessments 
 
 
Informed Consent 
 
 
 
Performed by: _____________________ 
 
Medical History and Physical Examination  Performed by: _____________________ 
 
ECG   
 
 
 
 
Performed by: _____________________ 
 
Laboratory Measures  
 
 
Performed by: ___ 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
 
DISPOSITION: 
Eligible
Not Eligible 
 
 
 
If eligible, schedule a baseline visit to occur within 30 days. 
 
BASELINE VISIT DATE: ___________________________ 
 
 
Comments: 
 
 
 
 
 
 
 
Signature of Coordinator: _________________________________ Date: _______________ 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
74(91) 
Visit 2 Overview 
 
 
SUBJECT ID: ____________________________ 
 
Date: _________________________  
 
Weight (kgs): _____________________    Blood Pressure (seated): __________________ 
 
Pulse (seated): __________________    Resting HR (supine from HRV): ________________ 
 
Height (inches):__________ 
 
 
 
 
 
 
 
Assessments 
 
HRV Testing   
 
 
 
Performed by:____ 
 
CARTs Testing  
 
 
 
Performed by: _____________________ 
 
Assess Hypoglycemia  
 
 
Performed by: _____________________ 
 
Medication Dispensing  
 
 
Performed by: _____________________ 
 
Adverse Events Monitoring   
 
Performed by: _____________________ 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable     
 
 
VISIT 3 Scheduled for: ___________________________ 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
Signature of Coordinator: _________________________________ Date: _______________ 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
75(91) 
Visit 3 Overview 
 
 
SUBJECT ID: _________________________Date: _________________________  
 
Weight (kgs): ________________ Blood Pressure (seated): __________________ 
 
Pulse (seated): _________________Resting HR (supine 5 mins): _______________ 
 
Height (inches): ___________________ 
 
Assessments  
 
Assess Hypoglycemia 
 
Performed by: ______________________ 
 
Medication Compliance  
  
Performed by: ______________________ 
 
Adverse Events Monitoring  
Performed by: ______________________ 
 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
VISIT 4 Scheduled for: ___________________________ 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Coordinator:___________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
76(91) 
Visit 4 Overview 
 
 
SUBJECT ID: _________________________ Date: _________________________  
 
Weight (kgs): __________________ Blood Pressure (seated): __________________ 
 
Pulse (seated): _____________ Resting HR (supine 5 mins): __________________ 
 
Height (inches): ___________________ 
 
Assessments  
 
Assess Hypoglycemia 
 
Performed by: ______________________ 
 
Medication Compliance  
 
Performed by: ______________________ 
 
Adverse Events Monitoring  
Performed by: ______________________ 
 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
VISIT 5 Scheduled for: ___________________________ 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Coordinator:___________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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Visit 5 Overview 
 
 
SUBJECT ID: ____________________________ Date: _____________________  
 
Weight (kgs): ___________________ Blood Pressure (seated): _________________ 
 
Pulse (seated): _______________ Resting HR (supine 5 mins): ________________ 
 
Height (inches): __________________ 
 
Assessments  
 
Medical History and Physical Examination  
Performed by: _____________ 
 
Laboratory Measures  
 
 
 
Performed by: _____________ 
 
HRV  
 
  
 
 
 
Performed by: _____________ 
 
CARTs Testing 
  
 
 
 
Performed by: _____________ 
 
 
Medication Compliance 
 
 
 
Performed by: _____________ 
 
 
Adverse Events Monitoring  
 
 
Performed by: _____________ 
 
Assess Hypoglycemia 
 
  
 
Performed by: _____________ 
 
EKG  
 
 
 
 
 
Performed by: _____________ 
 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
VISIT 6 Scheduled for: ___________________________ 
 
 
Comments: 
 
 
 
 
 
Signature of Coordinator: ___________________________ Date: _______________ 


Clinical Study Protocol 
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Visit 6 Overview 
 
 
SUBJECT ID: ______________________ Date: _________________________  
 
Weight (kgs): _____________________    Height (inches): _____________________ 
 
Pulse (seated): __________________    Blood Pressure (seated): _______________ 
 
Resting HR (supine 5 mins): _______________ 
 
 
Assessments 
 
Medical History and Physical Examination Performed by: ________________ 
 
ECG   
 
 
 
Performed by: _______________________ 
 
HRV  
 
 
 
Performed by: _______________________ 
 
Laboratory Measures  
 
Performed by: _______________________ 
 
CARTs Testing 
 
 
Performed by: _______________________ 
 
Assess Hypoglycemia 
 
Performed by: _______________________ 
 
Medication Dispensing  
 
Performed by: ______________________ 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
VISIT 7 Schedule for: ___________________________ 
 
Comments: 
 
 
 
 
 
 
 
 
Signature of Coordinator: ___________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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Visit 7 Overview 
 
 
SUBJECT ID: ________________________Date: _________________________ 
 
Weight (kgs): _____________________    Blood Pressure (seated): _____________ 
 
Pulse (seated): __________________    Resting HR (supine 5 mins): ____________ 
 
Height (inches): ___________________ 
 
Assessments  
 
Assess Hypoglycemia 
 
Performed by: ______________________ 
 
Medication Compliance  
 
Performed by: ______________________ 
 
Adverse Events Monitoring  
Performed by: ______________________ 
 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
VISIT 8 Scheduled for: ___________________________ 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Coordinator: ___________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
80(91) 
Visit 8 Overview 
 
 
SUBJECT ID: _______________________  Date: __________________  
 
Weight (kgs): _____________________    Blood Pressure (seated): _____________ 
 
Pulse (seated): __________________    Resting HR (supine 5 mins): ___________ 
 
Height (inches): ___________________ 
 
Assessments  
 
Assess Hypoglycemia 
 
Performed by: ______________________ 
 
Medication Compliance  
 
Performed by: ______________________ 
 
Adverse Events Monitoring  
Performed by: ______________________ 
 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
 
VISIT 9 Scheduled for: ___________________________ 
 
 
Comments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Coordinator: __________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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Visit 9 Overview 
 
 
SUBJECT ID: ________________________ Date: _________________________  
 
Weight (kgs): _____________________    Blood Pressure (seated):______________ 
 
Pulse (seated): __________________    Resting HR (supine 5 mins): ____________ 
 
Height (inches): __________________ 
 
 
 
Assessments  
 
Medical History and Physical Examination Performed by: _________________ 
 
Laboratory Measures  
 
Performed by: ______________________ 
 
HRV  
 
  
 
Performed by: ______________________ 
 
CARTs Testing 
  
 
Performed by: ______________________ 
 
 
Medication Compliance 
 
Performed by: ______________________ 
 
 
Adverse Events Monitoring  
Performed by: ______________________ 
 
Assess Hypoglycemia 
 
Performed by: ______________________ 
 
ECG  
 
 
  
Performed by: ______________________ 
 
 
Urine Pregnancy Test Completed for Women and Result:  
 
Negative 
Positive 
Not Done 
Not Applicable 
 
Comments: 
 
 
 
 
 
 
 
 
Signature of Coordinator: ___________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
82(91) 
DATE ___________  
VISIT: _________ 
 
 
 
 
 
           
SUBJECT ID ______________ 
 
STAFF INITIALS ____________ 
 
 
EKG Testing Cover Sheet  
 
 
Interpretation:  
 
 
 
 
Technician’s Signature: _________________________ 
Date: ______________ 
 
Physician’s Signature: ________________________ 
Date: ______________ 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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ECG Report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
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DATE _ _/_ _/_ _ _ _ 
       
mo               day                     yr  
SUBJECT ID   
_ _ _   
 
STAFF INITIALS     _ _ _   
 
Glucometer Download Data 
Technician’s Signature:_________________________ 
Date:______________ 
 
Physician’s Signature:________________________ 
Date:______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
85(91) 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
86(91) 
Medication Dispensing 
 
 
Subject ID: _____________________ 
Date of Visit: _____________________     Visit: ________ 
 
v  
Was medication picked up from IDS?  
Yes  
 
No  
 
Date picked up: ________________________ 
 
Medication picked up by: __________________________________  
 
Prescription #: _________________________________ 
 
Number of Tablets Dispensed: ______________________________ 
 
Number of daily tablets prescribed by the treatment team at the conclusion of the visit today: ______ 
 
Was the patient given the study medication? 
 
Yes 
 
No  
 
Date patient received study medication: _________________________ 
 
Medication given to patient by: ________________________________ 
 
Date patient started taking the study medication: _________________________ 
 
 
Comments:_________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________ 
 
 
 
 
 
 
 
 
 
 
Form Completed by: ________________________________________ Date: ___________________ 
 
 
 
v
v
v
v


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
87(91) 
Medication Compliance 
 
Subject ID: __________________  Visit Date: ___________________  Visit: ________ 
 
How often do you skip or forget to take your study medication?  
 
Never/rarely  
Once in a while  
Sometimes 
Usually  
All the time 
 
In the last week, how many doses of study medication did you skip or forget to take?  
 
0  
1-4  
5-10  
11-20  
21+ 
 
 
Number of Tablets Dispensed at Last Visit: _________ 
 
Days Prescribed ZERO Pills Per Day: ________________________ 
 
Days Prescribed ONE Pill Per Day: _____________________ 
 
Days Prescribed TWO Pills Per Day: _____________________ 
 
Total Number of Tablets Expected to Be Taken: ________________________ 
 
Number of Days Previous Visit Drug was in Use: ____________________________ 
 
Did the Patient Return Study Medication from Prior Visit? 
   Yes            No 
 
If yes, date received by study team: _______________________ 
 
Number of Tablets Returned by Patient: ___________________ 
 
Number of Pills Taken: _________________________________ 
 
Percent Compliance: __________________________________ 
 
Since the Last Visit, was the Medication Ordered to be Stopped?       Yes      No 
Date Study Medication was Stopped: __________________________ 
Automated 
Automated 
C l
l ti
Automated 
Automated 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
88(91) 
What was the Reason for Stopping the Study Medication?   
Intolerance/side effects 
Planned medical/surgical procedure 
Participant non-compliance with protocol 
Other (specify)  
If other, specify:______________________________________ 
 
Has Study Medication Been Restarted?    
Yes 
 
No 
If yes, date study medication was restarted:______________________ 
Stop Ordered by:_________________________________________________ 
 
Since the Last Visit, was the Study Medication Ordered to be Reduced? 
Yes 
 
  No 
 
Date Study Medication was Reduced: __________________________ 
 
What was the Reason for Reducing the Study Medication? 
Intolerance/side effects 
Planned medical/surgical procedure 
Participant non-compliance with protocol 
Other (specify) 
If other, specify: 
_____________________________________________ 
Has Study Medication Been Increased?   
Yes 
 
No 
 
If yes, date study medication increased: ________________________ 
 
Change Ordered by: ____________________________________________ 
 
 
Comments:  
 
 
Medication Compliance Completed by: ____________________ Date: ___________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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DAPA-CAN Payment Form 
 
Subject ID: ________________________  
Visit Date: _____________________ 
Visit: ________  
Amount Owed: $___________ 
 
Describe Reason for Amount: _____________________________________________ 
 
Participant Payment HSIP #: ___________________ 
 
 
Check that Patient Has Been Paid 
 
 
Date Participant was Paid: _____________________ 
 
Comments:  
 
 
 
 
 
 
 
 
 
Signature of Study Team Member: ___________________________ Date: _______________ 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
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Completion Data 
Subject ID:   
 
Is this a Screen Fail? 
Yes 
No 
Has the Patient Completed the Study? 
Yes 
No 
Date of Study Completion: 
N/A 
Date Patient Withdrew from/Stopped the Study: 
 
N/A 
Reason Patient Withdrew from/Stopped the Study: 
N/A 
Non-compliance 
Did not wish to continue in study 
Could not tolerate the supplement 
Hospitalization 
Other 
If Other, Explain:   
 
Date of Last Visit: 
Comments:  
 
 
 
 
 
Completed By: 
Date:   
 
UM IRBMED# HUM00121107 


Clinical Study Protocol 
Drug Substance Dapagliflozin 
 
91(91)