Conditions: Aging
Keywords: pre-diabetes aging glucose metabolism borderline diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: yes

Brief summary:
Inhibitors of the sodium-glucose co-transporter (SGLT2) are FDA-approved for the treatment of type 2 diabetes (T2DM). Their mechanism of action involves lowering of blood glucose concentration secondary to increased glucose excretion of glucose by the kidney. These drugs also improve body weight, blood pressure, and cardiac function. Based on these pleiotropic effects, including its calorie restriction-mimetic properties, the study team hypothesize that SGLT2 drugs will impact several basic aging-related processes, including reductions in oxidative damage to DNA and proteins, advanced glycation end products (AGE) and receptor for AGE (RAGE), cellular senescence, and mitochondrial function.

Detailed description:
Investigations into the aging process have identified major cellular dysfunctions that contribute to aging, including but not limited to increased burden of damaged DNA and protein, reduction in mitochondrial respiration, and the development of pro-inflammatory senescent cells. Developing and testing interventions that interact with multiple points of this spectrum may delay the aging process. Based on prior investigations, the study team believe the SGLT2 inhibitor class of drugs may target these basic mechanisms involved in the aging process and propose testing in a high-risk human population to evaluate their effectiveness in ameliorating aging-associated dysfunctions. Specifically, the investigators hypothesize that SGLT2i drugs will lead to reductions in oxidative damage to DNA and proteins, AGE-RAGE, and cellular senescence, which will be accompanied by improvements in mitochondrial function. If the hypothesis is correct, these findings could lead to the development of new approaches to increase both health-span and lifespan.

This is a single center, open-label, randomized controlled trial. The target enrollment for this pilot study is 20 completed subjects, split evenly between experimental and control groups. Each subject will be randomized to either the experimental group of dapagliflozin 10mg daily for 12 weeks or the control group of nutritional counseling for weight loss. Health-span and clinical evaluations will be taken at baseline and at weeks 10-12 of the study.

Arms:
arm 1: 10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks. arm 2: 10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks

Interventions: intervention 1: Dapagliflozin 10 mg intervention 2: Nutritional counseling
Intervention descriptions: intervention 1: 10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth intervention 2: 10 participants randomized to receive 12 weeks of weekly counseling on nutrition

Protocol document:
Prot_SAP_000.pdf: 
 
19-766H, Solis-Herrera, Form BB, 10-30-20, AMD.doc 
 
 
 
 
CONFIDENTIAL 
CLINICAL RESEARCH PROTOCOL 
IRB# HSC20190766H v2.4 
 
 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS 
PLAN 
 
 
 
 
 
Official Study Title: SGLT2 Inhibition in Older Obese Adults With Pre-
diabetes 
 
NCT number: NCT04401904 
 
IRB Approval Date: 10-30-2020 
 
Unique Protocol ID: HSC20190766H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Effect of SGLT2 inhibition on aging-related biomarkers in older 
obese adults with pre-diabetes 
 
 
 
 
 
Principal Investigator: 
Carolina Solis-Herrera, MD 
Assistant Professor/Clinical 
Department of Medicine, Division of Diabetes 
7703 Floyd Curl, MC 7886 
210-567-6691 
 
Funding Sponsor: 
San Antonio Older Americans Independence Center, Pilot 
and Exploratory Studies Core 
 
 
Study Product: 
Dapagliflozin 
Protocol Number: 
HSC 20190766H 
NCT#: 
NCT04401904 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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Initial version: v1.0 09/10/2019 last revised v2.4_10-29-2020 
 


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                                                           TABLE OF CONTENTS 
 
STUDY SUMMARY ................................................................................................................................................ 1 
1. INTRODUCTION ................................................................................................................................................ 3 
1.1. 
BACKGROUND .......................................................................................................................................... 3 
1.2. 
INNOVATION ............................................................................................................................................. 3 
1.3. 
PRELIMINARY DATA .................................................................................................................................. 4 
1.4. 
DOSE RATIONALE AND RISK/BENEFITS ...................................................................................................... 5 
2. 
STUDY OBJECTIVE ................................................................................................................................. 5 
3. 
STUDY DESIGN ........................................................................................................................................ 5 
3.1. 
SUBJECTS ............................................................................................................................................... 5 
3.2. 
GENERAL DESIGN .................................................................................................................................... 5 
3.3. 
STUDY ENDPOINTS .................................................................................................................................. 6 
3.4 
POTENTIAL RISKS TO SUBJECT SAFETY .................................................................................................... 6 
4. 
SUBJECT SELECTION AND WITHDRAWAL ......................................................................................... 7 
4.1. 
INCLUSION CRITERIA ................................................................................................................................ 7 
4.2. 
EXCLUSION CRITERIA ............................................................................................................................... 8 
4.3. 
SUBJECT RECRUITMENT AND SCREENING ................................................................................................. 8 
4.4. 
EARLY WITHDRAWAL OF SUBJECTS .......................................................................................................... 8 
4.4.1. 
When and How to Withdraw Subjects .......................................................................................... 8 
4.4.2. 
Data Collection and Follow-up for Withdrawn Subjects ................................................................ 9 
5. 
STUDY DRUG ......................................................................................................................................... 10 
5.1. 
DESCRIPTION ......................................................................................................................................... 10 
5.2. 
TREATMENT REGIMEN ............................................................................................................................ 10 
5.3. 
ADMINISTRATION OF STUDY DRUG AND COMPLIANCE TO REGIMEN ........................................................... 10 
5.4. 
PRIOR AND CONCOMITANT THERAPY ...................................................................................................... 10 
5.5. 
PACKAGING ........................................................................................................................................... 11 
5.6. 
HANDLING OF STUDY DRUG .................................................................................................................... 11 
5.6.1. 
Receipt of Drug Supplies ............................................................................................................ 11 
5.6.2. 
Storage........................................................................................................................................ 11 
5.6.3. 
Dispensing of Study Drug ........................................................................................................... 11 
5.6.4. 
Return or Destruction of Study Drug ........................................................................................... 12 
6. 
STUDY PROCEDURES .......................................................................................................................... 12 
6.1. 
STUDY VISITS. ........................................................................................................................................ 12 
6.1.1 Visit 1 (Day -17 to -21) ............................................................................................................................................... 12 
6.1.2 Visit 2 (Day -12 to -17) ............................................................................................................................................... 12 
6.1.3 Visit 3 (Day -12 to -17) ............................................................................................................................................... 12 
6.1.4 Visit 4 (Day -12 to -17) ............................................................................................................................................... 13 
6.1.5 Visit 5 (Day -12 to -17) ............................................................................................................................................... 13 
6.1.6 Visit 6 (Day -12 to -17) ............................................................................................................................................... 13 
6.1.7 Visit 7 (Week 8)........................................................................................................................................................... 13 
6.1.8 Visit 8 (Week 10-11) ................................................................................................................................................... 13 
6.1.9 Visit 9 (Week 10-11) ................................................................................................................................................... 14 
6.1.10 Visit 10 (Week 10-11) .............................................................................................................................................. 14 
6.1.11 Visit 11 (Week 11-12) .............................................................................................................................................. 14 
6.1.12 Visit 12 (Week 10-11) .............................................................................................................................................. 14 
6.2. 
VISIT SCHEDULE SUMMARY. ................................................................................................................... 14 
6.3. 
ANALYSES. ............................................................................................................................................ 15 


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7. 
STATISTICAL PLAN ............................................................................................................................... 16 
7.1. 
SAMPLE SIZE DETERMINATION ................................................................................................................ 16 
7.2. 
STATISTICAL METHODS .......................................................................................................................... 16 
8. 
SAFETY AND ADVERSE EVENTS ........................................................................................................ 16 
8.1. 
DEFINITIONS .......................................................................................................................................... 16 
8.2. 
RECORDING OF ADVERSE EVENTS .......................................................................................................... 18 
8.3. 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ........................................... 18 
8.4. 
MEDICAL MONITORING ........................................................................................................................... 19 
8.4.1. 
Investigator reporting of Protocol Deviations/Violations ............................................................. 19 
8.4.2. 
Definitions of Protocol Deviations/Violations .............................................................................. 20 
8.5. 
SAFETY PROCEDURES ........................................................................................................................... 20 
8.5.1. 
Designated Safety Officer ........................................................................................................... 20 
8.5.2. 
Research Drug Manager............................................................................................................. 20 
8.5.3. 
Sponsor Investigator ................................................................................................................... 20 
8.5.4. 
Clinical Study Coordinator .......................................................................................................... 20 
8.6. 
STOPPING RULES .................................................................................................................................. 22 
9. 
DATA HANDLING AND RECORD KEEPING ........................................................................................ 22 
9.1. 
CONFIDENTIALITY ................................................................................................................................... 22 
9.2. 
REGISTRATION WITH CLINICALTRIALS.GOV .............................................................................................. 22 
9.3. 
SOURCE DOCUMENTS ............................................................................................................................ 22 
9.3.1. 
Research Electronic Data Capture (REDCap) and origination of electronic source data .......... 22 
9.3.2. 
Paper source data ....................................................................................................................... 23 
9.3.3. 
Handwritten entries ..................................................................................................................... 23 
9.3.4. 
Remote and/or virtual research interactions ............................................................................... 23 
9.4. 
DATA MANAGEMENT .............................................................................................................................. 23 
9.5. 
RECORDS RETENTION ............................................................................................................................ 23 
10. 
STUDY MONITORING, AUDITING, AND INSPECTING ........................................................................ 24 
10.1. 
STUDY MONITORING PLAN ..................................................................................................................... 24 
10.2. 
AUDITING AND INSPECTING ..................................................................................................................... 24 
11. 
ETHICAL CONSIDERATIONS ................................................................................................................ 24 
12. 
STUDY FINANCES ................................................................................................................................. 25 
11.1. 
FUNDING SOURCE .................................................................................................................................. 25 
11.2. 
CONFLICT OF INTEREST .......................................................................................................................... 25 
11.3. 
SUBJECT STIPENDS OR PAYMENTS ......................................................................................................... 25 
13. 
PUBLICATION PLAN .............................................................................................................................. 25 
14. 
REFERENCES ........................................................................................................................................ 26 
15. 
ATTACHMENTS ...................................................................................................................................... 28 
SUMMARY OF PROTOCOL CHANGES ............................................................................................................. 29 
 


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List of Abbreviations 
SGLT: Sodium-glucose co-transporter 
T2DM: Type 2 Diabetes Mellitus 
AGE: Advanced Glycation End products 
RAGE: Receptor for Advanced Glycation End products 
GFR: Glomerular Filtration Rate 
OGTT: Oral Glucose Tolerance Test 
CPET: Cardio Pulmonary Exercise Test 
 
 
 


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CONFIDENTIAL 
       Study Summary 
Title 
Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults 
with pre-diabetes 
Protocol Number 
HSC20190766H 
Phase 
2b Pilot 
Rationale 
Inhibitors of the sodium-glucose co-transporter (SGLT2) are FDA-approved for 
the treatment of type 2 diabetes (T2DM).  Their mechanism of action involves 
lowering of blood glucose concentration secondary to increased glucose 
excretion of glucose by the kidney.  These drugs also improve body weight, 
blood pressure, and cardiac function.  Based on these pleiotropic effects, 
including its calorie restriction-mimetic properties, we hypothesize that SGLT2 
drugs will impact several basic aging-related processes, including reductions in 
oxidative damage to DNA and proteins, advanced glycation end products 
(AGE) and receptor for AGE (RAGE), cellular senescence, and mitochondrial 
function.  
Study Duration 
Treatment duration 12 weeks; complete study participation up to 6 months 
Study Center(s) 
UTHSCSA (MARC, FORU, BICRC) 
Objective 
Primary Endpoint: Determine if dapagliflozin significantly reduces aging-
associated biomarkers (AGE-RAGE, oxidative stress in DNA and protein, 
cellular senescence, skeletal muscle mitochondrial function.) 
Secondary Endpoint: Determine healthspan benefits of dapagliflozin treatment 
(VO2Max, insulin sensitivity, 6-minute walk test, grip strength, quadriceps 
strength) 
Number of Subjects 
20 
Inclusion Criteria 
Men and post-menopausal women age 60 and above; BMI 30-38 (BMI _29.5 
will be rounded up); diagnosis of pre-diabetes (HbA1c 5.7-6.4%); stable body 
weight (±3% for ≥3 months); Montreal Cognitive Assessment 21 and above; 
Subjects must be in good general health as determined by physical exam, 
medical history, blood chemistries, CBC, TSH, lipid profile, EKG and urinalysis.  
Exclusion Criteria 
Diagnosis of diabetes based on ADA criteria; impaired renal function with 
eGFR < 45 mL/min/1.73m2; impaired liver function with labs 3x ULN and 
above; hematocrit with LLN 30% and below; triglycerides with ULN 600 mg/dL 
and above; abnormal TSH of 0.3 and below to 10 and above; urinalysis with 
>5-10 WBC; history of frequent UTI; poorly controlled blood pressure (sysBP 
>180, diaBP > 100 mmHg); history of recent cardiovascular event in prior 6 
months, heart failure, active heart disease; current treatment with drugs known 
to affect glucose and lipid homeostasis; current treatment with anticoagulants 
(aspirin <326 mg and clopidogrel permitted if held 7 days prior to biopsies; 
active 
inflammatory, 
autoimmune, 
gastrointestinal, 
hepatic, 
infectious, 
malignant or uncontrolled psychiatric disease (controlled depression, anxiety, 
PTSD, etc. enrollment allowed); ; blood donation within 2 months prior to 
enrollment. 
Concomitant 
Medications 
Allowed: Standard of care medications for the management of hypertension, 
hyperlipidemia and other drugs that at the discretion of the investigator will not 
interfere with the results of the study. If patient on drugs that affect metabolism 
like levothyroxine, should be on a stable dose for the last 3 months. 
 
Prohibited: Any medications known to adversely affect glucose and lipid 
metabolism. Additionally, patients on warfarin or other blood thinners except 
for aspirin up to 325mg and clopidogrel will be excluded. 


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CONFIDENTIAL 
Study Product, Dose, 
Route, Regimen 
Dapagliflozin, 10mg, Oral, Daily 
Duration of 
administration 
12 weeks 
Statistical 
Methodology 
Comparisons of means between all the groups will be done by ANCOVA.  
Associations, within a group, between aging-related biomarkers vs metabolic 
outcomes and vs. healthspan outcomes will be determined by Pearson’s 
correlation. For tests of correlation coefficients between groups, we will use the 
Fisher’s Z transformation.  We will also determine the relationship between 
aging-related biomarkers vs metabolic outcomes and vs. healthspan 
outcomes, by using multiple regression analysis.  Scatter plots will be done to 
look for outliers and to verify linearity.   


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CONFIDENTIAL 
1. Introduction 
 
This document is a protocol for a human research study. This study will be conducted according to Good 
Clinical Practice guidelines as adopted by FDA, applicable government regulations, and Institutional research 
policies and procedures.  
1.1. 
Background 
 
Type 2 diabetes mellitus (T2DM) occurs in 9% of the US population, affects ~30 million individuals and its 
prevalence has increased dramatically (1) due to multiple factors: (i) increased longevity, (ii) increased 
incidence of obesity, (iii) decreased physical activity, (iv) rapid growth of minority populations at high diabetes 
risk. T2DM patients experience significant morbidity and mortality from microvascular and macrovascular 
complications. The cost of treating diabetes and associated complications in 2007 was $174 billion and is 
predicted to double by year 2030 (2). 
 
The Diabetes Control and Complications Trial (DCCT) (3) and United Kingdom Prospective Diabetes Study 
(UKPDS) (4,5) have documented that hyperglycemia is the major risk factor for microvascular and, to lesser 
extent, macrovascular (6,7) complications. Insulin resistance and impaired insulin secretion are characteristic 
features of T2DM (8,9,10).  The earliest expression of this insulin resistance and impaired insulin secretion is 
called prediabetes. Prediabetes is characterized either by impaired fasting glucose (IFG) or abnormal plasma 
glucose after a 75gm oral glucose tolerance test (OGTT) or an A1c value of 5.7% to 6.4% There are 
approximately 84.1 million adults with prediabetes (33.9% of the population) and 23.1 of these adults are 65 
years or older (1). Prediabetes has been shown to increase the risk of developing type 2 diabetes, heart 
disease and stroke. Other classic cardiovascular risk factors are frequently present in prediabetic individuals 
including classic hypertension, dyslipidemia, procoagulant state, obesity, endothelial dysfunction, insulin 
resistance, and inflammation (3,4).Since most of the morbidity and mortality in T2DM arises from long term 
complications, early detection and effective intervention to delay or prevent development of T2DM would be 
expected to have enormous beneficial clinical, social and economic impact. 
 
The inhibitors of the sodium-glucose co-transporter-2 (SGLT2i) are FDA-approved for the treatment of type 2 
diabetes (T2DM). This class of drugs have a unique mechanism of action that involves lowering of plasma 
glucose concentration secondary to an increase in glucose excretion by the kidney. This glucosuric effect 
results in a durable reduction in HbA1c, weight loss, improved insulin sensitivity, and enhanced beta cell 
function (11). Beyond the glucocentric effects of SGLT2i, they have now been shown in patients with 
cardiovascular disease (CVD) to reduce mortality and hospitalization for heart failure and provide renal 
protection. A variety of potential mechanisms have been invoked to explain the beneficial effects of SGLT2i on 
CV mortality and hospitalization for heart failure and these have been the subject of recent reviews (12,13,14).  
Of the potential mechanisms responsible for the improved CV benefit, hemodynamic factors, including the 
simultaneous reduction in preload (12) (secondary to mild intravascular volume depletion) and afterload 
(secondary to reduced blood pressure (12) and improved aortic distensibility (15) most commonly have been 
cited. These attributes have elevated SGLT2i’s to second- or third-line therapy for the treatment of T2DM 
patients in patients with or without CVD (16,17,18).  
1.2. 
Innovation 
Investigations into the aging process have identified major cellular dysfunctions that contribute to aging, 
including but not limited to increased burden of damaged DNA and protein, reduction in mitochondrial 
respiration, and the development of pro-inflammatory senescent cells (19). Developing and testing 
interventions that interact with multiple points of this spectrum may delay the aging process. Based on prior 
investigations, we believe the SGLT2 inhibitor class of drugs may target these basic mechanisms involved in 
the aging process and propose testing in a high-risk human population to evaluate their effectiveness in 


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CONFIDENTIAL 
ameliorating aging-associated dysfunctions. Specifically, we hypothesize that SGLT2i drugs will lead to 
reductions in oxidative damage to DNA and proteins, AGE-RAGE, and cellular 
senescence, which will be accompanied by improvements in mitochondrial 
function. If our hypothesis is correct, these findings could lead to the 
development of new approaches to increase both healthspan and lifespan. 
1.3. 
Preliminary data 
SGLT2 inhibitors have shown effects on systemic and tissue low-grade 
inflammation (20) In the CANTATA-SU study, 52 weeks of canagliflozin 300 mg 
daily to individuals with T2DM decreased IL-6 by 22% and CRP by 4.4% versus 
glimepiride (21) (Figure 1). CRP and other inflammatory marker data following 
SGLT2 administration are relatively scarce in humans, but in animals, several 
reports have shown reductions in cytokine and chemokine concentrations in 
parallel with protective effects against progression of atherosclerotic lesions 
(20). Experimental findings in rodents also suggest that part of the reno-
protective effects of SGLT2 inhibition may be related to anti-inflammatory and 
anti-fibrotic actions at the kidney level. Entry of glucose into the tubule cells 
may induce inflammatory and fibrosis genes, as well as increase apoptosis.  
Experimental administration of an SGLT2i prevents tubulointerstitial injury in 
obese T2DM mice (22). Underlying mechanisms to explain this anti-
inflammatory effect are varied, but may involve weight loss, reduction in 
adipose tissue inflammation and attenuation of oxidative stress (20). 
It is clear that the elevated glycemia can accelerate the formation of advanced 
glycation end-products (AGE’s) (23). There is also evidence that engagement 
of the AGEs receptor (RAGE) by AGE’s may elicit oxidative stress as well as 
generation of inflammatory and fibrotic reactions in tissues (23). Importantly, these implicated AGEs 
inflammatory/fibrotic pathways cause widespread tissue damage including the pancreatic beta-cells, renal 
cells, and the vascular system. This directly or indirectly increases the risk of progression to T2DM, increases 
the risk of complications of diabetes such as nephropathy, neuropathy, and 
retinopathy, and the development of CVD (24). In addition, RAGE may play a 
critical role in reactive oxygen species (ROS) production.  RAGE expression and 
activation may worsen AGE accumulation through decreased expression of key 
antiglycation enzymes (23). 
The effects of SGLT2i on AGEs have yet to be extensively studied in humans, 
though we have shown that these drugs additionally increase mitochondrial fatty 
acid oxidation, cause a small increase in ketone levels, a decrease in uric acid 
levels and are associated with attenuation of oxidative stress (25). Terami et al., 
showed in male db/db mice given SGLT2i for 12 weeks that SGLT2i reduced 
renal mesangial matrix expansion and renal fibrosis.  Proinflammatory genes, 
oxidative stress, and apoptosis were all decreased in renal tissue.  In addition, 
SGLT2i restored pancreatic beta-cell mass to non-diabetic (non-diabetic db/m 
mice) levels (26). In streptozotocin-induced diabetic rats (STZ) treated for 4 
weeks of SGLT2i versus a placebo buffer, SGLT2i decreased the expression 
levels of AGEs, and its receptor (RAGE) and other markers of oxidative stress at 
the kidney level (27) (Figure 2).  Additionally, Osorio et al. reported in a similar 
streptozotocin-induced diabetic rat model that SGLT2i restored several oxidative 
stress markers to control levels and prevented renal tissue 3-nitrotyrosine 
accumulation, a tissue marker of oxidative stress (28).  
In prediabetes there is limited information regarding the role of SGLT2 inhibitors, 
but the available data in humans show that prediabetic obese subjects treated with an SGLT2i had significant 
reductions in weight (29), which is an independent CV risk factor (30) and is associated with insulin resistance, 
Figure 1. Effects on Inflammatory
Biomarkers 
at 
Week 
52.
Canagliflozin 300 mg was associated 
with a 22%reduction in median 
serum IL-6 compared to glimepiride.
Change from baseline in serum 
inflammatory biomarkers at Week
52. IL-6, interleukin-6. 
Figure 
2. 
Effects 
of 
empagliflozin on AGE-modified 
protein 
levels 
and 
RAGE 
immunostaining. 
Total RNAs 
extracted from the kidney of 
control, 
STZ 
and 
STZ 
rats+empagliflozin 
with 
RNAqueous-4PCR kit.  
 


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diabetes, dyslipidemia, hypertension, cancer, stroke and nonalcoholic fatty liver disease (31-34). It is likely that 
the other known glucose and non-glucose lowering effects of SGLT2i could be extrapolated to prediabetic 
individuals. 
1.4. 
Dose Rationale and Risk/Benefits 
 
In the DPP trial, weight loss was proportional to diabetes prevention. There are no serious risks to losing 
weight at a reasonable rate.  Dapagliflozin 10mg daily is the maximum daily dose and has been shown to 
increase glucose urinary excretion more than 5mg daily. Dapagliflozin 10mg/day has been assessed in 
combination with exenatide treatment in prediabetic patients for one year and shows similar safety and 
tolerability to previous trials in diabetic patients (35). Dapagliflozin 10mg/day is also in use for the DAPA-HF 
study in a study population that includes prediabetics (36). Another SGLT2i, empagliflozin, has been assessed 
in prediabetics at a comparably high dose (25mg/day) for two weeks and did not show AE among treated 
subjects (37). The SAE’s associated with dapagliflozin include acute kidney injury, fall from orthostasis, 
gangrene of the perineum, and diabetic ketoacidosis. These risks will be mitigated in this study by monitoring 
subject status with biweekly phone check-ins with patients as well as monthly in-person visits during drug refill 
visits.  
2. Study Objective 
The primary objective is to determine whether SGLT2 inhibitors improve biomarkers of aging in older obese 
adults with pre-diabetes. 
 
The secondary objective is to determine whether changes in aging-related biomarkers resulting from SGLT2i 
therapy are linked to changes in glucose metabolism and healthspan.  
3. Study Design 
 
3.1. 
Subjects 
Recruited subjects for this study will be men and post-menopausal women aged 60 years and above, with a 
diagnosis of obesity as measured by BMI (30-38 kg/m2; BMI >29.5 will be rounded up) and who qualify as pre-
diabetic (HbA1c 5.7-6.4%). Screening at visits 1 and 2 will identify participants who meet entry criteria for the 
study. The target enrollment for this pilot study is 20 completed subjects, split evenly between experimental 
and control groups. Because this study seeks to identify novel SGLT2i effects on biomarkers of aging, we do 
not have direct data on the potential impact of dapagliflozin on biomarkers such as cellular senescence, AGE-
RAGE, or mitochondrial function to power our study. 
3.2. 
General Design 
This is a single center, open-label, randomized controlled trial.  20 completed subjects are planned.  Each 
subject will be randomized to either the experimental group of dapagliflozin 10mg daily for 12 weeks or the 
control group of nutritional counseling for weight loss.  Healthspan and clinical evaluations will be taken at 
baseline and at weeks 10-12 of the study.  
 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be entered into the study.  
 
The following treatment regimens will be used: 
• 
Dapagliflozin: 10mg per day for 12 weeks. Subjects will return to refill drug medication and perform 
compliance check at 4 weeks and 8 weeks after beginning treatment. 
• 
Control Group: Subjects will meet with a dietitian every 1-2 weeks throughout the study to discuss 
nutritional counseling with a goal to lose 3-5% of body weight over 12 weeks to mirror expected SGLT2 


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inhibitor-derived weight loss over the same period. During these hour-long sessions, volunteers will learn 
how to adjust their eating habits by following the recommendations of the American Heart Association for 
reducing dietary fat and substituting complex carbohydrates and reducing energy intake to induce gradual 
weight loss while maintaining recommended dietary composition. Volunteers also will receive education on 
portion sizes, meal timing, and meal preparation. Participants receive a notebook of course content and will 
weigh in prior to each session. Additional counseling visits and/or phone calls may be instituted if desirable 
weight loss is not achieved. Subjects may be asked to record their dietary intake for a 24-hour period 
throughout the intervention for review by the dietitian.   
 
Total duration of subject treatment will be 12 weeks.  Total duration of the study is expected to be 16-18 
weeks. 
 
3.3. 
Study Endpoints 
 
Primary outcome: The primary endpoint for this study is a reduction in urine AGE-RAGE measurements as a 
result of dapagliflozin treatment. We will be assessing AGE-RAGE in all subjects at baseline and after 
intervention 
 
Secondary outcomes:  Mitochondrial function: This measurement will assess changes in muscle 
mitochondrial respiration after dapagliflozin treatment. Measurements will occur using muscle samples 
obtained at baseline and after intervention. 
Insulin Sensitivity: This measurement will be obtained before and after the intervention using the HOMA-IR 
index derived from the fasting insulin and glucose concentrations. 
Oxidative Stress: This measurement will be assessed in muscle samples obtained at baseline and after 
intervention. 
Healthspan Measurements: These assessments will include grip strength, isometric knee extension, 6-minute 
walking distance, and a VO2Max obtained from CPET. We will be assessing these outcomes in all subjects at 
baseline and after intervention. Measurements obtained from these exams will evaluate the effect of 
dapagliflozin treatment on physical indicators of aging. 
Cellular Senescence: Senescent cell burden will be assessed in adipose tissue obtained at baseline and after 
intervention, using both senescence-associated beta-galactosidase staining as well as senescence-associated 
gene expression assays.  
DNA methylation: DNA methylation, a key biological marker of aging, will be evaluated in peripheral blood cells 
before and after intervention. 
3.4       Potential Risks to Subject Safety 
 
a) Dapagliflozin.  
Likely and not serious: 
These risks are expected to occur in more than 20 out of 100 subjects: None 
 
Less likely and not serious: 
These risks are expected to occur in 5-20 subjects or less out of 100 subjects: Genital mycotic 
infections (about 4%) Nasopharingytis and UTI (about 1%) and in less than 4 out of 100 
individuals low blood sugar (also called Hypoglycemia)  
 
Rare and serious: loss of consciousness (or syncope), decrease in blood pressure, and 
dehydration (less than 1%) 


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b) Blood Withdrawal. All studies involve the withdrawal of blood. Any subject who has donated blood in the 
previous two months will not be studied. The subjects will be instructed not to donate blood for two months 
after the study.  Any subject with a hematocrit of less than 34% will not be studied.  The maximal amount of 
blood to be drawn during the entire study for any given subject will be approximately 200 mL. Hematology 
comprehensive metabolic panel with lipids and liver function tests will be obtained to assess effects on 
blood cell count, liver function and lipid metabolism. Pain, bleeding, bruising or swelling may occur at the 
site of the needlestick. Study participants may also experience light headedness or fatigue. Local 
hematomas occur in 1-5% of blood draws. Infection and nerve damage are possible (<1%). A qualified 
phlebotomist will perform venipunctures to minimize these risks. 
c) IV lines.  Intravenous catheters may be used for venipuncture.  Local hematomas occur in about 1% of 
catheterizations.  Infection is possible (<1%), but we have not experienced this complication.   
d) Muscle biopsy.  At the time of biopsy, subjects may feel pain, discomfort, or pressure (variably described 
by different subjects) for about 5-10 seconds.  Pain or discomfort ceases as soon as the cannula is 
withdrawn. Some localized bruising is expected after biopsy. Local hematomas occur in <2% of subjects.  
One patient experienced a moderately painful hematoma that resolved within 2 weeks (0.1%).  About 1 in 
50 subjects report non-clinically evident numbness or altered sensation at the biopsy site, which is 
transient. There is the possibility that a future biopsy may not be done at the discretion of the PI in case the 
subject did not tolerate well a prior biopsy. 
e) Adipose tissue biopsy.  A burning discomfort will be felt for about 5-10 seconds during the application of 
lidocaine.  Subjects are likely to bruise at the biopsy site, which generally resolves within one week of the 
biopsy. Mild wound infections occur in <2% subjects.   
f) Radiation exposure. Subjects will also be exposed to a very small amount of radiation during the DEXA 
exam (0.04 mrem), which equals one day of natural background radiation. 
g) Home visits. When necessary to perform home visits, study staff will use precautions to reduce the risk of 
improper disclosure or loss of research records and research specimens. The study staff will not remove 
any original records from the research site and will only use the minimal amount of PHI necessary to 
accomplish the home visit. All study records being transported will be secured in a locked file case. 
Research specimens will be labeled and packed in accordance with the site’s laboratory regulations and 
returned to the research site (FORU) in a carrier regulated for biohazardous materials. Study records and 
specimens will never be left unattended during the home visit or when being transported to and from the 
study site.   
 
4.    Subject Selection and Withdrawal 
4.1. 
Inclusion Criteria 
1) Men or post-menopausal women. 
2) Age= 60+ years.  
3) All ethnic groups. 
4) BMI between 30-38 kg/m2 (BMI >29.5 will be rounded up). 
5) Diagnosis of pre-diabetes (HbA1c 5.7-6.4%). 
6) Stable body weight (±3% for ≥3 months). 
7) Willing to adhere to medication regimen for three months. 
8) Montreal Cognitive Assessment score ≥21. 
 


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4.2.      Exclusion Criteria 
1) Diagnosis of diabetes based on ADA criteria  
2) Impaired renal function with eGFR < 45 mL/min/1.73m2. Unstable or rapidly progressing renal 
failure. 
3) Impaired liver function with labs ≥3 times upper limits of normal range 
4) Abnormal hematocrit with lower limits of ≤30%  
5) Abnormal triglycerides with upper limits ≥600 mg/dL 
6) Abnormal TSH values ≤0.3 and ≥10 
7) Urinalysis results with >5-10 white blood cell count 
8) Current medications known to affect glucose and lipid homeostasis (anti-diabetes medications, 
glucocorticoids, atypical antipsychotics, anti-transplant rejection medications, anti-retrovirals). 
9) Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be 
permitted if these can be held for seven days prior to the biopsies. 
10) History of recent cardiovascular event in the last 6 months or Heart Failure (New York Heart 
Classification greater than class III-IV; recent EKG changes that suggest active heart disease 
11) Poorly controlled blood pressure (systolic BP>180, diastolic BP>100 mmHg) 
12) Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and uncontrolled 
psychiatric disease (Subjects with depression, anxiety, PTSD, etc. can enroll if controlled and on 
stable medication) 
13) Blood donation within 2 months prior to enrollment 
14) History of frequent UTI 
 
4.3. 
Subject Recruitment and Screening 
We will screen up to 100 potentially eligible candidates to achieve the target enrollment of 20 completes. 
More candidates will be screened if attrition (est. 20%) requires it.  
 
Subjects will be recruited by advertisement, web-based notices including social media, digital outlets, referrals 
from the Barshop Clinical Research Call Center, flyers distributed and posted in senior centers, private 
geriatric offices, and through the outpatient clinics of UT Health San Antonio/UT Medicine Physicians, and 
University Health System (UHS). 
 
Screening will be performed during Visits 1 and 2.   
 
4.4. 
Early Withdrawal of Subjects 
4.4.1. When and How to Withdraw Subjects 
Subjects have the right to withdraw fully or partially from the study at any time and for any reason without 
prejudice to his or her future medical care by the physician or at the institution. 
 
Withdrawal of full consent for a study means that the subject does not wish to receive further investigational 
treatment and does not wish to or is unable to continue further study participation including any follow-up in 
person, by phone, through third parties including relatives or friends, via discussion with other treating 
physicians, and by use of medical records; subject data up to withdrawal of full consent will be included in the 


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analysis of the study. Any subject may withdraw full consent to participate in the study at any time during the 
study. The Sponsor Investigator or sub-investigator will discuss with the subject appropriate procedures for 
withdrawal from the study. 
4.4.2. Data Collection and Follow-up for Withdrawn Subjects 
If subjects are withdrawn prematurely from the study, appropriately designated research staff will make efforts 
to collect at least survival data throughout the protocol defined follow-up period for that subject.  
 
Investigator will consult with Study Statistician with regard to any incomplete data set as compared to the full 
data set that fully supports the analysis.  If a subject withdraws consent to participate in the study, attempts 
will be made to obtain permission to record survival data up to the protocol-described end of subject follow-up 
period.  
 
Investigator and designated research staff make it a high priority to obtain survival data on all subjects lost to 
follow up. Lost to follow up will be defined as a subject missing 2 or more consecutive visits, not answering or 
responding to 3 follow up phone calls to subject or emergency contacts, or returned receipt of 1 certified 
letter.  
 


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5. Study Drug  
5.1. 
Description 
The inhibitors of the sodium-glucose co-transporter-2 (SGLT2i) are FDA-approved for the treatment of type 
2 diabetes (T2DM). This class of drugs have a unique mechanism of action that involves lowering of plasma 
glucose concentration secondary to an increase in glucose excretion by the kidney. This glucosuric effect 
results in a durable reduction in HbA1c, weight loss, improved insulin sensitivity, and enhanced beta cell 
function (11). Beyond the glucocentric effects of SGLT2i, they have now been shown in patients with 
cardiovascular disease (CVD) to reduce mortality and hospitalization for heart failure and provide renal 
protection.  These attributes have elevated SGLT2i’s to second- or third-line therapy for the treatment of 
T2DM patients in patients with or without CVD (16-18). Approximately 1/3 of older adults are pre-diabetic.  
In prediabetes there is limited information regarding the role of SGLT2 inhibitors, but the available data in 
humans show that prediabetic obese subjects treated with an SGLT2i had significant reductions in weight 
(19), which is an independent CV risk factor (20) and is associated with insulin resistance, diabetes, 
dyslipidemia, hypertension, cancer, stroke and nonalcoholic fatty liver disease (21-24). It is likely that the 
other known glucose and non-glucose lowering effects of SGLT2i could be extrapolated to prediabetic 
individuals. Dapagliflozin is an SGTL2 inhibitor given for the management and treatment of type 2 diabetes 
and will be the study drug used for these experiments.   
 
Dapagliflozin (Brand name Farxiga) is administered orally as a yellow pill in either 5mg or 10mg doses. The 
10mg dose that will be used in this study is a 4-sided yellow pill with 10 and 1428 printed on opposite sides.  
5.2. 
Treatment Regimen 
Administration Protocol.  
Following the completion of informed consent, screening visits, enrollment into the study, and baseline 
measurements, subjects will be provided study drug by the Study Coordinator at the conclusion of Visit 5. 
Subjects will take 1 pill daily (10mg) as directed during the study period. Subjects will self-administer drug 
according to product packaging, and compliance calls every two weeks from study investigators will ensure 
proper scheduling of drug administration as well as to monitor AE development. Subjects randomized to 
treatment group will receive a 30-day supply of drug during their Visit 5 randomization and will be required to 
return 4 weeks and 8 weeks later for refilling study drug. Method for Assigning Subjects to Treatment 
Groups 
 
The randomization key will be designed by an objective researcher or statistician not on the study team at 
the Barshop Institute or from Clinical Research Unit and provided to the Clinical Study Coordinator at the 
site.  The Study Coordinator, as assigned, stores the Enrollment key, which is kept in a locked cabinet. Study 
staff maintains source documents, data records and specimens in a de-identified manner using only the 
unique Subject ID/Randomization number. 
5.3. 
Administration of Study Drug and Compliance to Regimen 
Study Coordinator orders and obtains medication dispensed from the Research Drug Manager (or research 
pharmacy unit if available). Subjects will self-administer medication and will be instructed to bring back 
empty or partially empty bottles to each in-person study visit for medication reconciliation and compliance 
procedures. Subjects will be interviewed by phone every two weeks to ensure compliance with study 
regimen as well as to note potential AEs. 
 
5.4. 
Prior and Concomitant Therapy 
Exclusionary medications:  
Drugs that affect glucose and lipid homeostasis. Anti-diabetes drugs (including but not limited to 


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metformin, 
sulfonylureas, 
other 
SGLT2i, 
DPP 
inhibitors, 
etc). 
Glucocorticoids 
(prednisone, 
methylprednisone, hydrocortisone). Atypical antipsychotics (olanzapine, clozapine, etc). Anti-rejection 
medications (prograf, cellcept). Anti-retrovirals (protease inhibitors).  
Treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these 
can be held for seven days prior to the biopsies. 
5.5. 
Packaging    
 
Nature and Contents of the Container – bottle of 30 tablets 
 
 
.  
5.6. 
Handling of Study Drug 
Research Drug Manager will be responsible for receipt, storage, dispensing, handling and destruction of 
Study Drug. 
5.6.1. Receipt of Drug Supplies 
 
Any damaged or unusable study drug in a given shipment will be documented by the Research Drug 
Manager.  The Research Drug Manager will notify the Material Sponsor of any damaged study drug. 
5.6.2. Storage 
The drug product used for clinical studies should be stored at USP recommended room temperature.  
Excursions from the recommended room temperature will be documented by the Research Drug Manager 
and acted upon after consultation with Material Sponsor (or AstraZeneca, manufacturer).  Expirations on 
the study product will be honored. 
 
For more details, please see also Farxiga Package Insert or Farxiga Health Care Provider website: 
https://www.farxiga-hcp.com/  
 
5.6.3. Dispensing of Study Drug 
Designated staff from the Research Drug Management unit will maintain the Drug Administration Logs to 
track how, when and to whom the investigational drug was dispensed and assigned to subjects. Study 
clinical staff will keep administration records regarding dosing, unused drug, drug damaged, or wasted. 
 
Study drug may be dispensed to participants in person, at home visits, curbside delivery, or by U.S. mail.  
 


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Labeling study drug will include FDA required language including "Caution: New Drug--Limited by Federal 
(or United States) law to investigational use." 
 
Routine Study Drug reconciliation will be performed based on clinical site policy and standard operating 
procedures. 
5.6.4. Return or Destruction of Study Drug 
The procedures for final reconciliation of the site’s drug supply at the end of the study will be in accordance 
with local site Drug Management standard operating procedures. 
 
There are no special precautions cited for disposal of dapagliflozin. 
 
6. Study Procedures 
 
6.1. 
Study visits.   
Visits will be performed at the UT Health San Antonio Medical Arts and Research Center (MARC) or at the 
Barshop Institute Clinical Research Center (BICRC), except for magnetic resonance studies that will be done 
at the Research Imaging Institute.  Participants will arrive fasting (10-12 h) for visits involving lab work, 
imaging, or biopsies. If the study investigator determines that it is in the greater interest of the safety of the 
study staff and study participants, the study staff may perform home visits or video telehealth visits. . 
Participants will be given a Fitbit Bluetooth scale to obtain their weight measurement at home. The data will 
be transmitted to the research staff electronically through the Fitbit app. The study staff will receive the 
information in an individual, non-identifiable email account that the study staff will create for each study 
participant. If the participant does not have access to a mobile device or cannot access the Fitbit app, the 
study staff will collect the data during home visits or by telephone. The scales will be provided to study 
participants at no charge.  Visits that require DXA scans and MRI scans may be performed 
interchangeably due to availability of  the DXA and MRI scanners. 
6.1.1. Visit 1 (Day -17 to -21) 
Eligible subjects present to the research unit at appointed time for informed consent. Consenting subjects will 
arrive fasting to undergo vital sign evaluation, medical history, physical exam, safety labs [comprehensive 
metabolic panel (CMP), complete blood count with differential (CBC), coagulation labs (PT/PTT/INR), 
HbA1c, TSH, routine urinalysis, lipid panel,  insulin and FFA, and the Montreal Cognitive Assessment 
(participants must score ≥21 to be eligible). Visit results will help determine eligibility for study inclusion (i.e. 
HbA1c 5.7-6.4%).  
Investigators will routinely assess laboratory value excursions for clinical significance.  
 
Adverse events are assessed at every visit once subjects are consented and enrolled to undergo research 
procedures and study intervention. 
6.1.2. Visit 2 (Day --7 to -17 [+/- 2 weeks])+ 
Eligible subjects will present to the MARC research unit for vital signs, walk distance, grip strength, isometric 
knee extension strength testing, a body composition DXA scan and liver fibroscan.    
6.1.3. Visit 3 (Day -7 to -17 [+/- 2 weeks])+ 
Subjects will come to the Research Imaging Institute for intrahepatic liver fat measurement by Magnetic 
Resonance Spectroscopy/Imaging. 
 
+ Visits 2 and 3 may be performed interchangeably based on DXA and MRI scanner availability. 
 


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6.1.4. Visit 4 (Day -1 to -6) -- "Optional" 
Participants who opt in will come to the research unit for vital signs and VO2max testing. 
 
Cardiorespiratory fitness is determined by a CPET on an electronically braked cycle ergometer per the 
American College of Sports Medicine (ACSM) Testing Guidelines. Oxygen consumption and carbon 
dioxide production are measured by indirect calorimetry. ECG (12-lead) recordings and blood pressure 
are monitored at rest prior to testing and during the testing. A clinician interprets for contraindications to 
exercise prior to testing. AHA criteria are used to halt exercise testing [43].  
6.1.5. Visit 5 (Day 0) 
Eligible subjects present to the research unit fasting at appointed time for a vastus lateralis muscle biopsy 
(39) and subcutaneous fat biopsy (40). We apply local lidocaine for muscle and adipose biopsies.  The 
muscle biopsy is done using a modified Bergstrom technique with suction and the adipose biopsy is done 
using a mini-liposuction technique. Urine and blood samples also will be collected. These samples will be 
used for baseline assays of tissue cellular senescence, DNA methylation, oxidative stress and mitochondrial 
function. After the muscle and adipose tissue biopsies, subjects will be given breakfast and will receive 
assignment to treatment intervention (randomized) before being discharged to home. Both treatment and 
control groups will be given a brochure highlighting healthier eating habits. Subjects in the treatment group 
will be given a 30-day supply of dapagliflozin to begin use the next day. Subjects in the control group will 
receive a nutritional consultation with a dietician, which may also be conducted by video telehealth visit, with 
the goal of losing 3-5% body weight during the 3-month period of the study.   
 
• 
Once intervention phase begins, the study staff will contact subjects assigned to study drug for 
telephone follow up at Visit 5 +1 week and at or near midpoint between visits to the research unit up 
to Visit 8.  
• 
Subjects assigned to nutritional counseling group will receive weekly phone calls/video telehealth 
visits during the intervention phase which will last for 12 weeks. 
• 
Study team members may contact the subjects by phone at any time for AE follow up as needed. 
6.1.6. Visit 6 (Week 4) 
Subjects will come to the research unit for evaluation of the biopsy sites and undergo blood draw for CMP 
to monitor kidney function. Subjects will also have current weight checked at this visit. If necessary, the 
study coordinator may conduct Visit 6 by home visit and perform the biopsy site check by video telehealth 
visit. Control group subjects will receive nutritional counseling, which may be performed by home visit or a 
video telehealth visit. 
 
Drug Refill: Subjects in the treatment group will be given a 30-day supply of dapagliflozin by the Research 
Drug Manager to begin when their current supply runs out. Study coordinators will ensure treatment 
compliance by asking subjects to bring drug containers and any remaining dapagliflozin tablets to their 
visits. 
6.1.7. Visit 7 (Week 8) 
Subjects in the treatment group will return for T+8 drug refill (in person, by mail, or curbside delivery), and 
control group subjects will be weighed and receive nutritional counseling, which may be performed by home 
visit or a video telehealth visit. Control group subjects will receive nutritional counseling, which may be 
performed by home visit or a video telehealth visit. 
 
6.1.8. Visit 8 (Week 10-11 [+/- 2 weeks])+ 
Subjects will undergo post-treatment measurement of cognition (Montreal Cognitive Assessment), walk 


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distance, grip strength, isometric knee extension strength, DXA scan and liver fibroscan. Control group 
subjects will receive nutritional counseling, which may be performed by home visit or a video telehealth visit. 
6.1.9. Visit 9 (Week 10-11 [+/- 2 weeks])+ 
Subjects will return to the Research Imaging Institute to undergo post-treatment Magnetic Resonance 
Spectroscopy/Imaging for intrahepatic liver fat measurement. Control group subjects will receive nutritional 
counseling, which may be performed by home visit or a video telehealth visit. 
 
+ Visits 8 and 9 may be performed interchangeably based on DXA and MRI scanner availability. 
 
6.1.10. Visit 10 (Week 11-12) -- "Optional" 
Participants will come to the research unit for vital signs and VO2max testing (same as Visit 4) Control 
group subjects will receive nutritional counseling, which may be performed by home visit or a video 
telehealth visit. 
6.1.11. Visit 11 (Week 11-12)  
Subjects will arrive fasting to undergo vastus lateralis muscle biopsy, subcutaneous fat biopsy, and collection 
of blood and urine samples for research purposes. These samples will be used to evaluate treatment effects 
on tissue cellular senescence, oxidative stress, DNA methylation and mitochondrial function. Post-
intervention blood laboratory assays also will be done for CMP, CBC, HbA1c, and lipid panel. Control group 
subjects will receive nutritional counseling, which may be performed by home visit or a video telehealth visit. 
 
6.1.12. Visit 12 (Week 13) 
Subjects will come to the research unit for evaluation of the biopsy sites. This visit may be conducted by 
home visit, telephone visit or a video telehealth visit. Control group subjects will receive nutritional 
counseling, which may be performed by home visit or a video telehealth visit. 
 
6.2. 
Visit Schedule Summary 
 
VISIT   1 
VISIT     
2** 
VISIT   
3** 
VISIT 
 4  
VISIT 
5 
VISIT 
6 
VISIT 
7 
VISIT 
8*** 
VISIT 
9*** 
VISIT 
10  
VISIT 
11 
VISIT 
12 
Schedule 
-17 days 
to -21 
-7 days 
to -17, 
+/- 
2wks 
-7 days 
to -17, 
+/- 
2wks 
-1 days 
to -6 
Day 0 
Week 
4 
Week 
8 
Week 
10-11, 
+/- 
2wks 
Week 
10-11, 
+/- 
2wks 
Week 
11-12 
Week 
11-12 
Week 
13 
  
  
  
  
  
  
  
  
  
  
  
  
  
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
X 
 
 
 
 
 
X 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Labs (fasting):  
  
  
  
  
  
  
  
  
  
  
  
CBC 
X 
 
 
 
 
 
 
 
 
 
X 
 
CMP 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
X 
 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
X 
 
Insulin 
X 
 
 
 
 
 
 
 
 
 
X 
 
FFA 
X 
 
 
 
 
 
 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 


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Routine UA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA 
 
X 
 
 
 
 
 
X 
 
 
 
 
Liver Fibroscan 
 
X 
 
 
 
 
 
X 
 
 
 
 
MRS/MRI - RII 
 
 
X 
 
 
 
 
 
X 
 
 
 
Physical Performance: 
  
  
  
  
  
  
  
  
  
  
  
Walk Distance 
 
X 
 
 
 
 
 
X 
 
 
 
 
Grip Strength 
 
X 
 
 
 
 
 
X 
 
 
 
 
Isom. Knee Ext 
 
X 
 
 
 
 
 
X 
 
 
 
 
VO2max  CPET* 
 
 
 
X  
 
 
 
 
 
X  
 
 
Muscle Biospy 
 
 
 
 
X 
 
 
 
 
 
X 
 
SQ Fat Biopsy 
 
 
 
 
X 
 
 
 
 
 
X 
 
Research Labs: 
  
  
  
  
  
  
  
  
  
  
  
  
Blood  
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine 
 
 
 
 
X 
 
 
 
 
 
X 
 
Nutrition consult and weight (controls) 
 
 
X 
X 
X 
 
 
 
 
 
Nutrition Phone Follow Up 
 
 
weekly 
weekly 
weekly 
 
 
 
 
 
Treatment dispensed 
 
 
 
X 
X 
X 
 
 
 
 
 
Treatment Phone Follow Up 
 
 
 
V5+1w 
V6+2w 
V7+2w 
 
 
 
 
 
Biopsy check 
 
 
 
 
 
X 
 
 
 
 
 
X 
Assess AE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*CPET is optional (Visits 4 & 10) 
**Visits 2 and 3 may be performed interchangeably 
***Visits 8 and 9 may be performed interchangeably 
6.3. 
Analyses.  
Muscle (frozen): Protein oxidative damage will be evaluated from muscle biopsy tissue using 
immunoblotting against carbonylated protein side chains. DNA from muscle samples will be extracted and 
tested for 8-hydroxydeoxyguanosine (8-OHdG) content to evaluate oxidative DNA damage and total DNA 
methylation will be evaluated. 
Muscle (fresh): Tissue obtained will be evaluated by an Oroboros Oxygraph-2k high-resolution respirometer 
to measure mitochondrial respiration capacity. Skeletal muscle fibers will be mechanically separated and 
permeabilized in BIOPS as described previously to allow uptake of mitochondrial electron transport chain 
substrates (25). Tissue will then be tested in MiRO6 buffer using a substrate-uncoupler-inhibitor titration 
(SUIT) protocol to evaluate oxidative phosphorylation capacity. 
Fat (frozen): will be subjected to reverse-transcriptase qPCR for measurement of gene expression levels of 
senescence and SASP markers, including IL-6, TNFα, p16, p21, and MCP1. 
Fat (fresh): tissue will be subjected to beta galactosidase staining to test cellular senescence in the tissue 
as described previously (42).  
Blood/plasma: Circulating factors that include inflammatory markers IL-6 and IL-6R, AGE-RAGE levels, and 
SASP biomarkers such as plasminogen activator inhibitor (PAI) -1 and 2, intracellular adhesion molecule 
(ICAM)-1 and 2 will be tested using ELISA kits on blood samples obtained during study. 20mL of blood 
will be drawn (two (2) 10mL EDTA lavender top tubes), centrifuged to obtain 10mL of plasma, and stored 
in 0.5-1 ml aliquots to evaluate whether the treatment reduces pro-inflammatory blood markers of aging. 
Blood samples obtained during the glucose tolerance tests will be analyzed for insulin and free fatty acid 
concentrations. DNA methylation assays will be done in peripheral blood cells. 
Urine: A fasted urine sample will be obtained at baseline and post treatment for urinalysis, microalbumin, 
excreted IL-6, and AGE-RAGE levels to evaluate changes with treatment. 2-5 ml aliquots will be stored 
frozen for analysis. 


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7. Statistical Plan 
7.1. 
Sample Size Determination 
The effect of SGLT2 inhibitors on aging-related biomarkers in pre-diabetic subjects is not known.  The data 
generated through this study will guide sample size and power calculations for future studies. 
7.2. 
Statistical Methods 
Analytical Approach. 
Experimental results will be expressed as means ± SE.  Comparisons of means between all the groups will 
be done by ANCOVA.  Associations, within a group, between aging-related biomarkers vs metabolic 
outcomes and vs. healthspan outcomes will be determined by Pearson’s correlation. For tests of correlation 
coefficients between groups, we will use the Fisher’s Z transformation.  We will also determine the 
relationship between aging-related biomarkers vs metabolic outcomes and vs. healthspan outcomes, by 
using multiple regression analysis.  Scatter plots will be done to look for outliers and to verify linearity.   
 
We will use natural logarithmic transformation to evaluate median percent change. This pilot study is not 
powered to achieve statistical significance with a p <0.05 and is of exploratory nature. The data included in 
this study will be only of completers. A larger trial in the future based on this pilot data would follow an 
intention-to-treat analysis. 
 
The Biostatistics Core of the San Antonio Pepper Center, led by Dr. Gelfond, will guide the statistical 
analyses.   
 
8. Safety and Adverse Events 
8.1. 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRSO) 
Any incident, experience, or outcome that meets all of the following criteria:  
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators brochure, etc.) 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
Adverse Event (AE) 
In general, AE is used very broadly and encompasses physical and psychological harms and includes:   
 
Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated 
with the subject’s participation in the research, whether or not it is considered related to the subject’s 
participation in the research. 
Intercurrent illnesses or injuries should be regarded as adverse events.  Abnormal results of diagnostic 
procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 


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• is considered by the investigator to be of clinical significance 
 
Serious Adverse Event (SAE) 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that:  
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as it occurred); 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant disability/incapacity; 
• results in a congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health and may require 
medical or surgical intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse). 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from the 
initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as 30 days following the last administration of study treatment.  
 
Pre-existing Condition 
A preexisting condition is one that is present at the start of the study.  A pre-existing condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the end 
of the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event 
must also be recorded and documented as an adverse event.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a SAE unless specifically instructed otherwise in this protocol.  Any condition responsible for 
surgery should be documented as an AE if the condition meets the criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an AE in the 
following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  
• Surgery should not be reported as an outcome of an adverse event if the purpose of the surgery was 
elective or diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless 


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judged by the clinical investigator as worsening or increase in frequency of hospital admissions. 
8.2. 
Recording of Adverse Events 
At each contact with the subject, the investigator or study staff will seek information about adverse events 
by specific questioning and, if appropriate, by examination.  Information on all AEs will be recorded 
immediately in the source document, and also in the appropriate AE section of the case report form (CRF).  
AEs will be tracked using the HSC IRB AE tracking form or data management tool (See Section 9.3) to be 
reviewed by Site Investigator on a monthly and ad hoc basis, depending on severity and 
expected/unexpected nature of the event. All subjects will have study compliance calls every two weeks 
during which AEs can also be reported.  
 
All AEs occurring during the study period will be recorded. The clinical course of each event will be followed 
until resolution, stabilization, or until it has been determined that the study treatment or participation is not 
the cause.  SAEs that are still ongoing at the end of the study period will be followed up to determine the 
final outcome.  Any SAE that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded and reported per Institutional policy and according to 
FDA requirements. 
8.3. 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
Each participant will be evaluated for any adverse events (AE). Any incidents, experiences, and outcomes 
either reported by the subject to the PI or designated research staff or medical staff caring for the subject, 
and which meet AE criteria will be documented.  Any AE reported as serious (SAE) requires submitting a 
Prompt Report Form to the IRB and, if deemed appropriate by PI, SAE and or unanticipated risks to 
subjects or others (UPIRSO) may be reportable to the Pepper Center DSMB. A copy of the SAE or UPIRSO 
prompt report is submitted to the Pepper DSMB for review as well as the NIA Program Officer within 24 
hours of notification to PI. All AE that are not serious or UPIRSO will be summarized annually and submitted 
to the IRB and R&D Committees. 
 
SAE and or UPIRSO will be reported per IRB policy and procedure. Events that do not involve AE or SAE 
(non-AE UPIRSO), and which are a result of study participation are also promptly reported to the IRB per 
local policy. The report will include a description of the event, when and how it was reported, as well as any 
official chart records or documentation to corroborate the event or the reporting of the event. All AE will be 
graded as mild, moderate, or severe.    Any action resulting in a temporary or permanent suspension of this 
study (e.g. local site IRB actions) will be reported to FDA per IRB stipulations. Additionally, the PI will report 
SAE to the drug sponsor Astra-Zeneca. 
 
Serious adverse events (SAE) still ongoing at the end of the study period will be followed up to determine 
the final outcome and or referred to participants’ primary care provider.  Any SAE that occurs after the study 
period that is considered to be possibly related to the study treatment or study participation will be recorded 
and reported per Institutional policy and according to FDA requirements. 
Investigator responsibilities - The PI is responsible for: 
• Reviewing all incidents, experiences, and outcomes that may represent UPIRSO. 
• Determining whether event represents a possible UPIRSO 
• Promptly reporting to IRB per local policy 
• Contacting institutions involved 
• Implementing actions necessary to eliminate immediate hazard 
• Submitting follow up reports to IRB 
• Submitting amendments to IRB, if applicable or stipulated 
 


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Report SAE and UPIRSO immediately by phone and or secure email to: 
 
Carolina Solis-Herrera, MD 
Professor, Medicine-Diabetes 
210-619-3264 
SolisHerrera@uthscsa.edu 
 
 
Within the following 48 hours, the PI provides further information on the SAE or UPIRSO in the form of a 
written narrative.  This should include a copy of the completed Prompt Report Form, and any other 
diagnostic information that will assist the IRB to understand of the event.  A copy of the SAE or UPIRSO 
prompt report is submitted to the Pepper DSMB for review as well as the NIA Program Officer. 
 
For further special reporting requirements, please refer to the NIA DSMP document approved by the NIA 
Program Officer. 
 
Additional reporting requirements 
 
The site PI reports to the regulatory sponsor of the study. The study sponsor (or sponsor-investigator if 
investigator initiated) is responsible for reporting to FDA when applicable, according to 21 CFR 312 
regulations. Contact FDA for guidance. 
 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A or in a narrative format. The contact information for 
submitting safety reports is noted below: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Metabolism and Endocrinology Products 
5901-B Ammendale Road 
Beltsville, MD 20705-1266 
Phone: (301) 796-2290 
Fax: (301) 796-9712  
8.4. 
Medical Monitoring 
The Sponsor (or investigator initiating the study) will review the safety and progress of this study on a 
monthly basis or when needed if protocol deviations/violations, SAE or SAE-UPIRSO occurs.  The 
Designated Safety Officer is Devjit Tripathy, MD, PhD a Professor in the Department of Medicine, 
UTHSCSA, and Staff Physician at the Audie L Murphy VA Hospital.   
 
The PI and or Co-PI will review source documentation in the research record and or medical record when 
study coordinator provides an electronic alert or secure email to review.   
 
8.4.1. Investigator reporting of Protocol Deviations/Violations 
Departures during the conduct of a research study constitute a protocol deviation, violation or exception 
and as such must be reported to the UTHSCSA IRB. 
 
Tracking and reporting of protocol deviations and violations to the IRB is the responsibility of the PI. To 
determine whether deviations or violations require prompt reporting or other action, refer to the IRB 
document entitled “Decision Tree – Evaluating Departures” on the IRB website. Failure to report 


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departures from the protocol according to IRB policy may constitute possible non-compliance, which will 
require a Prompt Report Form and possible FDA reporting by IRB. 
 
Deviations and violations may be identified in a number of ways including:  
• 
A report by an individual can be made directly to the IRB Office.  
• 
The IRB may learn of event through its continuing review of ongoing research.  
• 
Compliance reviews (audits) conducted by the Office of Regulatory Affairs and Compliance or one 
of the HSC affiliated institutional compliance offices.  
• 
A report by an individual can be made directly to the Office of Regulatory Affairs and Compliance 
(Hotline) or one of the HSC affiliated institutional compliance offices.  
• 
A report by another committee, department, institution, or official.  
• 
An audit or report from the study sponsor or sponsor’s monitoring entity. 
8.4.2. Definitions of Protocol Deviations/Violations  
• 
Protocol deviations 
• 
Protocol violations  
• 
Emergency violations  
• 
For more information , refer to UTHSCSA IRB Policy website: 
https://research.uthscsa.edu/irb/policy/deviations  
 
8.5. 
Safety Procedures 
See Section 5.8 – If, in the case of SAE or SAE-UPIRSO, the Clinical Study Coordinator or appropriately 
designated study staff will contact the Designated Safety Officer (Section 8.6) to assess the need for 
stopping research activities until further information can be gathered. 
 
8.5.1. Designated Safety Officer 
 
• 
Assess SAE or SAE-UPIRSO to determine if prompt reporting is required and, if yes, notify 
pharmacist to halt dispensing until further information is obtained. 
• 
Compare event data to intervention/assignment to determine if SAE is related to study intervention 
• 
Assess study and subject safety to determine if stopping rules should be invoked 
• 
Create the Safety Officer record without personal identifiers and communicate to Sponsor 
Investigator and Clinical Study Coordinator with overall impression and recommended plan of action 
 
8.5.2. Research Drug Manager 
 
• 
Suspend dispensing of study drug until SAE reporting is complete 
 
8.5.3. Sponsor Investigator 
 
• 
Receive and review Safety Officer report with Clinical Study Coordinator, Pharmacist and Study 
Statistician 
• 
Assess and implement stopping rules, if required 
• 
Ensure that IRB, FDA, and funding sponsor are notified as appropriate to local or agency policy 
• 
If applicable, notify Pepper Center DSMB 
 
8.5.4. Clinical Study Coordinator  
 
• 
Obtain a copy of Safety Officer or DSMB report/record to file in study binder/file and forward a copy 
to the Regulatory Coordinator 
• 
Ensure appropriate medical care and follow up is scheduled and implemented until SAE resolved 


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• 
Create FDA report, if applicable 
 


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8.6. 
Stopping Rules  
 
In the unlikely event that a study-related death or SAE occurs, the decision to stop the trial, either temporarily 
or permanently, will be the responsibility of the Designated Safety Officer in collaboration with the Principal 
Investigator. 
There are several reasons why the researchers may need to end the subject’s participation in the study. 
Some reasons are: 
1. The researcher believes that it is not in the subject’s best interest to stay in the study 
a. Adverse drug reaction that does not resolve by dosing titration or if reaction is severe 
b. Subject becomes ineligible to participate due to concomitant use of an exclusionary 
medication 
2. Subject’s health condition changes and needs treatment that is not allowed while participating in the 
study 
3. Subject does not follow instructions from the research team. 
4. The study is stopped 
The research team will discuss options for medical care with the subject when participation in the study ends. 
 
9. Data Handling and Record Keeping 
9.1. 
Confidentiality 
Information learned about all subjects will be kept confidential.  All data and protected health information in 
paper form will be kept confidential by assigned uniquely coded identifier and kept secured (password 
protected and/or double locked). Subjects will not be identified in any way in any publication.   
9.2. 
Registration with Clinicaltrials.gov 
 
As per UT Health San Antonio (UTHSA) Office of Clinical Research policy 1.1.3, this study and other 
investigator initiated studies that meet criteria of “applicable clinical trial” must be registered by the 
“Responsible Party” in the Protocol Registration and Results System/PRS (https://register.clinicaltrials.gov ). 
Results must be conveyed within one year of study completion as defined by PRS. 
9.3. 
Source Documents 
Source data will be originated both electronically and on paper. Electronic data may be originated in either 
the medical record or in REDCap (questionnaires answered verbally). The study team will maintain a list of 
forms to identify where source data are generated for this protocol. 
 
Print all entries legibly in black ink.  Erasures and white-out material are prohibited. If any entry error has 
been made on paper, to correct such an error, draw a single straight line through the incorrect entry and 
enter the correct data above it.  All such changes must be initialed and dated.  For clarification of illegible or 
uncertain entries, print the clarification above the item, then initial and date it. 
 
9.3.1. Research Electronic Data Capture (REDCap) and origination of electronic source data 
Contemporaneous medical histories, physical exams, concomitant medications, checklists of consent 
processing, and documentation of eligibility criteria may be originated electronically in REDCap with date and 
time stamp and e-signed by the study team member obtaining the data. Then REDCap forms will be 
downloaded in PDF format containing saved source data and printed to file in the paper participant record at 
the research site. Other electronically originated data in REDCap include: adverse event (AE) assessments 
and AE logs, enrollment logs, protocol deviation logs, and other study management checklists. Other 


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electronic medical record data including pre-existing history, exams, medication lists, and such may be 
accepted as source data. 
 
All missing data will be routinely queried, corrected, and or explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable 
to the individual case, write “N/A”.   
 
9.3.2. Paper source data 
Paper source data will be collected from handwritten subject diaries, drug management logs, then entered 
into the REDCap database. All missing data will be routinely queried, corrected, and or explained.  If a space 
is left blank on paper because the procedure was not done or the question was not asked, write “N/D”, 
initialed and dated by the staff member.  If the item is not applicable to the individual case, write “N/A”.   
• 
Lab reports originating from medical records will be printed and filed in paper participant files to 
facilitate investigator review.  Lab data will be entered to REDCap to facilitate analysis. 
• 
Questionnaires and assessments (e.g., cognitive assessments verbally administered according to 
purchased test booklets and copyrighted material) may be originated electronically in REDCap. 
Otherwise, it may be necessary to originate survey data on a paper source and transfer the data 
elements to REDCap for calculation, data management and analysis. Paper sources will be filed in 
paper subject records. 
• 
Supervising physician investigators will sign and date paper records upon review. 
 
9.3.3. Handwritten entries 
All handwritten entries will be created contemporaneously to the visit or phone call, and legibly in blue or 
black ink. Erasures and white-out material are prohibited. If any entry error has been made on paper, to 
correct such an error, draw a single straight line through the incorrect entry and enter the correct data above 
it.  All such changes must be initialed and dated.  For clarification of illegible or uncertain entries, print the 
clarification above the item, then initial and date it. 
 
9.3.4. Remote and/or virtual research interactions 
This study involves remote and/or virtual research interactions with participants by the research staff. 
Research activities will be audio and/or video recorded by the conferencing platform, Zoom. Therefore, 
privacy and confidentiality are not guaranteed due to the nature of the electronic conferencing platform that 
will be used. 
 
9.4. 
Data Management 
Database Management Software: All data collection for this project will be maintained using the UT Health 
San Antonio REDCap platform which is managed by the Department of Epidemiology and Biostatistics.  
Data System: REDCap is a computing environment developed by Vanderbilt University consisting of a 
collection of instruments, under the management of UT Health San Antonio’s Information Management 
systems, policies, and procedures that govern its informatics operations. Data projects are designed to be end-
user oriented and constructed to optimize workflow and minimize errors.  
All data will be input using a web front-end interface. All users are individually assigned authorization for 
access to specific components of the database application based on approved study roles and responsibilities. 
Information that is input is checked for logical and range consistency and mandatory data fields must be 
entered in order to input a record.  
9.5. 
Records Retention 
The regulatory binder is maintained by a designated regulatory coordinator. 
 
The Principal Investigator is responsible for maintaining study essential documents for at least 3 years after 
the funding grant period ends or at least 2 years have elapsed since the formal discontinuation of clinical 


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development of the investigational product, whichever is longer. Records retention policy is 6 years after the 
study is inactivated. 
 
These documents should be retained for a longer period if required by a funding agency, the FDA or other 
institutional retention policy.  In such an instance, it is the responsibility of the sponsor or Principal 
Investigator to inform the institution as to when these documents no longer need to be retained.  
10.   Study Monitoring, Auditing, and Inspecting 
10.1. Study Monitoring Plan 
The Principal Investigator (PI) will be responsible for ensuring the timely monitoring of the data and safety of 
study participants. The PI will communicate with other members of the study staff to review adverse events 
and protocol compliance on a weekly basis within 7-10 calendar days of the most recent study visit or phone 
encounter.  
 
This study will be reviewed by the Pepper Center Data and Safety Monitoring Board (Pepper DSMB) at least 
annually. The Pepper Center DSMB meets 2-3 times a year, by teleconference call, to review study progress 
and participants’ safety of designated studies. The PI will be required to submit DSMB reports of study 
progress, adverse events summaries and protocol deviation logs to the Pepper DSMB when requested by 
the Pepper DSMB Chair. 
 
The Diabetes Division assigns a staff member to conduct quarterly assessments for data quality 
control/assurance on collected data, which is also reviewed on an annual basis by the designated regulatory 
coordinator and the PI at the time of preparing continuing review documentation for IRB submission. 
 
The Principal Investigator will ensure that the designated regulatory coordinator or other quality assurance 
reviewer is given access to all the above noted study-related documents and study related facilities (e.g. 
Research Drug Manager, diagnostic laboratory, etc.), and has adequate space to conduct study monitoring 
visits as assigned. 
10.2. Auditing and Inspecting 
The Principal Investigator will permit study-related monitoring, audits, and inspections by the IRB, the funding 
sponsor, the OAIC Pepper Center Data Safety and Monitoring Board (Pepper DSMB), government regulatory 
bodies, and University compliance groups of all study related documents (e.g. source documents, regulatory 
documents, data collection instruments, study data etc.).  The investigator will ensure the capability for 
inspections of applicable study-related facilities (e.g. drug management unit, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11.    Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical Practice (FDA 
Title 21 part 312) applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the Institutional Review Board (IRB), in agreement 
with local legal prescriptions, for formal approval of the study conduct.   
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  


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12.  Study Finances 
12.1. Funding Source 
This study is financed through a grant from the San Antonio Older Americans Independence Center Pilot and 
Exploratory Studies Core. 
12.2. Conflict of Interest 
UT Investigators are required to submit Conflict of Interest disclosures, if any, with every new study 
submitted for review by UTHSA IRB and VA Research and Development Committee.  
12.3. Subject Stipends or Payments 
This study will reimburse subjects for time and transportation.  A schedule of payments is shown below. The 
total potential reimbursement to a subject is $470 for the study for all visits, or payments may be prorated to 
include the last visit completed if study participation is terminated early. Manual payments for additional 
visits, if necessary, will be handled on an ad-hoc basis with prior approval from the funding sponsor. 
 
Visit 1  
$20 
Visit 2  
$20 
Visit 3  
$20 
Visit 4A 
$20 
Visit 4B 
$20 
Visit 5  
$125 
Visit 6 
$10 
Visit 7 
$20 
Visit 8 
$20 
Visit 9 
$20 
Visit 10A 
$20 
Visit 10B 
$20 
Visit 11 
$125 
Visit 12 
$10 
Manual Payment (unscheduled visit, lab visit, or AE) $50 
 
13.    Publication Plan 
The Institution or respective designees may present or publish the results of a scientific investigation 
involving this Study in accordance with International Committee of Medical Journal Editors (ICMJE). The 
Sponsor Investigator, funding agency, or PI initiating the study will collaborate to determine who has 
publication rights for authorship upon review and approval of proposed manuscripts. 


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38. Defronzo RA. Glucose intolerance and aging: evidence for tissue insensitivity to insulin. Diabetes. 
1979;28(12):1095-101. PubMed PMID: 510806. 
39. Chavez AO, Coletta DK, Kamath S, Cromack DT, Monroy A, Folli F, et al. Retinol-binding protein 4 is 
associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in 
Mexican Americans. Am J Physiol Endocrinol Metab. 2009;296(4):E758-64. Epub 2009/02/05. doi: 
90737.2008 [pii]10.1152/ajpendo.90737.2008. PubMed PMID: 19190263. 
40. Tantiwong P, Shanmugasundaram K, Monroy A, Ghosh S, Li M, DeFronzo RA, et al. NF-kappaB activity in 
muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions. Am J 
Physiol 
Endocrinol 
Metab. 
2010;299(5):E794-801. 
Epub 
2010/08/27. 
doi: 
ajpendo.00776.2009 
[pii]10.1152/ajpendo.00776.2009. PubMed PMID: 20739506. 
41. Pesta D, et al.  Similar qualitative and quantitative changes in mitochondrial respiration following strength 
and endurance training in normoxia Am J Physiol Regul Integr Physiol. 2011 Oct; 301(4): R1078-87. 
42. Tchkonia T, Morbeck DE, Von Zglinicki T, et al. Fat tissue, aging, and cellular senescence. Aging Cell. 
2010;9(5):667-84. 
43. Fletcher, G.F., et al., Exercise standards for testing and training: a scientific statement from the American 
Heart Association. Circulation, 2013. 128(8): p. 873-934. 
 
 
 
 
 
 
 


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15.   Attachments 
A. Dapagliflozin Full Prescribing Information Handout 
 


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SUMMARY OF PROTOCOL CHANGES 
Date 
Version 
Section 
Before 
After 
09/10/19 
1.0 
All 
 
IRB submission version 
 
11/07/19 
1.1 
Section 5.6 
 
Section 8.5 
 
 
Section 8.5.2 
Unblinding of Study 
Drug 
Unblinding Procedures 
 
 
Unblinding verbiage 
Renamed “Handling of 
Study Drug”  
Renamed “Safety 
Procedures” 
 
Removed unblinding 
verbiage 
11/08/19 - 11/15/19 
1.2 
Section 5 and 
throughout 
 
 
Throughout document 
 
 
Section 6, Study 
Procedures and Visits 
Research Pharmacy or 
Pharmacy verbiage 
 
 
STX VA clinical site 
 
 
Redundancies in visit 
language 
Replace with Research 
Drug Manager or 
management unit; 
added FDA required 
language for labeling 
 
Replace with UT MARC 
site 
 
Streamlined verbiage 
and added fibroscan and 
MRS/MRI at RII 
 
12/05/19 
1.2.1 dated 11-15-19 
Cover page 
 
 
SAE Reporting 
Administrative update 
needed 
 
Empty cells on pg. 17 
Updated IRB# and 
versioning 
 
Removed empty cells 
12/18/19 
1.3 
CTO changes 
 
Approved Stips met - 
new study by IRB  
03/20/20 
2.0 
Cover sheet 
Study Summary  
Eligibility Criteria 
Stopping Rules 
Section of Visits 
Needed Updates               
Study duration 
Safety lab ranges 
Needs to be added 
Separate Visits 4 and 10 
into 4A-B and 10A-B 
Versioning updated 
Treatment phase v total 
Exclusionary lab ranges  
Added rules 
Relax physical 
performance burden 
05/26/20 
2.1 
Study Summary 
 
 
 
Exclusion Criteria 
 
 
 
 
Required updates. 
 
 
 
Required updates 
 
 
 
 
Study site, exclusion 
criteria & statistical 
methodology updated 
 
Blood donation in prior 2 
months & h/o frequent 
UTI added; renal failure 
clarified 
 


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Section 3.4 (Potential 
risks to Subject Safety) 
 
 
Section 5.6.3 
(Dispensing of Study 
Drug 
 
Section 6.1. (Study 
Visits) 
 
 
 
 
 
 
 
 
Section 6.3 (Analyses) 
 
Section 7 (Statistical 
Methods) 
 
 
 
 
 
 
Section 8 (Reporting 
AEs & UPs) 
 
9.3.4 (Telehealth Visits) 
Required updates 
 
 
 
 
Required updates 
 
 
 
Required updates & 
clarification 
 
 
 
 
 
 
 
 
Required clarification 
 
 
ANOVA 
 
 
 
 
 
Required clarification 
 
 
 
Required updates 
Risks for dapagliflozin 
updated; added potential 
risks of home visits;  
 
Added dispensed at 
home visit, by mail or 
curbside delivery 
 
Text added to clarify 
muscle biopsy 
procedure at Visit 5; 
added home & video 
telehealth visits; added 
BICRC study site; CPET 
made optional; urine 
HCG removed 
 
Blood/plasma volume 
clarified 
 
ANCOVA will be used 
for comparisons 
between groups; the 
study will only use data 
from pts. who complete 
the study 
 
 
Added clarification for 
reporting SAEs 
 
 
Telehealth visits 
description added 
07/22/20 
2.2 
Study Summary;Study 
Design;  4.1 Inclusion 
Criteria; 6.1.8 
 
3.3, Study Endpoints 
 
 
 
6.1, Study Visits 
 
 
6.1.1; Visit Schedule 
Summary 
Required update 
 
 
 
Matsuda index using 
OGTT 
 
 
Required update 
 
 
Required update 
Removed OGTT  
 
 
 
HOMA-IR index using 
fasting insulin & glucose 
 
 
Added Bluetooth scale 
 
Removed OGTT, added 
insulin & FFA 
08/11/20 
2.3 
Inclusion Criteria 
 
 
3.2, General Design 
BMI 30-37 
 
 
Correction 
BMI 30-38 (>29.5 will be 
rounded up) 
 
Study treatment period 
and total study duration 
corrected. 
08/31/20 
2.3.1 
3.4, Potential Risks to 
Subject Safety 
Blood Withdrawal 
Added risks of 
venipuncture by 
needlestick w/o catheter 
10/16/20 
2.3.2 
4.3 Subject 
Recruitment & 
Screening 
will screen up to 40 
potentially eligible 
candidates 
will screen up to 100 
potentially eligible 
candidates 
10/29/20 
2.4 
6.1 Study Visits; 6.2 
Visit Summary 
Schedule 
Required update 
Due to availability of 
DXA and MRI 
scanners.Visits 2&3 


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will be performed 
interchangeably, as 
well as Visits 8&9, 
Visit windows, also, 
expanded to +/- 2 
weeks. 
 

ICF_001.pdf: 
Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
diabetes 
 
19-766H, Solis-Herrera, Form D, 09-22-21, AMD.docx 
 
 
 
UTHSCSA Research Consent and Authorization Documents (v May 10 2019) 
Page 1 of 23 
 
COVER PAGE FOR PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
Official Study Title: SGLT2 Inhibition in Older Obese Adults With Pre-diabetes 
 
NCT number: NCT04401904 
 
IRB Approval Date: 09-22-2021 
 
Unique Protocol ID: HSC20190766H 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
diabetes 
 
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Page 2 of 23 
Concise Summary 
Important Information  
This information gives you an overview of the research.  More information about these topics may be found in the 
pages that follow.  You may choose not to take part in the study or may choose to leave the study at any time.  
Deciding not to participate, or deciding to leave the study later, will not result in any penalty or loss of benefits to 
which you are entitled and will not affect your relationship with us. 
 
1. What problem is this study trying to solve? 
You are being asked to participate in a research study.  Scientists do research to answer important questions which 
might help change or improve the way we do things in the future. The purpose of the research study is to evaluate 
whether pre-diabetic older adults can benefit from taking a drug called dapagliflozin (Brand name FARXIGA) to 
reduce cellular damage, pro-inflammatory cells of aging also called “senescent cells”, and other known markers of 
biological aging.  
 
For more information, please see the Why is this Study being Done section below.   
 
2. What will happen to me during the study and how is this different from continuing with usual care? 
What are all my options for treatment, including the pros and cons? 
Eligible participants will undergo laboratory assessments of blood and urine, assessment of memory, and receive by 
random assignment either the study medication or nutritional counseling over a 12-week period. Participants 
complete pre- and post-treatment testing including: medical history, physical examination, physical performance 
measures like walk distance, handgrip strength and knee extensions, riding an exercise bike to measure oxygen 
consumption, and muscle and fat sampling. Other pre- and post- measures include a body composition scan (called 
a DEXA), a liver ultrasound scan, and magnetic resonance (MR) testing to evaluate fatty deposits in the liver. 
 
For more information, please see the What will be done if you decide to be in the research section below.   
 
3. How much time will I spend on the study? 
This study involves 14 total visits (Visit 1,2,3,4,5,6,7,8,9,10,11,12) over the course of approximately 16-18 weeks. 
Visits are scheduled every 2-4 weeks and may last anywhere from 30 minutes to 3 hours depending on the 
procedures involved. 
 
4. Could taking part in the study help me and are there risks?  
We cannot guarantee that you will benefit from participating in this study other than to receive study medication and 
study related clinical care at no cost to you, and a small amount of reimbursement for your time and travel to the 
research unit. 
 
The risks associated with your participation may include medication side effects, pain or bleeding from blood draws 
and muscle or fat samplings, emotional distress from assessments, or fatigue from physical performance measures. 
 
For more information, please see How could you or others benefit from your taking part in this study section 
below.  For details and a list of risks you should know about, please see the What are the risks of participation in 
the research section below. 
 
5. What else should I consider before I make my decision? 
This study will involve attending study visits at UT Health San Antonio (UTHSA) McDermott Clinical Sciences 
Building (MCD), the UTHSA Research Imaging Institute (RII at MCD) and the UTHSA Medical Arts & Research 
Center (MARC) at 8300 Floyd Curl Drive, and Barshop Institute Clinical Research Center (BICRC) 4939 Charles 
Katz Dr.  
 
Please review the rest of this document for additional details about these topics and other information you 
should know before making a decision about participating in this research. 
 
 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
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Consent to be part of a Research Study 
To be conducted at  
University of Texas Health Science Center at San Antonio, 
 
Information about this form 
You may be eligible to take part in a research study.  This form gives you important information about the 
study.   
 
Please take time to review this information carefully.  You should talk to the researchers about the study and 
ask them any questions you have.  You may also wish to talk to others (for example, your friends, family, or a 
doctor) about your participation in this study.  If you decide to take part in the study, you will be asked to sign 
this form.  Before you sign this form, be sure you understand what the study is about, including the risks and 
possible benefits to you. 
 
Please tell the researchers or study staff if you are taking part in another research study. 
 
Voluntary Participation - You do not have to participate if you don't want to.  You may also leave the study at 
any time.  If you leave the study before it is finished, there will be no penalty to you, and you will not lose any 
benefits to which you are entitled.   
 
General Information – “Who is conducting this research?” 
Principal Investigator 
The Principal Investigator (PI) is the researcher directing this study; the PI is responsible for protecting your 
rights, safety and welfare as a participant in the research.  The PI for this study is Carolina Solis-Herrera, MD, 
Assistant Professor UTHSA Department of Medicine, Diabetes Division. 
 
Funding  
Non-Profit or Federal Agency Funding 
The National Institute of Aging (NIH-NIA) Claude D. Pepper Older Americans Independence Center, a federal 
agency that promotes scientific research, is funding this study.  This organization is providing money to UTHSA 
Sam and Ann Barshop Institute for Longevity and Aging Studies so that the researchers can conduct the study. 
 
Purpose of this study – “Why is this study being done?” 
The purpose of the research study is to evaluate whether pre-diabetic older adults can benefit from taking a drug 
called dapagliflozin (Brand name FARXIGA) to reduce cellular damage, pro-inflammatory cells of aging (senescent 
cells), and other known biological markers of aging.  
 
You are asked to participate in this research study of pre-diabetes and aging, neither of which are known to 
have current medical treatment except for lifestyle and behavioral changes (diet, exercise, sleep).  
 
The researchers hope to learn whether dapagliflozin can influence physical performance, biomarkers of aging, 
and delay the onset of diabetes if used in the pre-diabetic state.   
 
Investigation Use of Drug  
This study involves the use of an investigational drug called dapagliflozin (Brand name FARXIGA). 
“Investigational” means that the drug has not yet been approved by the U.S. Food & Drug Administration (FDA) 
for treating/preventing/diagnosing pre-diabetes and is approved for use in diabetes.  
 
This study will help find out what effects, good and/or bad, this drug has on people who take it and its effect on 
aging and pre-diabetes. The safety of this drug in humans has been tested in prior research studies; however, 
some side effects may not yet be known.   
 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
diabetes 
 
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UTHSCSA Research Consent and Authorization Documents (v May 10 2019) 
Page 4 of 23 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of the 
results. You can search this Web site at any time.  
 
Information about Study Participants – “Who is participating in this research?” 
You are being asked to be a participant in this study because you are age 60 years or more and have pre-
diabetes. 
 
This study will enroll approximately 30 study participants. 
 
Information about Study Procedures – “What will be done if you decide to be in the research?” 
While you are taking part in this study, you will be asked to attend approximately 12 visits with the researchers 
or study staff. It may be necessary for you to return to the clinic every 2 to 4 weeks. 
 
Screening – After you sign this consent to participate, exams, tests, and/or procedures may be done as 
described below to find out if you can continue in the study; this is called screening. We may be able to use the 
results of exams, tests, and/or procedures you completed before enrolling in this study.  You will be told which 
results we will obtain and which procedures will not have to be repeated.  You will be told which procedures 
are for “research only”. 
 
Screening Procedures (research only) 
Participants will be asked to arrive in a fasting state to the research unit for vital signs and screening 
procedures. Please see Visit 1 for details. 
 
The results of the screening exams, tests, and/or procedures will be reviewed to determine whether you will be 
allowed to continue in the study.  If you are not allowed to continue in the study, the researcher will discuss the 
reasons with you. 
 
If screening lab test results are abnormal, the investigator will make a clinical decision whether to repeat the 
tests and when that should occur. 
 
While taking part in this study, participants will spend at least 30 min-4 hours at each visit depending on 
procedures being done. 
 
Assignment to Study Groups – happens at Visit 5 (research only) 
When it is determined that you are eligible for the study, you will be assigned by chance (like flipping a coin to 
one of two study groups. 
❖ Take the study drug (open label), dapagliflozin (Brand Name: FARXIGA) 10 milligrams by mouth for 12 
weeks (study drug may be dispensed in person, during home visits, curbside delivery, or by U.S. mail), 
-or- 
❖ Receive nutritional counseling and no study drug 
 
Study Procedures  
❖ Visits will be performed at the UT Health San Antonio Medical Arts and Research Center (MARC),  or 
the Barshop Institute Clinical Research Center, except for magnetic resonance studies (MRI imaging) 
that will be done at the Research Imaging Institute.  You will be asked to arrive fasting (10-12 h) for 
visits involving lab work, imaging, or biopsies. 
❖ Please note that your participation in this study may involve remote and/or virtual research interactions 
with our research staff. You will be audio and/or video recorded using the conferencing platform, Zoom, 
for the remote visit. Therefore, privacy and confidentiality are not guaranteed due to the nature of the 
research environment. 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
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UTHSCSA Research Consent and Authorization Documents (v May 10 2019) 
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❖ You will be given a Fitbit Bluetooth digital scale that will allow you to weigh yourself at home and submit 
your weight to the study staff electronically using the Fitbit app. Your scale will be connected to an 
email account that will be created and managed by the study staff and will only be used to collect the 
data from your scale. The study staff will help you install and setup the Fitbit app on your mobile device 
and connect your scale. If you do not have access to a mobile device or are unable to use the Fitbit app 
on your device, you will use the scale to take your weight and provide your documented weight to the 
study staff during home visits or by telephone. The scale will be provided to you free of charge. 
❖ Visits that require DEXA scans and MRI scans may be performed in reverse order based on scheduling 
availability of the DEXA and MRI procedures.  
 
Visit 1 – Screening (research only) 
The screening procedures are for research purposes.  
 
❖ Vital signs – typical assessments like blood pressure, heart rate, respiration rate, and temperature; 
may also include height and weight  
❖ Medical history – a listing of your history of illnesses, surgeries, social habits, medications and 
allergies 
❖ Physical examination – a general exam like what you would have in your primary physician’s office 
❖ Safety labs, a blood draw used to assess your general health status 
• 
complete blood count (CBC)  
• 
blood chemistry/comprehensive metabolic panel (CMP) and lipid panel (lipids) 
• 
coagulation tests (PT/PTT/INR) to assess how fast your blood will clot 
• 
hemoglobin A1c (HbA1c, a 3-month average reading of blood glucose levels) 
• 
insulin and FFA (free fatty acids) 
• 
thyroid stimulating hormone (TSH, an indicator of your thyroid function) 
• 
routine urinalysis (UA) to rule out urinary infection 
❖ Montreal Cognitive Assessment (MoCA) an assessment of memory and thinking to ensure the 
understanding of study intent (purpose of the study) and the consent document 
 
Your appointment for Visit 1 will take about 2.5  to 3 hours. 
 
Visit 2 - Strength testing, Body composition (DEXA) and Liver Fibroscan (baseline) Research only** 
Eligible participants will present to the MARC research unit to undergo the following: 
❖ Vital signs 
❖ Walk distance – to measure the distance you can walk over a period of 6 minutes 
❖ Grip strength – using an instrument called a dynamometer that measures hand grip strength when 
you squeeze as hard as you can 
❖ Isometric knee extension strength testing – to measure your leg strength, we will use a leg press 
machine like you would see in the gym 
❖ DEXA scan – we will measure the total amount of fat and muscle in your body by a technique called 
Dual Energy X-ray Absorptiometry. During this procedure, which will last about 10 minutes, you will 
lie on an imaging table while an x-ray camera passes over your body from head to foot. The distance 
between the camera and your body will be about two feet. During the DEXA study, you will have to 
lie flat on your back. You will receive a small amount of radiation during the test. Other than this, 
there are no known risks associated with this exam.  
❖ Liver fibroscan - we will perform a test that uses ultrasound to measure the amount of fibrosis 
(thickening or scarring of tissues) in your liver. It can be used alone or with other tests (such as 
biopsy, blood tests, ultrasounds) to see how much scarring there is on your liver. Fibroscanning is a 
pain-free diagnostic test that uses an ultrasound wand placed on your abdomen in the right upper 
quadrant where the liver is located using a lubricant gel to create a special image of your liver. The 
procedure usually takes about 5-10 minutes. 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
diabetes 
 
19-766H, Solis-Herrera, Form D, 09-22-21, AMD.docx 
 
 
 
UTHSCSA Research Consent and Authorization Documents (v May 10 2019) 
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❖  Assessment of adverse events – we will ask you if you have had any (unexpected) medical 
experiences (events) since the last visit 
❖ You will be given an appointment for imaging at Visit 3 and directions to the UT Health San Antonio 
Research Imaging Institute 
 
Your appointment for Visit 2 will take about 2 hours. 
 
Visit 3 – Magnetic Resonance Spectroscopy and Imaging (baseline) Research only** 
You will be asked to go to the UT Health San Antonio Research Imaging Institute to undergo: 
❖ Assessment of adverse events – we will ask you if you have had any (unexpected) medical 
experiences (events) since the last visit 
❖ Magnetic Resonance spectroscopy (MRS) and Magnetic Resonance Imaging (MRI) of the liver - this 
exam will assess the intrahepatic liver fat (fatty tissue situated or occurring within or originating in the 
liver) that may be deposited there.  
o The MRS provides a non-invasive view of the biochemical processes within the body, in this 
case, the liver.  
o There is no radiation associated with this procedure. You will be required to remove any 
external metal objects (cell phone, watch, jewelry, etc.) from your person because the magnet is 
very strong.  
o If you have severe claustrophobia (fear of confined spaces, like a crowded elevator), have metal 
implants in your midsection or upper body, or have a pacemaker, you will (not have the 
procedure done). 
 
Your appointment for Visit 3 will take about 1.5 hours. 
 
** Visits 2 and 3 may be performed in reverse order based on scheduling availability of the DEXA and MRI 
scans. 
 
Visit 4 -- Cardiopulmonary exercise testing (baseline) Research only --  {Optional}: 
You will be asked to present to the BICRC for the following: 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
❖ Cardiopulmonary (heart and lung) exercise testing (CPET/VO2max) – cycling on a stationary bike to 
determine how much oxygen your body requires during 10 minutes of endurance exercise. As part of 
this assessment, you will receive a 12-lead electrocardiogram (test which measures the electrical 
activity of your heart) (ECG) to monitor your heart rate and rhythm while you exercise while 
measuring the level of oxygen you require and carbon dioxide that is produced as a result.  
o This visit is optional. You may choose to not complete this visit by initialing below: 
 
_________ I do not wish to complete Visit 4 (heart and lung exercise testing and electrocardiogram) 
 
Your appointment for Visit 4 will take about 1 hour. 
 
Visit 5 – Muscle and Fat sampling (Day 0) Research only 
You will be asked to present in a fasting state (no food or drink past a specified time the night before the exam) 
to the BICRC to undergo the following procedures. 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
❖ Muscle biopsy 
o We will take 1-2small samples of your thigh muscle using a special needle. These are called 
muscle biopsies. 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
diabetes 
 
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UTHSCSA Research Consent and Authorization Documents (v May 10 2019) 
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o To do this, we will clean your thigh and inject a local anesthetic (numbing medicine like your 
dentist uses) to numb a small area of your skin. We may have to shave a small area for the 
incision. We will clean the area with a special antiseptic solution. Next, we will make a small cut 
in your skin (about ¼ inch). The biopsy needle will then be passed through this cut into the 
muscle and a piece of muscle tissue about the size of a pea will be obtained. At the time the 
muscle is obtained, many people feel pressure and a thumping sensation. About a third of 
people feel cramping or pain. The pain is mild to moderate and lasts 5-10 seconds. The pain 
stops when the needle is removed but your muscle may be sore for a few days. 
o In the areas where the biopsies were done, we will apply strips of adhesive tape (Steri-strips®) 
that will help the skin to close. The adhesive tape will come off on its own, and you do not need 
to peel it off.   
o We will give you lunch and monitor how you feel until you are ready to go home. 
❖ Fat biopsy 
o We will take 1-2 small samples of fatty tissue about the size of a grape from the area on your 
belly below the navel level. This is called fat biopsy.  
o To do this, we will clean an area on your belly below navel level and inject a local anesthetic 
(numbing medicine like the dentist uses) to numb the area first. We will clean the area with a 
surgical-grade antiseptic solution.  
o Next, we will make a small cut in your skin (about ¼ inch) of the numb area to administer more 
numbing solution in a technique known as infiltration (spreading the numbing solution under the 
skin across an area about the size of the span of your fingers).  
o Using an instrument that looks like a narrow straw (called a cannula) we will connect the 
instrument to the suction apparatus to collect tissue in a manner similar to a liposuction 
procedure.  
o If the sample amount appears to be enough, we will apply a bandage and cover it for protection. 
We will instruct you how to care for the wound. 
o If the sample appears to be not enough tissue from the “first pass”, and while the area is still 
numb, we may make a “second pass” with the straw-like instrument through the same incision 
to collect a little more tissue. 
o After the procedure, we will give you lunch and monitor how you feel until you are ready to go 
home. 
❖ Blood draw – similar to the blood draw at Visit 1, approximately 2 tablespoons will be drawn for 
research-only to analyze blood markers of inflammation that are thought to be related to aging 
❖ Urine specimen – similar to a routine urine collection that will be analyzed for urine markers of 
inflammation related to aging 
❖ Treatment assigned (randomization) 
o You will be assigned to either the drug treatment group (dapagliflozin group) or to the nutritional 
counseling group (control group) 
o If assigned to dapagliflozin you will be dispensed a 1-month supply of study medication with 
verbal instructions for administration  
o If assigned to the control group, you will be weighed and scheduled for nutritional counseling.  
The nutritional counseling visit may be conducted by video, using your phone or computer. 
 
After treatment begins, study staff will contact you by phone to follow up 1 week after Visit 5, and every 2 
weeks between visits until Visit 8. 
 
This visit will take approximately 2 to 2.5 hours.  
 
Visit 6 – Biopsy check and treatment follow up (Week 4) Research Only 
You will be asked to return to the BICRC research unit to have your biopsy site checked and for the 
procedures listed below. If necessary, you may be scheduled for a home visit or a remote video visit and may 
receive your medication in person, by mail or curbside delivery: 


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
diabetes 
 
19-766H, Solis-Herrera, Form D, 09-22-21, AMD.docx 
 
 
 
UTHSCSA Research Consent and Authorization Documents (v May 10 2019) 
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❖ Biopsy check – we will examine the area on the thigh where the biopsy procedure occurred  
❖ Blood draw – CMP to monitor kidney function 
❖ Treatment dispensing – based on your group assignment, you will receive either study medication 
with follow up instructions or nutritional counseling 
o If taking study drug, please bring any unused medications with you to this appointment for 
medication reconciliation (counting and inventory) 
o If you are in the control group, you will be weighed 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
 
This visit will take approximately 1 hour.  
 
 
Visit 7 – Follow up visit (Week 8) Research Only 
You will be asked to return to the BICRC research unit. If necessary, you may be scheduled for a home visit or 
a remote video visit and may receive your medication in person, by mail or curbside delivery. This visit will 
include: 
 
❖ Treatment dispensing – based on your group assignment, you will receive either study medication or 
nutritional counseling; if in the control group, you will be weighed. 
o If taking study drug, please bring any unused medications with you to this appointment for 
medication reconciliation 
o If you are in the control group, you will be weighed 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
 
This visit will take approximately 30-45 minutes. 
 
Visit 8 – Post-treatment visit (Week 10-11 [+/- 2 weeks]) Research only** 
You will be asked to return in a fasting state to the MARC research unit for: 
 
❖ Vital signs 
❖ Walk distance – to measure the distance you can walk over a period of 6 minutes 
❖ Grip strength – using an instrument called a dynamometer that measures hand grip strength when 
you squeeze as hard as you can 
❖ Isometric knee extension strength testing – to measure your leg strength, we will use a leg press 
machine like you would see in the gym 
❖ DEXA scan – we will measure the total amount of fat and muscle in your body by a technique called 
Dual Energy X-ray Absorptiometry. During this procedure, which will last about 10 minutes, you will 
lie on an imaging table while an x-ray camera passes over your body from head to foot. The distance 
between the camera and your body will be about two feet. During the DEXA study, you will have to 
lie flat on your back. You will receive a small amount of radiation during the test. Other than this, 
there are no known risks associated with this exam.  
❖ Liver fibroscan – we will perform a test that uses ultrasound to measure the amount of fibrosis 
(thickening or scarring of tissues) in your liver. It can be used alone or with other tests (such as 
biopsy, blood tests, ultrasounds) to see how much scarring there is on your liver. Fibroscanning is a 
pain-free diagnostic test that uses an ultrasound wand placed on your abdomen in the right upper 
quadrant where the liver is located using a lubricant gel to create a special image of your liver. The 
procedure usually takes about 5-10 minutes. 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit  
 


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Your appointment for Visit 8 will take about 2 hours. 
 
Visit 9 – Post-treatment visit (Week 10-11 [+/- 2 weeks]) Research only** 
You will be asked to go to the UT Health San Antonio Research Imaging Institute (RII) to undergo: 
 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
❖ Magnetic Resonance spectroscopy (MRS) and Magnetic Resonance Imaging (MRI) of the liver to 
assess the intrahepatic liver fat (same as in Visit 3)  
 
This visit will take approximately 1.5 hours. 
 
** Visits 8 and 9 may be performed in reverse order based on scheduling availability of the DEXA and MRI 
scans. 
 
Visit 10 – Post-treatment visit (Week 11-12) Research only {Optional} 
You will be asked to present to the BICRC where you will undergo: 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
❖ Cardiopulmonary (heart and lung) exercise testing (CPET/VO2max) – cycling on a stationary bike to 
determine how much oxygen your body requires during 10 minutes of endurance exercise. As part of 
this assessment, you will receive a 12-lead electrocardiogram (test which measures the electrical 
activity of your heart) (ECG) to monitor your heart rate and rhythm while you exercise while 
measuring the level of oxygen you require and carbon dioxide that is produced as a result.  
o This visit is optional. You may choose to not complete this visit by initialing below: 
 
_____ I do not wish to complete Visit 10 (heart and lung exercise testing and electrocardiogram) 
 
This visit will take approximately 1 hour. 
 
Visit 11 – Post-treatment visit (Week 11-12) Research only 
You will be asked to present in a fasting state to the BICRC where you will undergo:  
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
❖ Muscle and fat biopsies like in Visit 5.  
❖ You will also have blood and urine collections for research purposes (like Visit 5) as well as blood 
collection for safety labs like Visit 1 (CBC, CMP, Lipids, HbA1c, insulin, FFA). 
 
This visit will take approximately 1 to 1.5 hours. 
 
Visit 12 – Post-treatment visit and end of study (Week 13) Research only 
You may be scheduled for a home visit, a telephone visit or a remote video visit. This visit will include: 
❖ Assessment of adverse events – we will ask you if you have had any untoward medical experiences 
since the last visit 
❖ We will check the sites of muscle and fat biopsy for healing wounds 
 
This visit will take less than 30 minutes. 
 
 


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Visit Schedule Summary 
 
 
VISIT   
1 
VISIT     
2** 
VISIT   
3** 
VISIT 
4 
VISIT 5 
VISIT 
6 
VISIT 
7 
VISIT 
8*** 
VISIT 
9*** 
VISIT 
10 
VISIT 
11 
VISIT 
12 
Schedule 
-17 days 
to -21 
-7 days 
to -17, 
+/- 2wks 
-7 days 
to -17, 
+/- 2wks 
-1 days 
to -6 
Day 0 
Week 
4 
Week 
8 
Week 
10-11, 
+/- 
2wks 
Week 
10-11, 
+/- 
2wks 
Week 
11-12 
Week 
11-12 
Week 
13 
  
  
  
  
  
  
  
  
  
  
  
  
  
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
 
 
 
 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
MoCA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Labs (fasting):  
  
  
  
  
  
  
  
  
  
  
  
CBC 
X 
 
 
 
 
 
 
 
 
 
X 
 
CMP 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
X 
 
PT/PTT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
X 
 
Insulin 
X 
 
 
 
 
 
 
 
 
 
X 
 
FFA 
X 
 
 
 
 
 
 
 
 
 
X 
 
TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
Routine UA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DXA 
 
X 
 
 
 
 
 
X 
 
 
 
 
Liver Fibroscan 
 
X 
 
 
 
 
 
X 
 
 
 
 
MRS/MRI - RII 
 
 
X 
 
 
 
 
 
X 
 
 
 
Physical Performance: 
  
  
  
  
  
  
  
  
  
  
  
Walk Distance 
 
X 
 
 
 
 
 
X 
 
 
 
 
Grip Strength 
 
X 
 
 
 
 
 
X 
 
 
 
 
Isom. Knee Ext 
 
X 
 
 
 
 
 
X 
 
 
 
 
VO2max  CPET* 
 
 
 
X 
 
 
 
 
 
X 
 
 
Muscle Biospy 
 
 
 
 
X 
 
 
 
 
 
X 
 
SQ Fat Biopsy 
 
 
 
 
X 
 
 
 
 
 
X 
 
Research Labs: 
  
  
  
  
  
  
  
  
  
  
  
  
Blood  
 
 
 
 
X 
 
 
 
 
 
X 
 
Urine 
 
 
 
 
X 
 
 
 
 
 
X 
 
Nutrition consult and weight (controls) 
 
 
X 
X 
X 
 
 
 
 
 
Nutrition Phone Follow Up 
 
 
weekly 
weekly 
weekly 
 
 
 
 
 
Treatment dispensed 
 
 
 
X 
X 
X 
 
 
 
 
 
Treatment Phone Follow Up 
 
 
 
V5 +1w 
V6+2w 
V7+2w 
 
 
 
 
 
Biopsy check 
 
 
 
 
 
X 
 
 
 
 
 
X 
Assess AE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*V02max CPET is optional (Visit 4 & 10) 
**Visits 2 and 3 may be performed in reverse order 
***Visits 8 and 9 may be performed in reverse order  
 
 
Future Use of Your Information or Biospecimens Collected as Part of Your Participation 


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Identifiers may be removed and the de-identified information or biospecimens could be used for future 
research studies or distributed to another investigator for future research studies without additional informed 
consent from you or your legally authorized representative.  
 
Your biospecimens, even if identifiers are removed, may be used for commercial profit and you would not 
share in this commercial profit. 
Research involving your biospecimens might include whole genome sequencing and epigenetic analyses. 
Whole genome sequencing is the process of determining the complete DNA sequence of a person or other 
organism’s genome at a single time.  DNA is short for deoxyribonucleic acid. DNA contains information that 
determines, in part, the traits that are passed on from parent to child, such as eye color, height, or disease risk. 
Epigenetic analyses refer to changes that affect gene activity and expression. 
 
Return of Research Test Results for Genetic Tests to Subjects 
It is possible that this study will identify information about you that was previously unknown, such as disease 
status or risk.   
 
There are no plans to provide this information to you or your physician unless the information indicates that you 
may be at risk for a serious illness known at the time of testing to be treatable and it can be confirmed by a 
clinical laboratory.  In that case, we will attempt to notify you using the contact information you have provided.   
 
Ending Participation Early 
Could your participation end early? There are several reasons why the researchers may need to end your 
participation in the study (early withdrawal).  Some reasons are: 
• 
The researcher believes that it is not in your best interest to stay in the study. 
• 
You become ineligible to participate. 
• 
Your condition changes and you need treatment that is not allowed while you are taking part in the study. 
• 
You do not follow instructions from the researchers. 
• 
The study is stopped. 
 
The researchers will discuss your options for medical care when your participation in this study ends. 
 
Risks – “What are the risks of participation in the research?” 
Risks from the specific research procedures (drug(s), interventions, or procedures) 
The following section will describe the risks related to your participation in this research study.  One risk is that 
you may have side effects while on the study. Side effects can range from mild to serious. Serious side effects 
are those that may require hospitalization, are life-threatening or fatal (could cause death). The frequency that 
people experience a certain side effect can range from many (likely), few (less likely) or only one or two 
(rarely).  
 
Side effects from this study will usually go away soon after you stop taking the drug. In some cases, side 
effects can be long-lasting or may never go away.  
 
Everyone taking part in the study will be watched carefully for any side effects. However, the study doctors 
don’t know all the side effects that may happen. Be sure to tell your study doctor immediately, about any side 
effect that you have while taking part in the study.  
 
The following section will describe the risks related to each drug, intervention or procedure that is part of this 
research study. You should talk to your study doctor about any side effects or other problems that you have 
while taking part in the study.  
 
Risks and side effects related to the study include those which are:  


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Questionnaire data collection  
 
Less likely (less than 5-30subjects out of 100) and Not Serious: 
• 
Uncomfortable answering questions –If you feel uncomfortable answering questions, one of the 
investigators will speak with you to help clarify your doubts. Your responses will be kept confidential. You 
do not have to respond to any question that you do not feel comfortable answering.  
 
Rare (less than 5 subject out of 100) and Serious: 
Breach of confidentiality- It is possible in a rare occurrence there may be a breach of confidentiality.  However, 
the researchers have taken steps to minimize this risk such as keeping focus group audio recordings and 
materials in a secure, locked location. 
 
Physical assessment  
 
Not Serious and Less Likely (less than 5-30 subjects out of 100) :  
• 
Brief, temporary fatigue with walking 10-ft and/or using handheld dynamometer to measure grip strength 
• 
There is minimal risk of injury during the lower extremity strength testing. You will be asked to slowly 
increase your exertion and to stop if any abnormal discomfort is felt. 
 
Needlestick blood draw: 
Likely, and may not be serious (5-30 subjects out of 100): 
• 
Some people experience bleeding, bruising or swelling at the site of the needle entry. Fainting or 
lightheadedness may, also, occur. A qualified phlebotomist will perform your blood draw. 
Less likely, and may or may not be serious (1-5 subjects in 100): 
• 
Bleeding may occur outside of the blood vessels (hematoma). 
Rare, and may or may not be serious (less than 1 in 100 needlestick procedures): 
• 
There is a small risk of infection and nerve damage at the needle entry site. 
 
Catheter blood draw: 
Not serious and Less Likely (less than 1 in 100):  
• 
During the study catheters may be inserted into the veins in your arm. Some people experience mild pain 
from the catheter.  
• 
There is a small risk of bleeding when veins are punctured and a catheter is placed into the vein.  
• 
Bleeding will be seen as bruising (black and blueness) at the place where the blood was obtained. The 
bruising usually goes away within 3 to 4 days, although sometimes it may take a week. The bruising is 
helped by using hot packs.  
• 
There is a small risk of infection where your veins are punctured.  
 
Muscle biopsy:  
Less likely and not serious (1-2 in 100):  
• 
At the time the muscle is obtained, most people feel a pressure sensation, and some people feel a 
thumping sensation.  
• 
People might feel cramping, pain or soreness. In the people who feel cramping, pain or soreness, this will 
usually be mild to moderate in severity and will last 5 to10 seconds. The pain stops when the needle is 
removed, but your muscle may be sore for a few days.  
• 
Bleeding from a muscle biopsy may occur will be seen as bruising at the place on your leg where we take 
the muscle. The swelling or bruising usually goes away with rest within 2-3 days, although sometimes it 
may take a week. The bruising is helped by using hot packs.  
Rare and Serious (less than 1 in 500 of these procedures):  
• 
Rarely, bleeding from a muscle biopsy may be severe enough to require hospitalization. 


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Rare and Serious (less than 1 in 1,000) 
• 
Very rarely some subjects may experience numbness or tingling at the biopsy site. This usually is 
temporary and goes away in a few days. There is the possibility that nerve damage could be permanent.  
 
Rare and Serious (less than 1 in 100) 
• 
There is a small risk of infection at the site of the muscle biopsy. Symptoms of an infection would include 
pain, redness, swelling, and yellow-greenish (pus-looking) discharge in the biopsy site, and is usually 
accompanied by fever. Because multiple biopsies of the muscle will be performed, the risk of infection and 
pain in the leg may increase. Infections can be usually treated effectively with antibiotics taken by mouth. In 
very rare occasions, hospitalization is required to give antibiotics through the vein, and an operation could 
be needed to clean the infected area.  
• 
Allergic reactions to the local anesthetic we use for the muscle biopsy are extremely rare, but could include 
a skin sore, swelling, or hives.  
 
There is the possibility that a future biopsy may not be done at the discretion of the PI in case the subject did 
not tolerate well a prior biopsy. 
 
Risks from Radiation Exposure  
 
Risks from radiation exposure for the optional body composition: 
Participation in this portion of the research study involves exposure to radiation from DXA scans.   The amount 
of radiation exposure that you will receive from this procedure is equivalent to a uniform whole-body dose of 
0.2 mrem (a unit of radiation exposure) which is less than 0.1 percent the average amount of radiation 
exposure (620 mrem dose) that each member of the general public receives per year. There is no known 
minimum level of radiation exposure that is recognized as being totally free of the risk of causing genetic 
defects (abnormal cells) or cancer. However, the probability of harm from such risk associated with the amount 
of radiation exposure that you will receive from this study is considered to be low when compared to other 
everyday risks each member of the general public receives per year, depending on the amount of radiation you 
personally have been exposed to in the past, particularly in the previous year. 
 
The radiation exposure described here is what you will get from this research study only.  It does not include 
any exposure you may have received or will receive from other medical tests outside of this study that are a 
part of your medical care. Radiation risk builds up with each exposure. You should think about your own history 
of radiation exposure from tests (like x-rays or CT scans) in deciding about the radiation in this study. If you 
have questions about the total amount of radiation you will be receiving, you should ask your doctor. 
 
The following are the risks associated with treatment of Dapagliflozin: 
Less likely and not serious: 
These risks are expected to occur in 5-30 subjects or less out of 100 subjects:  
• 
Diarrhea,  
• 
Constipation,  
• 
GI upset,  
• 
Dizziness,  
• 
Fatigue,  
• 
Headache,  
• 
Runny nose,  
In Less than 4 out of 100 individuals  
• 
Low blood sugar (also called Hypoglycemia),  
• 
Urinary tract (about 1 out of 100 subjects) and genital infections (about 4 out of 100 subjects) 
 
Rare and serious:  


Title of Study: Effect of SGLT2 inhibition on aging-related biomarkers in older obese adults with pre-
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• 
Loss of consciousness (or syncope),  
• 
Decrease in blood pressure (less than 1 out of 100 subjects),  
 
 
Safety considerations for dapagliflozin and other SGLT2 inhibitors: 
Dapagliflozin – is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and 
exercise to improve glycemic control in adults with type 2 diabetes mellitus and is a member of a class of  
antidiabetic medications that work by increasing the glucose excretion in the urine. Dapagliflozin (FARXIGA) 
has been approved by the U.S. FDA. Side effects reported with dapagliflozin will be summarized below based 
upon the package insert from the drug manufacturer Astra Zeneca. 
 
(1) Hypotension 
Dapagliflozin may cause intravascular volume contraction. Symptomatic hypotension can occur 
after initiating dapagliflozin particularly in patients with impaired renal function (eGFR less than 
60 ±5 mL/min/1.73 m2), elderly patients, or patients on loop diuretics. Subjects with eGFR less 
than 60 ±5 ml/min/1.73 m2 will not be allowed in the study. Signs and symptoms of hypotension 
after initiating therapy will be monitored. If a participant experiences any of these, the 
dapagliflozin will be stopped and the participant will be discontinued from the study.  
 
(2) Renal Function 
A small decrease in kidney function (eGFR) and increase in serum creatinine has been 
observed when dapagliflozin is initially started. The eGFR gradually returns toward normal while 
the drug is continued and returns to normal if drug is stopped. If the eGFR drops below 60 or if 
the serum creatinine rises by ≥3 mg/dl the dapagliflozin will be stopped and the participant will 
be discontinued from the study.  
 
Sudden kidney injury (acute kidney injury) has happened to people taking dapagliflozin. Talk to 
your doctor right away if you: 
• 
reduce the amount of food or liquid you drink for example, if you are sick or cannot eat or 
• 
you start to lose liquids from your body for example, from vomiting, diarrhea or being in 
the sun too long.  Seek medical attention immediately if you experience signs and 
symptoms while taking these medicines such as: 
o Decreased urine 
o Swelling in your legs or feet 
 
(3) Hypoglycemia  
Hypoglycemia (low blood sugar) – can occur with any antidiabetic medication. In studies of 
dapagliflozin, the frequency of hypoglycemia was less than 5% and similar to that in the placebo 
group. Subjects will be told to call the investigator if symptoms (sweating, rapid thumping 
heartbeat, mental confusion) of hypoglycemia occur and to drink a glass of orange juice with a 
packet of sugar. Any subjects with hypoglycemia will be evaluated for potential causes. If the 
hypoglycemia recurs, the subject will be discontinued from the study.  
 
(4) Serious urinary tract infections 
Serious urinary tract infections that may lead to hospitalization have happened in people who 
are taking dapagliflozin. Tell your doctor if you have any signs or symptoms of a urinary tract 
infection such as a burning feeling when passing urine, a need to urinate often, the need to 
urinate right away, pain in the lower part of your stomach (pelvis), or blood in the urine. 
Sometimes people also may have a fever, back pain, nausea or vomiting. You should seek 
medical attention and contact your study doctor immediately if you experience any of these 
symptoms.  
 


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(5) Genital Mycotic Infections 
Vulvovaginitis, balanitis and related genital infections were reported in 4.8% and 0.9% of 
subjects who received dapagliflozin 10 mg and placebo, respectively. Most infections were mild 
to moderate, and subjects responded to an initial course of standard treatment and rarely  
resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in 
females (6.9% and 1.5% for dapagliflozin and placebo, respectively), and subjects with a prior 
history were more likely to have a recurrent infection.  
If you experience a genital infection call the study doctor. You will be treated with a local 
antifungal cream or oral antibiotic therapy. 
 
 
(6) Necrotizing Fasciitis of the perineum (or Fournier’s gangrene) 
Cases of a rare, but serious, infection of the genitals and areas around them have been 
reported with the drug class, SGLT2 inhibitors, like dapagliflozin.  This serious condition, called 
necrotizing fasciitis of the perineum or Fournier’s gangrene, is a life-threatening infection 
requiring urgent antibiotics and surgical intervention. 
 
Seek medical attention immediately if you experience any symptoms of tenderness, redness, or 
swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 
100.4°F or a general feeling of being unwell. These symptoms can worsen quickly, so it is 
important to seek treatment right away.  Serious outcomes have included hospitalization, 
multiple surgeries, and death.   
 
(7) Volume depletion 
Dapagliflozin increases the amount of salt and water that is excreted in the urine.  Reactions 
related to volume depletion (including dehydration, hypovolemia, orthostatic hypotension, or 
hypotension) were reported in 0.8% and 0.4% of subjects who received dapagliflozin 10 mg and 
placebo, respectively; serious reactions occurred in < 0.2% of subjects balanced between 
dapagliflozin 10 mg and placebo. 
Call the investigator if you experience symptoms of volume depletion. 
 
(8) Malignancies 
During clinical trials, the overall proportion of subjects with malignant or unspecified tumors was 
similar between those treated with dapagliflozin (1.47%) and placebo/comparator (1.35%), and 
there was no carcinogenicity or mutagenicity signal in animal data. When considering the cases 
of tumors occurring in the different organ systems, the relative risk associated with dapagliflozin 
was above 1 for some tumors (bladder, prostate, breast) and below 1 for others (e.g. blood and 
lymphatic, ovary, renal tract), not resulting in an overall increased tumor risk associated with 
dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ 
systems. If you have a prior history of bladder, prostate, or breast cancer please tell us.  
 
(9) Bone Health  
Bone mineral density measurements in patients with normal or mildly impaired renal function did 
not indicate bone loss over a treatment period of one year, and there was no increase in 
fracture risk in these individuals with normal or mildly impaired renal function. However, it 
cannot be excluded that with longer periods of treatment there will be a decrease in bone 
mineral density or increase in bone fracture risk.  
If you experience a bone fracture contact the study doctor.  
 
(10) LDL Cholesterol  
A small increase in LDL cholesterol of about 4% has been observed in diabetic patients treated 
with dapagliflozin.  


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(11) Cardiovascular Events  
No increased risk of cardiovascular events (myocardial infarction, stroke, cardiovascular death) 
has been observed with dapagliflozin. Any participant who experiences a stroke or myocardial 
infraction will be discontinued from the study and the IRB and sponsor will be notified. If these 
individuals should experience a cardiovascular event while taking dapagliflozin, we discontinue 
them from the study.  
 
(12) Hypersensitivity Reactions  
Severe hypersensitivity reactions, including angioedema and urtricaria have been reported in 
patient taking dapagliflozin, although a causal association has not been established. Serious 
anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported 
in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients. If such a 
reaction occurs in any participants, the dapagliflozin will be stopped and the subject will be 
discontinued from the study.   
 
(13) Pre-clinical Concerns  
Dapagliflozin did not induce tumors in either mice or rats at any of the doses evaluated in 2-year 
carcinogenicity studies. There was no carcinogenicity or mutagenicity signal in animal studies, 
suggesting that dapagliflozin does not represent a genotoxic risk to humans.  
 
The U.S Food and Drug Administration has warned that the use of dapagliflozin (a class of drugs, called 
sodium-glucose cotransporter-2 (SGLT2) inhibitors) may lead to ketoacidosis, a serious condition where the 
body produces high levels of blood acids called ketones that may require hospitalization. You should pay close 
attention for any signs of ketoacidosis and seek medical attention immediately if you experience symptoms 
such as difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. 
Do not stop or change your diabetes medicines without first talking to your prescriber. Your doctor will evaluate 
for the presence of acidosis, including ketoacidosis, if you are experiencing these signs or symptoms; 
discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis 
and monitor sugar levels. 
 
If the study doctor is not available and your symptoms do not improve seek immediate emergency medical care 
if necessary. 
 
Do not stop or change your diabetes medicines without first talking to your prescriber. Your doctor will evaluate 
for the presence of acidosis, including ketoacidosis, if you are experiencing these signs or symptoms; 
discontinue SGLT2 inhibitors if acidosis is confirmed; and take appropriate measures to correct the acidosis 
and monitor sugar levels. 
 
If any participant develops any sort of tumors, the Dapagliflozin will be discontinued and the IRB and sponsor 
will be notified. 
 
Risks and Side Effects Related to Electrocardiogram (ECG):   
Rare and not Serious: 
In 100 people, approximately 5 or less may have: 
• 
Mild skin irritation (e.g., itching, rash), occurring where the electrodes are stuck on the skin 
• 
Discomfort from lying in one position for 5 – 10 minutes while the ECG is being recorded 
 
Risks related to MRI Scanning  
Less Likely, and Not Serious  
In 100 people, approximately 10 or less may have: 
• 
Skin or eye irritation caused by the dyes from tattoos or tattooed eyeliner 


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• 
Slight warming of the body due to prolonged exposure to radio waves during the MRI 
• 
Claustrophobia or psychological distress during the scan. All equipment and testing will be explained to 
you prior to the beginning of testing. Usually, conversation and reassurance will remove any anxieties. 
If you experience severe anxiety during the study, you are free to end the session.  
 
Less likely and serious 
In 100 people, approximately 5 or less may have: 
Implanted metal devices or artificial limbs may malfunction or cause injury 
 
For more information about risks and side effects, ask one of the researchers or study staff. 
We will tell you about any significant new findings which develop during the course of this research which may 
relate to your willingness to continue taking part.   
 
Risks related to home visits: 
During home visits there is a risk of improper disclosure or loss of research records and research specimens. 
When necessary to perform home visits, the study staff will use precautions to reduce these risks. The study 
staff will not remove any of your original records from the research clinical site and will only use the minimal 
amount of protected health information necessary to accomplish the home visit. The study staff will keep study 
records in a locked file case. Research specimens will be labeled and packed according to the study site’s 
laboratory requirements and returned to the research site (FORU) in a carrier designated for biohazardous 
materials. Study records and specimens will never be left unattended during the home visit or when being 
transported to and from the study site. 
 
Risks related to remote and/or virtual visits: 
Due to the use of online conferencing systems, your privacy and confidentiality is not guaranteed. The 
research staff will use precaution during these visits and will not collect any information that could be damaging 
to your financial standing, employability, insurability and reputation. 
 
Fitbit Bluetooth Scale: You will be provided with a Fitbit Bluetooth Scale and the associated email/password to 
login into the Fitbit user account.  Research staff will be able to access, view, and download fitbit data through 
the Fitbit platform. Agreeing to participate in this study is an acceptance of the Fitbit Terms of Use and Privacy 
Policy.  
 
Genetic Informational risks related to the study 
This study will/may include genetic testing.  Human tissue contains genes that determine many of a person’s 
physical characteristics, such as the color of eyes and hair.  In some cases, genetic testing of tissues can be 
used to indicate a risk for the development of certain diseases.  Genetic information is unique to each 
individual and could potentially be used to discover possible changes in a person’s future health status or life 
expectancy, or that of his/her children and family members. Even if your tissues are used for this type of 
research, the results will not be put in your health records. Releasing this information to you could cause 
psychological distress, anxiety or family problems.   
 
Releasing this information to others, such as including it in your medical record, may pose a possible risk of 
discrimination, or increase difficulty in obtaining or maintaining disability, long-term care, or life insurance.   
 
These risks would occur if your information is released by mistake.  The measures being taken to protect your 
privacy are discussed below and make this possibility unlikely. 
 
Even though the results of genetic testing may not be linked to you, it is possible that people of your ethnic 
background may be found to be at more risk for certain diseases based on future genetic research and this 


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information might harm you in the future as a member of the group. Also, there may be unknown risks of 
genetic testing in the future. 
 
 
Are there Risks related to withdrawing from the study?  
If you decide to withdraw from this study early, please discuss your decision with the principal investigator.  
The researcher will ask you to complete study withdrawal procedures at a final study visit.  This visit would 
include as much as possible of the post-treatment data collection (visits 8-11). There is no risk to you if you do 
not complete the final withdrawal procedures and you can choose not to participate in them. 
 
Reproductive Risks 
Women who are not post-menopausal, and less than 60 years of age, cannot take part in this study. 
 
Are there risks if you also participate in other research studies? 
Being in more than one research study at the same time, may increase the risk to you.  It may also affect the 
results of the studies.  You should not take part in more than one study without approval from the researchers.   
 
What if a research-related injury occurs?  
The researchers have taken steps to minimize the known or expected risks.  However, you may still 
experience problems or side effects, even though the researchers are careful to avoid them.  In the event of a 
research-related injury or if you experience an adverse reaction, please immediately contact your study doctor.  
See the section “Contact Information” for phone numbers and additional information.  You may also need to tell 
your regular doctors. 
 
If you are injured or made sick from taking part in this research study, medical care will be provided. This care 
may be billed to you or your insurance. Depending on the circumstances, this care may be provided at no cost 
to you. We have no plans to give you money if you are injured. The investigator can provide you with more 
information. 
 
If you sign this form, you do not give up your right to seek additional compensation if you are harmed as a 
result of being in this study. 
 
Benefits – “How could you or others benefit from your taking part in this study?” 
The possible benefit of your participating in this study is to receive updated lab results related to your blood 
sugar. You will also receive compensation for participation which could be of small benefit to you. 
 
We hope the information learned from this study will benefit other people with similar conditions in the future. 
 
Alternative procedures or course of treatment – “What other options are there to participation in this 
study?” 
There are other options available to you.  Your other choices may include: 
 
Treatment of elevated blood sugar (pre-diabetes or impaired glucose tolerance) using other treatments such as 
nutritional counseling, diet and exercise, or the medication metformin. You may also choose not to get any 
other treatment.  
 
Payments – Will there be any payments for participation? 
The researchers will provide you with a MasterCard®.  Compensation will be automatically credited after 
completion of each study visit that includes a reimbursement to you for your time and the cost of parking. If you 
complete all visits and procedures, the total compensation will be $540.00. Your name, address and date of 


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birth will be shared with a third-party solely for the purposes of compensation processing.  This information will 
only be used for the administration of the compensation (ClinCard) and will be kept strictly confidential.   
 
Visit 1  
$25 
Visit 2  
$40 
Visit 3  
$40 
Visit 4-optional 
$25 
Visit 5  
$125 
Visit 6 
$15 
Visit 7 
$25 
Visit 8 
$40 
Visit 9 
$40 
Visit 10-optional 
$25 
Visit 11 
$125 
Visit 12 
$15 
Manual Payment (unscheduled visit, lab visit, or AE) Up to $50 
In addition to the compensation on the card, you may also elect to receive study-related messages (text and/or 
email). These messages may contain information confirming that money has been loaded onto your card. You 
may also receive reminder messages with information about your next appointment with researchers or study 
staff.   
 
Please indicate your willingness to receive study-related messages: 
□ Yes, I would like to participate (please select the best method(s) for communication) 
o Cell Phone (text messages) 
o Email 
□ No, I choose not to participate 
 
If you are paid, the money you receive may be taxable.  When the total of any study payments is $600 or more 
in one calendar year, the institution must report the amount to the IRS.  The IRS considers it earned income 
and treats it like any other income.  
 
Costs – Will taking part in this study cost anything? 
You or your health insurance company will be responsible for the cost of treatments and procedures that would 
be done whether or not you took part in this study, such as an illness, medication, or adverse event that is not 
study related. It is important to understand that some insurance companies do not cover some costs (for 
example, approved drugs used in a way different from the package instructions). If your insurance company 
does not cover these treatments or procedures, you will be required to pay for them. Ask the researchers if you 
have any questions about what it will cost you to take part in this study (for example bills, fees, or other costs 
related to the research). 
 
The Principal Investigator will provide the study drug free of charge during this study.  At the end of your 
participation you must return all unused study drug to the researcher.   
 
There will be no direct cost to participating in the study.  The Fitbit Bluetooth Scale can be used at no 
additional cost.  However, there may be additional charges to your cellular phone plan due to use of text 
messages and the telehealth portal depending on your cellular data plan.  
 
Confidentiality – How will your records be kept confidential? 
Information we learn about you in this study will be handled in a confidential manner, within the limits of the 
law.  If we publish the results of the study in a scientific journal or book, we will not identify you.  The 
Institutional Review Board and other groups that have the responsibility of monitoring research may want to 
see study records which identify you as a subject in this study.    


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To help us protect your privacy, we have obtained a Certificate of Confidentiality from the Federal Government. 
With this Certificate, the researchers cannot be forced to disclose information that may identify you, even by a 
court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings.  
The researchers will use the Certificate to resist any demands for information that would identify you, except as 
explained below.  The Certificate cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of federally funded projects or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug Administration (FDA).  
You should understand that a Certificate of Confidentiality does not prevent you or a member of your family 
from voluntarily releasing information about yourself or your involvement in this research.  If an insurer, 
employer, or other person obtains your written consent to receive research information, then the researchers 
may not use the Certificate to withhold that information. 
 
The Certificate of Confidentiality does not prevent the researchers from disclosing voluntarily, without your 
consent, information that would identify you as a participant in the research project under certain 
circumstances.  Circumstances that warrant the release of your information without your permission include: 
abuse and/or neglect, intention to harm yourself or others, or certain communicable diseases. 
 
Limits of Confidentiality 
Even without your consent, suspected or known abuse or neglect of a child, disabled, or elder abuse, 
threatened violence to self or others or other local health reporting requirements will be reported to appropriate 
authorities. 
 
Research policies require that private information about you be protected and this is especially true for your 
health information.  However, the law sometimes allows or requires others to see your information.  The 
information given below describes how your privacy and the confidentiality of your research records will be 
protected in this study. 
 
What is Protected Health Information (PHI)?   
Protected Health Information is information about a person’s health that includes information that would make it 
possible to figure out whose it is.  According to the law, you have the right to decide who can see your 
protected health information.  If you choose to take part in this study, you will be giving your permission to the 
investigators and the research study staff (individuals carrying out the study) to see and use your health 
information for this research study.  In carrying out this research, the health information we will see and use 
about you will include: medical history, blood work, information gathered from your medical record if available, 
treatments prior to the study, information you provide during participation in the study, results of blood tests, 
and demographic information like your age, marital status, race or ethnicity, and education you have 
completed. 
We will get this information by asking you, asking your doctor, and by looking at your chart if one is available at 
UT Health San Antonio or University Health System (including Texas Diabetes Institute).  
 
How will your PHI be shared?   
Because this is a research study, we will be unable keep your PHI completely confidential.  We may share your 
health information with people and groups involved in overseeing this research study including: 
• 
the UT Health San Antonio Claude D. Pepper Older Americans Center the study 
• 
the company (for example, McKesson) that provides the study drug 
• 
the UT Health San Antonio Claude D. Pepper Older Americans Center Data and Safety Monitoring Board, 
which is the committee that checks the study data and safety on an ongoing basis, to determine if the study 
should be stopped for any reason. 
• 
the members of the local research team 
the Institutional Review Board and the Compliance Office of the University of Texas Health Science Center 
at San Antonio, and other groups that oversee how research studies are carried out.  


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• 
the Research offices at UT Health San Antonio  
• 
the Food and Drug Administration (FDA) and other U.S. and international governmental regulatory agencies 
involved in overseeing drug research 
 
If you decide to participate in this study, you will be giving your permission for the groups named above, to 
collect, use and share your health information.  If you choose not to let these groups collect, use and share 
your health information as explained above, you will not be able to participate in the research study. 
 
Parts of your PHI may be photocopied and sent to a central location or it may be transmitted electronically, 
such as by e-mail or fax. The groups receiving your health information may not be obligated to keep it private.  
They may pass information on to other groups or individuals not named here.  
 
The Genetic Information Nondiscrimination Act (GINA) is a Federal law that will protect you in the following ways: 
• 
Health insurance companies and group plans may not request genetic information from this research; 
• 
Health insurance companies and group plans may not use your genetic information when making 
decisions regarding your eligibility or premiums; 
• 
Employers with 15 or more employees may not use your genetic information when making a decision to 
hire, promote, or fire you or when setting the terms of your employment. 
 
GINA does not protect you against genetic discrimination by companies that sell life insurance, disability 
insurance, or long-term care insurance.  GINA also does not protect you against discrimination based on an 
already-diagnosed genetic condition or disease. 
 
How will your PHI be protected?   
In an effort to protect your privacy, the study staff will use code numbers instead of your name, to identify your 
health information.  Initials and numbers will be used on any photocopies of your study records, and other study 
materials containing health information that are sent outside of UT Health San Antonio MARC, or RII for review 
or testing.  If the results of this study are reported in medical journals or at meetings, you will not be identified. 
 
Do you have to allow the use of your health information? 
You do not have to allow (authorize) the researchers and other groups to see and share your health 
information.  If you choose not to let the researchers and other groups use your health information, there will 
be no penalties, but you will not be allowed to participate in the study. After you enroll in this study, you may 
ask the researchers to stop using your health information at any time.  However, you need to say this in writing 
and send your letter to Dr. Carolina Solis-Herrera, Assistant Professor, Medicine-Diabetes, 7703 Floyd 
Curl Drive, San Antonio, TX 78229-3900. If you tell the researchers to stop using your health information, 
your participation in the study will end and the study staff will stop collecting new health information from you 
and about you for this study.  However, the study staff will continue to use the health information collected up 
to the time they receive your letter asking them to stop. 
 
Can you ask to see the PHI that is collected about you for this study?   
The federal rules say that you can see the health information that we collect about you and use in this study.  
Contact the study staff if you have a need to review your PHI collected for this study. 
You will only have access to your PHI until 12/31/2029. Because of the type of research, you can only access 
your PHI when the study is done.  At that time, you have the right to see and copy the medical information we 
collect about you during the study, for as long as that information is kept by the study staff and other groups 
involved.   
 
How long will your PHI be used?   
By signing this form, you agree to let us use and disclose your health information for purposes of the study until 
December 31, 2029. This permission to use your personal health information expires on the date noted above. 
 
 


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Contact Information – Who can you contact if you have questions, concerns, comments or 
complaints? 
If you have questions now, feel free to ask us.  If you have additional questions, concerns, comments or 
complaints later or you wish to report a problem which may be related to this study please contact: 
 
Carolina Solis-Herrera, MD can be reached at (210) 567-6691 during normal business hours or after hours (for 
urgent medical issues) by calling 210-220-0445. In case of a medical emergency, please call 911 for 
assistance.  
 
Primary contact: 
• 
Carolina Solis-Herrera, MD can be reached at (210) 567-6691 during normal business hours. 
• 
Nicolas Musi, MD, can be reached at (210) 617-5197 during normal work hours and (210) 630-5001 
after business hours. 
 
The University of Texas Health Science Center committee that reviews research on human subjects 
(Institutional Review Board) will answer any questions about your rights as a research subject, and take any 
concerns, comments or complaints you may wish to offer.  You can contact the IRB by calling 210-567-8250, 
or by mail to IRB, UTHSCSA, Mail Code 7830, 7703 Floyd Curl Drive, San Antonio, TX  78229-3900. 


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Research Consent & Authorization Signature Section 
If you agree to participate in this research and agree to the use of your protected health information in this 
research sign this section.  You will be given a signed copy of this form to keep.  You do not waive any of your 
legal rights by signing this form.   
 
SIGN THIS FORM ONLY IF THE STATEMENTS LISTED BELOW ARE TRUE 
• 
You have read the above information. 
• 
Your questions have been answered to your satisfaction about the research and about the collection, use 
and sharing of your protected health information.   
 
Adult Signature Section 
• 
You have voluntarily decided to take part in this research study. 
• 
You authorize the collection, use and sharing of your protected health information as described in this form. 
 
 
 
 
 
 
 
AM 
PM 
Printed Name of Subject 
 
 
 
Signature of Subject 
 
 
Date 
 
Time 
 
AM 
PM 
Printed Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
Time 
 
  Check if consent and authorization obtained from an individual who is unable to read and/or write but can otherwise communicate and/or comprehend 
English. Have witness initial below. 
Declaration of witness:  I was present for the entire consent process.  ________ ←(initials of witness) 
 
 
 
 
 
 
AM 
PM 
Printed Name of Person Obtaining 
Consent and Authorization 
 
Signature of Person Obtaining Consent 
and Authorization 
 
 
Date 
 
Time 
Consent and authorization was obtained from this individual who is unable to read and/or write but can otherwise communicate and/or comprehend 
English.   The method used for communication with the subject was: ______________________.   
The specific means by which the subject communicated agreement to participate was: 
____________________________________ 
  
 
Please indicate whether you give your permission to be videotaped during remote and/or virtual visits: 
  
☐ Yes     
        _________________________________________________           _________________________ 
         Initials of participant or individual authorized to consent on   
Date 
          behalf of the participant  
 
☐ No     
         _________________________________________________           _________________________ 
          Initials of participant or individual authorized to consent on   
Date 
           behalf of the participant