Conditions: Diabetes
Keywords: type 2 diabetes new onset combination therapy new onset type 2 diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 318
Healthy volunteers: no

Brief summary:
Type 2 diabetes is a systemic metabolic disease with significant morbidity and mortality due to damaging blood vessels. Increased blood sugar level is a hallmark of diabetes and is an contributes to the development of many of its complications. Multiple defects, e.g. impaired insulin secretion and impaired insulin action, contribute to the development of the disease. The aim of this study is to test the efficacy and durability of combination of drugs which correct the defects that lead to the development of diabetes on achieving adequate and durable control of blood sugar levels. Achieving adequate and durable control of blood sugar will prevent many of diabetes complications.

Detailed description:
Subjects will be randomized (using a table of random numbers) to receive, in open label fashion, one of the following treatment regimens: (i) Group I will be started on pioglitazone (15 mg/day) plus metformin (1000 mg/day) with the supper meal and exenatide (5 mcg s.c. bid 30 min before breakfast and supper) and up-titrated to 45 pioglitazone plus 2000 metformin and 10 mcg s.c. bid exenatide to achieve HbA1c \<6.0%; (II) Group II will be started on metformin, 1000 mg with breakfast and 1000 mg with supper, glyburide and basal insulin will be added and up titrated to achieve HbA1c \<6.0% The study team will compare the efficacy of two therapeutic regimens: (i) triple therapy (pioglitazone, metformin, exenatide) at the time of diagnosis of T2DM versus (ii) stepwise therapy starting with metformin and subsequent addition of sulfonylurea and basal insulin (i.e., the "standard" approach) in achieving this goal. The first intervention is based on the novel concept of initiating therapy at the time of diagnosis with combination therapy using agents that correct specific pathophysiologic defects that are characteristic of T2DM (insulin resistance and beta cell failure). The second intervention is based upon stepwise addition of antidiabetic agents to reduce the HbA1C according to the current ADA therapeutic recommendation.

Arms:
arm 1: initiation a combination of metformin (1000 mg), pioglitazone (15 mg) and exenatide (5 microgram bid) at the time diabetes is diagnosed arm 2: sequential addition of metformin, glyburide and basal insulin

Interventions: intervention 1: metformin\pioglitazone\exenatide intervention 2: metformin, glyburide and glargine
Intervention descriptions: intervention 1: metformin (1000 mg), pioglitazone (15 mg) and exenatide (5 microgram bid) are started and dose is up titrated to achieve HbA1c \< 6.5% intervention 2: subjects are started on metformin 500 mg bid and dose is up titrated and glyburide (up to 5 mg) and glargine are sequentially added to maintain HbA1c \< 6.5%

Protocol document:
Prot_SAP_000.pdf: 
 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
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Official Study Title: Durability of Combination Therapy With 
Exenatide/Pioglitazone/Metformin vs. Conventional Therapy in New Onset 
T2DM 
 
 
NCT number: NCT01107717 
 
 
IRB Approval Date:12.04.2019 
 
 
Unique Protocol ID: HSC20080456H 


 
 
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Click here for a complete set of instructions for this form. 
 
If an item does not apply to your research project, simply indicate that the question is "not applicable." 
 
For the following Sections: 1. “Purpose and Objectives”; 3. “Study Design”; and 4. “Study Population,” and 5 – 12,  you may copy 
and paste the relevant passages from the sponsor’s full protocol or grant application (only citing the page number and section will 
not be acceptable). 
For Section 2, “Background” you may cite the relevant passages (page number and section) from the sponsor’s full protocol or grant 
application. 
 
Click once on the highlighted entry in each box to provide your response.  Click the item number/letter for detailed instructions 
for that question.  If your response requires inserting a table, picture, etc, you will need to first delete the box that surrounds the 
answer and then insert your table or other special document. 
 
 
1.  Purpose and objectives. 
List your purpose and objectives: 
 
We hypothesize that initiation of combination therapy at the time of initial diagnosis of type 2 diabetes with antihyperglycemic drugs 
(pioglitazone, metformin, and exenatide) that specifically target known pathogenic defects (insulin resistance and beta cell 
dysfunction) responsible for impaired glucose homeostasis will achieve superior and more durable glycemic control and more 
effectively reduce cardiovascular risk factors compared to the stepwise approach currently recommended by the American 
Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD).  
Specifically, We will test the effect of initiating therapy in newly diagnosed type 2 diabetic subjects with combination 
pioglitazone/metformin/exenatide therapy compared to the ADA recommended approach (start with metformin and add a second 
or third oral agent, and then proceed to insulin) on: 
1) 
Achievement and maintenance of glycemic control (HbA1C <6.5%) 
2) 
Reduction in whole body (muscle) insulin resistance and improvement in beta cell function. 
3) 
Improvement in cardiovascular risk factors 
4) 
Decrease in carotid intima media thickness, a surrogate measure of atherosclerosis 
 
 
 
2.  Background. 
 
Describe past experimental and/or clinical findings leading to the formulation of your study. For research involving investigational 
drugs, describe the previously conducted animal and human studies.  For research that involves FDA approved drugs or devices, 
describe the FDA approved uses of this drug/device in relation to your protocol.  Attach a copy of the approved labeling as a product 
package insert or from the Physician’s Desk Reference.  You may reference sponsor’s full protocol or grant application (page 
number and section) or if none, ensure background includes references. 
 
The prevalence of type 2 diabetes mellitus (T2DM) has increased progressively to epidemic proportions 
over the last 20 years. More than 150 million individuals worldwide were affected by the disease in the year 
2000 and this number is expected to increase to more than 300 million by the year 2025 (1) The epidemic 
of type 2 diabetes is closely related to the epidemic of obesity (2) which, not only has resulted in a marked 
increase in the incidence of diabetes, but also in a decrease in the age of the disease onset. Type 2 diabetes, 
once a rare disease in youth, now frequently is encountered among adolescents and children (1-2). The 
decrease in the age of disease onset will result in a more prolong period of hyperglycemic exposure and 
eventuate in an increased risk for both micro- and macrovascular complications.  
T2DM individuals experience increased morbidity and mortality secondary to vascular damage involving 
both the microvasculature (retinopathy, nephropathy, neuropathy) and macrovasculature (heart attack, 
stroke, amputation) (3). Diabetes is the leading cause of blindness and end stage renal disease in western 
countries (4), and T2DM individuals have a 2.5-4 fold increase in the risk of cardiovascular disease - heart 
attack and stroke (5).  Moreover, clinically significant morbidity often is present long before the diagnosis 
of diabetes is made (6), and eventually, one-third to one-half of all people with diabetes have evidence for 
organ/tissue damage (7).  Although not everyone with diabetes is destined to develop complications, a recent 


 
 
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epidemiological study (7) reported that two or more complications are apparent in almost one-fifth of people 
with diabetes. 
The increased prevalence of T2DM, together with its associated morbidity and mortality, have placed a 
heavy burden on the health care system.  In the US, the estimated annual cost for the treatment of diabetes 
exceeds $100 billion (8).  Unfortunately, less than half of all T2DM patients in the US achieve the ADA’s 
recommended goal (HbA1C ≤ 7.0%) for glycemic control (9).  Therefore, more effective therapeutic 
strategies with durable glycemic control will be required in order to reduce morbidity/mortality from 
vascular complications and decrease the cost of therapy for this devastating metabolic disease.  
Glycemic Control and Diabetic Complications 
Two landmark studies, the DCCT (10) and the UKPDS (11), as well as others (12-15) unequivocally have 
documented that improved control of the plasma glucose concentration in T2DM subjects reduces the risk 
of both microvascular and macrovascular complications, demonstrating that chronic exposure of tissues to 
hyperglycemia triggers pathologic processes that lead to organ damage. A 1% decrease in HbA1C has been 
shown to cause an ~35% reduction in the incidence of microvascular complications (10,11,14) and 
maintaining the HbA1C <6% has been reported to completely prevent the development of retinopathy in 
T2DM subjects (13). Further, in the DCCT continuation study (EDIC), subjects who initially were treated 
aggressively with intensive insulin therapy and achieved a HbA1C <7% early in the course of their disease 
maintained a lower risk for microvascular complications many years later even though their HbA1C increased 
to 8% compared to subjects who initially were less controlled (16).  This observation emphasizes the 
importance of achieving good glycemic control at the time of diagnosis and of maintaining the level of 
glycemic control in order to reduce the risk of microvascular complications. The UKPDS (11), DCCT (15), 
and Kumamoto [14] studies also have shown that improved glycemic control reduces the risk of 
atherosclerotic cardiovascular complications. The results of these studies have prompted the professional 
organizations of health care providers (American Diabetes Association [17], American College of 
Physicians [18], American Association for Clinical Endocrinology (AACE) [19], and the European 
Association for the Study of Diabetes [20]) to recommend glycemic goals as close to normal as possible 
while avoiding hypoglycemia.  The ADA’s target goal for HbA1C is ≤7.0%, while the AACE’s and the 
EASD’s goal is ≤ 6.5%. 
ADA Recommendation for Therapy 
The ADA recommends that, at the time of diagnosis, subjects with type 2 diabetes be started on metformin, 
in addition to lifestyle intervention (17). Metformin is safe and effective, reducing HbA1C by ~1.5% (21).  
However, its efficacy wanes with time (22,23).  Both the UKPDS (23) and ADOPT (22) studies have 
demonstrated that, despite a significant initial decrease in HbA1C following initiation of metformin therapy, 
beta cell function continues to deteriorate progressively, resulting in subsequent treatment failure. The 
current ADA (and EASD) recommendation is to add a sulfonylurea (less commonly a thiazolidinedione) or 
basal insulin in stepwise fashion upon therapeutic failure, i.e. increase in HbA1C to > 7.0% (17,20).  Although 
this therapeutic approach will achieve adequate glycemic control in many T2DM subjects, diabetes is a 
progressive disease (22,23) and after 1-2 years the HbA1C rises to values > 7.0%, requiring the addition of a 
second antidiabetic medication, usually a sulfonylurea.  Moreover, this therapeutic approach is based upon 
reduction of the plasma glucose concentration rather than on correction of the underling defects which cause 
the hyperglycemia (beta cell failure and insulin resistance). Most importantly, we (24) and others (25) have 
shown that at the stage of impaired glucose tolerance (i.e., upper tertile of 2-hour plasma glucose during 
OGTT = 180-199 mg/dl) approximately 75-80% of beta cell function has been lost (24-26).  Thus, if therapy 
is initiated with drugs, i.e., metformin or sulfonylureas that do not halt the progressive beta cell failure 
(22,23,27), eventually there will be a complete loss of beta cell function, rendering the diabetic patient 
dependent on insulin therapy for glycemic control (28).  In most studies (28-30) insulin therapy is associated 


 
 
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with significant weight gain and an increased rate of hypoglycemia, which presents a major obstacle in 
achieving the desired level of glycemic control (28-30). 
Despite the irrefutable evidence for the beneficial effect of plasma glucose reduction in the prevention of 
microvascular complications, and the ADA’s recommendation to maintain glycemic control as close to 
normal as possible, in current clinical practice many of type 2 diabetic subjects do not achieve the 
recommended treatment goals. In a recent survey from the NHANES (9), the mean HbA1C in the US was 
~7.2% and only ~55% of subjects achieved a HbA1c < 7%.  In a survey of US academic medical centers, 
only 29% of subjects have achieved HbA1c < 7% (31). Increased frequency of hypoglycemia, associated 
with improved glycemic control, and progressive beta cell failure are the principal obstacles which have 
prevented the attainment of recommended levels of HbA1C (10,28,29). 
From the above discussion, it is clear that, despite the availability of a number of therapeutic agents with 
various mechanisms of action, including insulin, the majority of type 2 diabetic individuals remain 
suboptimally controlled and, therefore, are at increased risk for both microvascular and macrovascular (see 
below) complications.  In the present study I propose a new therapeutic strategy for achieving and 
maintaining target levels of glycemic control, HbA1C <6.5%. 
Diabetes and Cardiovascular Disease   
Subjects with type 2 diabetes have a markedly increased risk for cardiovascular disease (heart attack and 
stroke) and a worse prognosis following any cardiovascular event (5,31,32).  Poor glycemic control is an 
important risk factor for cardiovascular disease (11,15) but improved glycemic control only modestly 
reduces the increased risk of cardiovascular disease (11). The UKPDS has demonstrated that 
hyperglycemia per se has a less prominent role in the development of macrovascular complications 
compared to microvascular complications (11). Hypertension (34-36) and dyslipidemia (37) are major risk 
factors for coronary artery disease. Nonetheless, despite reduction of blood pressure (35,36) and plasma 
LDL cholesterol to target levels (37), the cardiovascular risk in subjects with type 2 diabetes remains 
greater than in nondiabetic subjects. Many recent studies (38-41) have demonstrated that insulin resistance 
is an additional risk factor for cardiovascular disease.  Insulin resistance also has been shown to be 
associated with a cluster of metabolic-cardiovascular risk factors (central obesity, hypertriglyceridemia, 
hypertension, elevated procoagulant and inflammatory markers) which collectively have been referred to 
as the Metabolic Syndrome (42,43,43a).  In the present study, we also will examine whether antidiabetic 
therapy, which corrects known pathophysiologic abnormalities responsible for type 2  diabetes (i.e., 
insulin resistance), improves cardiovascular risk factors compared to therapy which reduces plasma 
glucose without direct effects to improve insulin sensitivity. Some evidence in support of this concept has 
been presented.  Thus, pioglitazone, which improves muscle insulin resistance in type 2 diabetic subjects, 
has been shown to reduce cardiovascular risk factors, (i.e., plasminogen activator inhibitor-1, 
inflammatory markers, TNF alpha, and NFkB) independent of its glucose lowering effect and these 
beneficial actions may, in part, contribute to the decrease in carotid intima medial thickness compared to 
other hypoglycemic therapies (27,44-47).  In the PROACTIVE study, pioglitazone tended to decrease the 
composite primary cardiovascular endpoint and significantly reduced the principal secondary endpoint 
(heart attack, stroke, death) (48).  
Pathophysiology of Type 2 Diabetes: Implications for Therapy 
Subjects with type 2 diabetes manifest two major pathophysiologic defects (49-51): (i) impaired insulin 
secretion in response to glucose and other stimuli, i.e beta cell failure, and (ii) impaired insulin action in the 
liver and peripheral (muscle and adipose) tissues, i.e. insulin resistance. Both insulin resistance and beta cell 
failure are present long before the onset of overt diabetes (49-54). The earliest detectable abnormality in 
glucose metabolism is an increase in insulin resistance in liver, muscle, and other insulin target tissues. Both 
genetic and environmental factors, e.g. obesity and sedentary lifestyle, contribute to the development of 


 
 
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insulin resistance (50). In response to insulin resistance, the beta cell increases its secretion of insulin (both 
under fasting conditions and in response to nutrient stimuli) and this results in hyperinsulinemia. 
Longitudinal and cross sectional studies have demonstrated that, initially, the compensatory 
hyperinsulinemia is sufficient to offset the insulin resistance and maintain normal glucose tolerance 
(51,54,55). Most overweight and obese individuals are insulin resistant (2,42,51), but the majority maintain 
normal glucose tolerance throughout life due to the ability of the beta cell to fully compensate for the insulin 
resistance. However, when the beta cell fails to adequately compensate for the insulin resistance, glucose 
homeostasis deteriorates. Initially, this is manifest as impaired glucose tolerance and later as overt diabetes 
(51,54).  By the time overt diabetes is diagnosed, ~80% of beta cell function has been lost (24,25). 
Furthermore, the deterioration in beta cell function continues after diabetes is diagnosed and is the major 
factor responsible for the progressive deterioration in glycemic control in subjects with type 2 diabetes 
despite an initial good response to “standard” antidiabetic therapies, i.e. metformin and sulfonylureas 
(22,23,27). Thus, only drugs which halt/slow the progressive beta cell failure can be expected to achieve 
durable glycemic control. Results from the UKPDS indicate that subjects who were started on monotherapy 
with metformin, sulfonylurea, or insulin continue to experience a deterioration in glycemic control and beta 
cell function at a rate which is identical to subjects treated with diet alone (23). These results suggest that 
none of the “standard” antidiabetic agents (i.e., metformin, sulfonylureas, insulin), when used alone in 
sequential therapy, prevent the progressive decline in beta cell function observed in subjects with type 2 
diabetes.    
Alternative Approach for More Effective and Durable Glycemic Control      
Two novel classes of antihyperglycemic drugs have been developed in the past decade: (i) 
thiazolidinediones and (ii) the GLP-1 analogue, exanetide. Thiazolidinediones are peroxisome proliferator 
activated receptor-gamma (PPARγ) agonists and are potent insulin sensitizers in skeletal muscle, liver, and 
adipocytes (56-58). Two thiazolidinediones currently are approved for the treatment of T2DM: 
rosiglitazone and pioglitazone. In this study we propose to initiate therapy with pioglitazone at the time of 
diagnosis of T2DM.  Pioglitazone has a much more favorable plasma lipid profile than rosiglitazone (58a) 
and reduced cardiovascular events (heart attack, stroke, death) in high risk T2DM patients in the 
PROactive Study (48).  Clinical trials have demonstrated that the efficacy of pioglitazone in reducing the 
fasting plasma glucose concentration and HbA1C is similar to that of metformin and sulfonylureas. In drug 
naïve subjects, pioglitazone decreases the HbA1C by ~ 1.5% (59-61). Studies in humans with IGT and 
T2DM (62-65) and in experimental animals (66-68) have demonstrated that the thiazolidinedione class of 
drugs, in addition to their insulin sensitizing action, improve and preserve beta cell function. Consistent 
with its effect to preserve beta cell function, recent clinical trials have reported more durable glycemic 
control with thiazolidinediones compared to sulfonylureas (22,27).  In the recently completed ACT NOW 
study, pioglitazone compared to placebo reduced the conversion rate of IGT to T2DM by 85% over a 
period of 3.75 years via its combined effects to improve beta cell function and augment insulin sensitivity 
(Ralph A. DeFronzo, PI, unpublished results).  Pioglitazone also has been shown to reduce plasma FFA 
(69), adipocytokine/other inflammatory markers/procoagulant factors and increase plasma adiponectin 
concentration (44-47,70), all of which would be expected to provide cardiovascular benefit. Pioglitazone 
also decreases insulin resistance (by 35-40%) in skeletal muscle and liver (62) and, together with the 
decrease in plasma triglyceride and increase in HDL cholesterol concentrations (58a), would be expected 
to provide additional cardiovascular benefits, independent of the reduction in plasma glucose 
concentration (71-73). A recent study has demonstrated that pioglitazone slows the progression in carotid 
intima medial thickness in subjects with type 2 diabetes (27) and in a large clinical trial (PROactive study), 
the addition of pioglitazone as an adjunct to “standard” antihyperglycemic therapy resulted in significant 
16% reduction in the combined endpoint of myocardial infarction, stroke and death compared to placebo 


 
 
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in subjects with type 2 diabetes and pre-existing cardiovascular disease (48). Collectively these results 
indicate that pioglitazone, in addition to lowering plasma glucose concentration, reduces insulin resistance, 
preserves beta cell function, and  may have a direct action on the vasculature (74) to reduce the vascular 
complications of diabetes above and beyond its glucose lowering effect. 
Exenatide is a GLP-1 mimetic drugs which binds to the GLP-1 receptor on the beta cell and markedly 
augments glucose-stimulated insulin secretion (75,76). Because its stimulatory effect on insulin secretion 
is glucose dependent, hypoglycemia is rarely encountered when exenatide is used as monotherapy or in 
combination with metformin or a thiazolidnedione (77-79). Exenatide also acts on the alpha cell to 
suppress glucagon secretion (78). The combination of increased insulin secretion and decreased glucagon 
secretion results in suppression of basal/post-meal hepatic glucose production (HGP) and enhanced 
peripheral tissue (muscle) glucose disposal (80). Clinical studies have demonstrated that exenatide causes 
a significant reduction in fasting (decreased HGP) and post-prandial (increased muscle glucose uptake) 
plasma glucose concentration, leading to a significant drop in HbA1c (79-84), and is well tolerated when 
added to metformin (84) or to a thiazolidinedione (79). Exenatide also has extrapancreatic actions: it 
delays gastric emptying, thereby reducing postprandial hyperglycemia (85), and suppresses appetite, 
resulting in significant weight loss (86,87). The weight loss is associated with a decrease in plasma 
triglycerides, an increase in plasma HDL concentration, and a reduction in blood pressure (80-86).  These 
latter actions of exenatide would be expected to have a favorable effect to reduce cardiovascular 
complications (88,89). Studies in humans have demonstrated that exenatide markedly enhances beta cell 
function in subjects with type 2 diabetes (90).  In experimental animals exenatide stimulates beta cell 
neogenesis and replication and inhibits beta cell apoptosis (91).  If these later effects were to extend to 
humans, additional beneficial effects on beta cell health would be expected.  
No previous study has evaluated the efficacy and durability of combined pharmacological therapy at the 
time of diagnosis of diabetes with drugs that preserve beta cell function. Furthermore, no previous study 
has achieved the recommended goal of glycemic control (HbA1C <6.5%) as its primary outcome. In this 
study we will initiate therapy in subjects with type 2 diabetes at the time of diagnosis with triple therapy 
(pioglitazone, metformin, exenatide).  Pioglitazone and exenatide both exert effects to preserve beta cell 
function, while pioglitazone, and metformin to a lesser extent, are excellent sensitizers.  All three drugs 
effectively reduce the HbA1C and have beneficial cardiovascular actions.  The primary outcome variable is 
the achievement and maintenance of the recommended target for glycemic control (HbA1c <6.5%) in 
subjects with type 2 diabetes. We will compare the efficacy of two therapeutic regimens: (i) triple therapy 
(pioglitazone, metformin, exenatide) at the time of diagnosis of T2DM versus (ii) stepwise therapy starting 
with metformin and subsequent addition of sulfonylurea and basal insulin (i.e., the “standard” approach) in 
achieving this goal. The first intervention is based on the novel concept of initiating therapy at the time of 
diagnosis with combination therapy using agents that correct specific pathophysiologic defects that are 
characteristic of T2DM (insulin resistance and beta cell failure).  The second intervention is based upon 
stepwise addition of antidiabetic agents to reduce the HbA1C according to the current ADA therapeutic 
recommendation.            
 
 
 
3.  Study Design.  
 
Describe the study design (e.g., single/double blind, parallel, crossover, etc.)  Consider inserting a scheme to visually present the 
study design. 
 
Research Design and Methods 
Subjects: 


 
 
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720 newly diagnosed T2DM subjects (less than 2 years) in good general health as determined by physical 
exam, medical history, blood chemistries, CBC, TSH/free T4/total T4, lipid profile, urinanalysis, and EKG 
will take part in the study.  Subjects must have a HbA1c > 6.5% and must not have taken any oral or 
injectable antidiabetic medication for more than 2 days, except metformin, and must not be taking any 
medications known to affect glucose homeostasis.  Only subjects whose body weight has been stable (± 3lbs) 
over the preceding three months and who do not participate in an excessively heavy exercise program will be 
included.  Individuals with evidence of proliferative diabetic retinopathy, albuminuria >300 mg/dl, 
symptomatic diabetic neuropathy, or history of cardiovascular disease (class III-IV CHF) will be excluded.  
Subjects with AST or ALT greater than 3.5-foldl above the upper limit of normal will be excluded.  All 
subjects must be GAD antibody negative.  Subjects meeting these criteria will meet with a dietician and be 
instructed in a weight maintaining diet containing 50% carbohydrate, 30% fat, and 20% protein.  They also 
will receive instructions about a modest intensity exercise program (40 minutes of walking 3-4 times per 
week).  After one week on the diet, all subjects will receive:  (1) oral glucose tolerance test; (2) 
hyperglycemic clamp-will be performed in a subgroup of 50 subjects (25 in each group) to provide a 
measure of beta cell function; (3) DEXA for total body fat content/fat distribution; (4) carotid ultrasound-for 
measurement in carotid intima media thickness; (5) fundus examination; (6) 24-hour urine for albumin and 
creatinine; (7) ankle arm blood pressure measurement. 
Following completion of these tests, subjects will be randomized (using a table of random numbers) to 
receive, in open label fashion, one of the following treatment regimens: (i) Group I will be started on 
pioglitazone  (15 mg/day) plus metformin (1000 mg/day) with the supper meal and exenatide (5 mcg s.c. bid 
30 min before breakfast and supper) and up-titrated to 45 pioglitazone plus 2000 metformin and 10 mcg s.c. 
bid exenatide to achieve HbA1c <6.0%; (II) Group II will be started on metformin, 1000 mg with breakfast 
and 1000 mg with supper, glyburide and basal insulin will be added and up titrated to achieve HbA1c <6.0% 
Subjects will be recruited during the first year and followed up for additional two years. After completing the 
repeat studies, subjects will be asked to continue in the study and with the study medications without any 
change.  Follow up visits will occur every 3 months) until the last patient recruited into the study completes 2 
–years of follow-up. At the Follow visit Fasting Glucose and HbA1C will be performed. At the annual visits 
blood work to check the following: fasting glucose, HbA1C, and other repeat labs.  Every 2 years or if the 
subject decides to discontinue participation, we will repeat the annual labs, OGTT, eye photographs, and 
carotid ultrasound.  
 
4.  Study Population(s).  
You will be drawing subjects from one or more populations.  In medical research, for example, a population can be individuals with 
type 2 diabetes controlled with diet, or a population of healthy individuals.  In social behavioral research, a population can be 
individuals attending an education program, etc. 
a.  How many different populations are you enrolling in this study?   
1 
b.  For each different population, provide a short descriptive label:  (e.g., 
normal-healthy, diabetics, patients needing surgery, parents, child, etc.) 
720  Newly diagnosed type 2 diabetic subjects 
Will be enrolled to have 600 completers .  
 
 
For each specific population identified 4b, provide the following information in the table provided below.  (One table is provided, 
use copy and paste for additional tables if enrolling more than one population.) 
Population # [Type # given to population in 4b] 
 
XCheck here if enrolling only one population 
Population Descriptive Label:  [Insert short label from 4b] 
Enrollment of [Insert #] requested to obtain [Insert #] completers. 
(1) 
Identify the criteria for inclusion: 


 
 
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1) Subjects with type 2 diabetes diagnosed in the past 2 years 
2) subjects must be on diet or metformin only 
3) age 18-75 years 
4) must be in general good health and without a major organ disease 
5) must have creatinine < 1.5 
6) must have LFT < twice the upper normal limit 
7) subjects must have HbA1c > 6.5% 
(2) 
Identify the criteria for exclusion: 
1) subjects with type 1 diabetes or positive for anti diabetic antibodies 
2) subjects with type 2 diabetes who were diagnosed more than 2 years or who receive insulin or pharmacological therapy 
other than metformin  
3) subjects with a cardiovascular event in the past year 
 
(3) 
Recruitment 
Describe plans how the population will be identified for the purpose of recruiting. (Consider HIPAA Waiver if needed to 
allow those without existing legitimate access to PHI to use it to identify potential subjects.) 
(e.g., database search, personal contacts, referrals, patients under the care research team, etc.) 
Advertising material will be posted in the medical center and near by hospitals or in primary care offices (advertising material 
is included for IRB approval). Subjects interested in participating in the study will be asked to contact one of the investigators.  
We also have access to TDI patient database that can search and select patients that are newly diagnosed diabetic patients 
or have diabetes markers such as HbA1c .  We are planning on identifying such potential subjects and then contacting their 
health care providers for referral. We will send out “dear Doctor” letter informing the providers about our research study and 
ask them to contact participants. The treating physician will be making the initial patient contact, not the researcher.  If the 
patient is interested, then either the patient will contact the PI or, with the permission of the patient, the PI will be invited to talk 
with the patient about study participation.  
 
(4) 
Recruitment 
Describe how initial contact will be made with potential subjects.  Describe how those making initial contact have a 
legitimate access to the subjects’ identity and the subjects’ information. (Consider HIPAA Waiver if needed to disclose 
PHI to individuals who would not have otherwise had legitimate access.) 
Subjects who express their interest in participating in the study will be contacted  via phone by Dr DeFronzo or one of the co 
investigators. During this initial telephone conversation the study aim and procedures are explained to the patient, he also will 
be questioned about the inclusion and exclusion criteria. During this conversation subjects will be encouraged to discuss their 
participation in the study with their doctors. Subjects who fulfill the inclusion criteria and express their interest in participating 
in the study will be invited to the clinical research center for visit I 
(5) 
Recruitment 
Describe the setting in which an individual will be initially approached.  (e.g., private room, inpatient unit, waiting area, 
group setting, over internet, over phone, in public).  Also, describe all interaction between the research staff and the 
potential subject between the time they contact the research team or vice versa and the time they sign a consent form 
(including pre-screening activities-see instructions for detailed guidance) 
Subjects who will respond to the advertisement  will be contacted  via telephone and asked about possible exclusion criteria. 
Subjects who are interested in participating in the study and met the inclusion criteria will be invited to the GCRC for the first 
visit 
(6) 
Recruitment 
Specify if any advertising will be performed.  xYes  
No  
Pending (e.g., submitting amendment after approval) 
If yes, please see Section 4, Form L for instructions on attaching copies of the information to be used in flyers or 
advertisements.  Advertisements must be reviewed and approved by the IRB prior to use. 
Adverising material is included in this submission (See form L) 


 
 
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(7) 
Consent Process 
Describe the consent/assent procedures to be followed by the research team.   
(Be sure to cover how information is provided, how the consent interview is conducted, the person(s) who will conduct 
the consent interview and how the consent is signed (privacy, who signs the consent, etc.).) 
If consenting a single subject will involve more than one member of the research team, describe how this process will 
be coordinated from start to finish. 
During visit 1 all subjects will be interviewed by Dr. DeFronzo or one of the co-investigators, who will 
describe in detail the purpose, nature and potential risks of the study.  Each subject is then asked to read 
the consent form.  Subjects then will be asked if they have any questions concerning any aspect of the 
study.  All questions will be answered thoroughly and candidly by Dr. DeFronzo or one of the co-
investigators.    Immediately prior to the study, subjects are asked to sign the consent form and are given 
a photocopy to keep for themselves.  The consent forms will be kept in room at TDI. 
The quality and content of the consent process will be monitored throughout the study period and any 
changes will be communicated to IRB and the GAC.  
 
(8) 
Consent Process 
Describe the timing of obtaining informed consent, whether there is any waiting period between informing the 
prospective subject and obtaining consent.  (e.g., take consent home, waiting period of X hours, after consulting with 
family members, etc.) 
Subjects will be consented at the first visit, there will be no waiting period. 
(9) 
Describe measures taken to minimize the possibility of coercion or undue influence during consent.   
The study procedures will be explained for the subjects via the phone during the initial contact. They will be encouraged to 
consult their primary care doctors about their participation in the study. It will be explained to them that their participation in the 
study is voluntary and there is no penalty for not participating in the study. 
(10) 
Will subjects from this population be assigned to different research groups? 
X Yes    No 
If yes, list the groups using a short descriptive label.  E.g., experimental group A, B, etc., control group, etc.  (this information 
is needed later in the Risk: Benefit Analysis section) 
[Group I:  Combination therapy; Group II: Conventional therapy 
 
5.  Informed Consent for Research Involving Non-English Speaking Subjects 
 
A 
Individuals who do not speak English will not be enrolled.  
 
 
There is no expected benefit for those participating. (Skip B, and (1) and (2) below this table and go to 
#6) 
 
B. X 
Individuals who do not speak English will be enrolled.  The foreign language translation of the consent will be 
submitted to the IRB: 
 
Immediately following approval of the English consent document. (go to (1) and (2) below this table.) 
 
X 
Only after a potential non-English speaking participant is identified.  Indicate why this method that will 
result in a delay in consenting non-English speaking subjects is acceptable by selecting on of the choices 
below: 
 
 
There is no expected benefit for those participating. (go to (1) and (2) below this table.) 
 
 
X 
There is an expected benefit for those participating. The anticipated delay in enrolling non-
English speaking subjects is acceptable because: [Describe the rationale for determining as 
acceptable, the potential delay in start of the research related treatment pending approval 
under this circumstance then go to (1) and (2):] 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 10 of 26 
 
 
 
We rarely encounter non-English speaking individuals.  However, if an individual who 
speaks Spanish is to be recruited we anticipate being able to develop the consent form and 
get it approved by the IRB within 2-3 weeks. Since during the time period between 
identification of subjects and the start of the intervention patient will continue their previous 
care for their diabetes,  the delay will not have any significant adverse effect on the patient’s 
diabetes condition and/or treatment ot increase their risk compared to English speaker 
participants. 
 
 
(1)  If you are recruiting non-English speaking subjects, the method by which consent is obtained should be in language in 
which the subject is proficient.  Describe the process for obtaining informed consent from prospective subjects in their respective 
language (or the legally authorized representative’s respective language). 
 
If a Spanish speaking individual is to be recruited, a nurse or individual listed on the consent form who is fluent in Spanish will 
obtain the consent. 
 
 
(2)  In order to ensure that individuals are appropriately informed about the study when English is their second-language, 
describe a plan for evaluating the level of English comprehension, and the threshold for providing a translation, or explain why an 
evaluation would not be necessary. 
 
Subjects will be asked if English is their first language.  If not, they will be consent with a consent form that has been translated 
into Spanish. 
 
 
6.  Research Plan / Methods:   
 
a. Description of Methods – Provide a comprehensive narrative describing the research methods.  Provide the sequence of 
events for conducting the research and a description of the methods used to protect privacy during the study. 
Specific Methods: 
1) OGTT: A 75 gram OGTT will be performed at 0800h after a 10-12 hour overnight fast. Plasma 
glucose, insulin, C-peptide, and FFA concentrations are measured at baseline (15, -10 and 0 min) 
and every 15 min for 2 hours.  Insulin sensitivity will be measured with the Matsuda index =  
 
 
 
10,000/        (FPG x FPI) • (PG x PI) 
 
This index agrees closely with insulin sensitivity measured with euglycemic insulin clamp 
technique (92).  The following indices of insulin secretion will be measured:  early insulin response 
(ΔI0-30/ΔG0-30) and total insulin response (ΔI0-120/ΔG0-120 and ΔISR0-120/ΔG0-120) (24,26,52,93), 
where ISR = insulin secretory rate calculated by deconvolution of the plasma C-peptide curve (93).  
The insulin secretion/insulin resistance (so called “disposition”) also index will be calculated as 
ΔI/ΔG x Matsuda index and ΔISR/ΔG x Matsuda index. 
Total blood loss for OGTT is up to 88 ml. Total blood loss for screening tests is up to 40 ml. 
2) Adipocytokines plasma(adiponectin, leptin, resistin, IL6, TNFα), urinary alpha-1 isoprostane (a 
measure of reactive oxygen species [94]), and highly sensitive C-reactive protein (hsCRP) will be 
measured as previously described (94a).   
3) Whole Body DEXA.  Total and regional fat and fat-free mass will be measured by a licensed 
radiology technician using a Discovery 010-1596 instrument from Hologic that is housed on the 
CRC at the TDI.   
4) Carotid Intima Media Thickness: Carotid IMT will be measured by high resolution B-mode 
carotid artery ultrasound using an HDI 5000 Ultrasound System with a linear-array 7.5-MHz 
transducer (Philips Medical System, Wash). All scanning throughout the study will be performed 
by a single ultrasonographer at the same location using the same equipment. The mean difference 
between 2 readings amongst 20 examinations is 0.002 mm (SD 0.002).  The HDI 5000 Ultrasound 
system is housed on the CRC of the TDI and a skilled ultrasonographer , will make the 


 
 
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Page 11 of 26 
measurements and read them blindly.  Because the HDI 5000 is owned by the Diabetes Division, 
there is no cost for the procedure. Previous studies with thiazolidinediones have shown that 
significant reductions in carotid IMT are observed within 12-18 months or less (27,72,73). 
5) Measurement of Ankle-Arm Blood Pressure will be performed and ankle brachial index (ABI) 
will be determined as previously described (95).   The ABI measurement is independently and 
inversely related to carotid and femoral arterial intima-media thickness and to the extent of 
coronary artery disease and enables early detection of atherosclerosis (95).  ABI is computed by 
dividing the ankle systolic blood pressure by the arm systolic blood pressure.  In normal 
individuals ankle pressures are similar to (or somewhat higher than) arm pressures when the patient 
is supine.  When peripheral arterial occlusive disease is present, a low ABI (less than 0.9 is 
considered to represent presence of PAD) is found. 
6) Hyperglycemic Clamp: (96) After a 10-12h overnight fast, subjects will report to the CRC at the 
TDI at 0600 h and catheters will be placed into an anteculital vein (for glucose infusion) and 
retrogradely into a vein on the dorsum of the hand (for blood withdrawal).  Low dose insulin (4-10 
mU/m2 • min) will be started to reduce plasma glucose concentration to ~100 mg/dl. 30-60 minutes 
after plasma glucose concentration is stabilized at ~100 mg/dl, the hand will be inserted into a 
heated box (700C)  to ensure arterialization of the venous blood.  Following the collection of three 
baseline blood samples (-20, -10, and 0 minutes), the plasma glucose concentration will be acutely 
raised and maintained at 125 mg/dl above baseline (i.e., from about 100 mg/dl to 225 mg/dl) for 90 
minutes. Plasma glucose, insulin, and C-peptide concentrations are measured every 2 minutes 
during the first 10 minutes and every 15 minutes until 90 minutes. At 90 minutes, the plasma 
glucose concentration is raised and maintained at 400 mg/dl for an additional 90 minutes. Plasma 
glucose, insulin, and,  C-peptide are measured every 2 minutes from 90 to 105 minutes and every 
10-15 minutes from 105 to 180 minutes. This will provide a maximum hyperglycemic stimulus for 
insulin secretion, with an early phase of insulin release during the first 10 minutes of each 
hyperglycemic clamp step followed by a gradually increasing phase of insulin release over the 
subsequent 80 minutes. At 180 minutes, an intravenous bolus of 5 grams of arginine will be given 
and the plasma glucose, insulin, and C-peptide levels will be measured every 2 minutes for 10 
minutes and every 5 minutes thereafter for a total of 30 minutes following the arginine injection. 
The combination of hyperglycemia plus hyperargininemia provides a maximal stimulus for insulin 
secretion (97) and the insulin secretory rate (quantitated by deconvolution of the plasma C-peptide 
concentration) provides the most sensitive recognized measure of beta cell health (55).  Under 
steady state conditions of physiologic (+125 mg/dl) hyperglycemia (60-90 minute time period of 
the hyperglycemic clamp), the glucose infusion rate divided by the mean plasma insulin 
concentration provides a measure of insulin sensitivity that agrees closely (r=0.92) with the 
euglycemic insulin clamp (95).  Total blood loss for the procedure is up to 255 ml. 
7) 7) EUGLYCEMIC INSULIN CLAMP On a separate day, subjects will be admitted to the CRC 
6:45 and 8 AM for a four-hour, two-step hyperinsulinemic euglycemic insulin (20 and 80 
mU/m2•min) clamp with a prime-continuous infusion of 3-3H-glucose. The 3-3H glucose prime 
will be 25 µCi x (fasting plasma glucose/100); the continuous infusion will be given at the rate of 
0.40 µCi/min for 240  minutes Plasma samples for tritiated glucose will be obtained at 5-15 minute 
intervals during the 30 minutes before and throughout the insulin clamp, to quantitate rates of 
whole body glucose disposal and suppression of endogenous (primarily hepatic) glucose 
production. Continuous indirect calorimetry (Deltatrac, Sensormedics, Anaheim, CA) will be 
performed for 30 minutes prior to the start of the insulin clamp, and during the 210-240 period of 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 12 of 26 
the insulin clamp to calculate rates of glucose and lipid oxidation Total blood loss for the 
procedure is up to 160 ml. 
8) Fundus Examination: All diabetic subjects seen at the Texas Diabetes Institute have an annual 
ophthalmologic examination as part of their routine care.  The fundus photographs will be read 
blindly by University of Wisconsin-Madison, Department of Ophthalmology and Visual Sciences. 
 
Following completion of these tests, subjects will be randomized (using a table of random numbers) to 
receive, in open label fashion, one of the following treatment regimens: 
 
GROUP I: Group I will be started on pioglitazone  (15 mg/day) plus metformin (1000 mg/day) with 
the supper meal and exenatide (5 mcg s.c. bid 30 min before breakfast and supper). 
 
 
If, after month one, the FPG ≥ 110 mg/dl or HbA1C ≥6.0%, the exenatide dose will be 
increased to 10 mcg bid, pioglitazone will be increased to 30 mg/day, and metformin to 1000 mg bid. 
 
 
If, after month two, the FPG ≥ 110 mg/dl or HbA1C ≥ 6.0%, pioglitazone will be increased 
to 45 mg/day.  Subjects who will not tolerate 5 mg bid exenatide because of GI side effects will be 
started on lower dose (1 mg s.c bid 30 min before breakfast and supper): and the dose will be titrated 
up to the maximal tolerated dose. 
 
 
If, at any time after achieving a HbA1c ≤ 6.0%, the HbA1c rises above 6.0% and the 
subject is on submaximal doses of metformin or pioglitazone or exenatide, the medication(s) will be 
titrated up to the maximally effective dose and the subject will not be considered a treatment failure. 
 
 
If, after month six, the HbA1C > 6.0% and the subject is on maximum doses of all triple 
therapy medications, the subject will be considered a treatment failure.  If, after month 6, the HbA1c 
rises to > 6.5%, bedtime glargine insulin (10-20 units) will be started and titrated to a maximum of 60 
units to achieve a FPG < 110 mg/dl and HbA1c < 6.0%.  If more than 60 units of glargine insulin is 
required to reduce the HbA1c < 6.5%, regular insulin will be added to each meal and adjusted based 
upon the pre- and post-meal blood glucose levels. These “treatment failure” subjects will continue with 
all follow up visits/procedures.  Throughout the titration process, downward adjustments will be 
allowed for the development of hypoglycemia, as defined by a blood glucose less than 60 mg/dl with 
(symptomatic hypoglycemia) or without (asymptomatic hypoglycemia) symptoms.  Serious 
hypoglycemia is defined as any hypoglycemic reaction requiring assistance from a third party for 
recovery. 
 
GROUP II: Group II will be started on metformin, 1000 mg with breakfast and 1000 mg with supper. 
 
 
If, after month one, the FPG ≥ 110 mg/dl or HbA1C ≥6.0%, glipizide (5 mg) will be added: 
1-2 tablets with breakfast depending on the FPG, HbA1C, and discretion of the investigator in order to 
avoid hypoglycemia. 
 
 
If, after month two, the FPG ≥ 110 mg/dl or HbA1C ≥6.0%, the glipizide dose will be 
increased to 4 tablets (20 mg/dl). 
 
 
If, after month three, the FPG > 110 mg/dl or HbA1C > 6.0%, bedtime basal insulin (10-20 
units) will be started and titrated up to achieve a FPG <110 mg/dl or HbA1c <6.0% 
 
 
If, at any time after achieving a HbA1c < 6.0%, the HbA1c rises above 6.0% and the 
subject is on submaximal doses of metformin or glipizide or glargine insulin, the medication(s) can be 
titrated up to the maximally effective dose and the subject will not be considered a treatment failure.  
If, after month six, the HbA1C > 6.0%, and the subject is on maximum doses of metformin, glipizide, 
and glargine insulin, the subject will be considered a treatment failure. Regular insulin will be added to 
each meal when the HbA1c rises to > 6.5% and adjusted based upon the pre- and post-meal blood 
glucose levels.  These “treatment failure” subjects will continue with all follow up visits/procedures.  


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 13 of 26 
 
Throughout the titration process, downward adjustments will be allowed for the development of 
hypoglycemia, as defined by a blood glucose less than 60 mg/dl with (symptomatic hypoglycemia) or 
without (asymptomatic hypoglycemia) symptoms.  Serious hypoglycemia is defined as any hypoglycemic 
reaction requiring assistance from a third party for recovery.  
 
Following their enrollment into the study, all T2DM participants will return to the Clinical Research 
Center (CRC) at the TDI for follow up visits every 3 months.  Telephone calls also will be made to each 
participant every 6 weeks.  During the telephone/CRC visits, subjects will be asked questions about 
interim medical history, home glucose monitoring results, and compliance with the medical regimen. 
 
During each 3-month follow-up visit to the CRC, body weight, waist circumference (Gulick III 
tape measure), and blood pressure (Dynamop) will be measured.  Blood will be drawn for FPG and 
HbA1C, and pharmacological therapy will be adjusted based on the HbA1c, FPG, and HBGM results (see 
prior algorithm).  Plasma lipids and 24-hour urine albumin excretion will be measured annually or more 
frequently as indicated by test results.  In addition to glycemic control, all subjects will receive therapy for 
any abnormal cardiovascular risk factors: hypercholesterolemia (goal LDL <100 mg/dl), 
hypertriglyceridemia (goal <150 mg/dl), hypertension (goal <130/80 monthly), albumin excretion (goal < 
30 mg/day).  At the end of three years, the OGTT, DEXA, fundus photography, 24 hour urine for albumin, 
hyperglycemic clamp, ankle-arm blood pressure, and carotid IMT will be repeated. 
 
Primary End Point: The primary end point of the study is the difference in HbA1c between Group I (triple 
combination therapy at time of initial diagnosis) and Group II (stepwise therapy).  
Secondary End Points: The following parameters will be measured as secondary endpoints; 
1) Number of subjects in each group with HbA1C < 6.0% 
2) Number of treatment failures in each group as defined by HbA1C >6.0%and requiring the addition 
of rapid acting insulin with meals 
3) Change in beta cell function 
4) Change in whole body insulin resistance 
5) Incidence of hypoglycemia (asymptomatic, symptomatic, serious) 
6) Change in body weight, total body fat, and waist circumference 
7) Change in carotid intima media thickness 
8) Change in ankle-arm blood pressure           
9) Change in stage of diabetic retinopathy 
Change in GFR and urinary albumin secretion rate 
 
Subjects who will complete 3-year follow-up and the repeat studies will continue to receive therapy as 
described above and continue in the follow-up visit every 3 months as previously described until the last 
subjects recruited to the study has completed 2-year follow-up.  During this follow up period we will 
repeat the OGTT, eye photographs, DEXA and carotid ultrasound every other year (Year 3 and 6). 
 
Washout Phase 


 
 
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At 6 years, all baseline studies will be repeated as stated above (OGTT, annual labs, eye photographs, 
ankle-arm blood pressure and carotid ultrasound). After the completion of the repeat studies, hepatic fat 
content and liver fibrosis will be measured with fibroscan and MRI Spectroscopy.  
MRI Spectroscopy  is the gold standard method to quantitate hepatic fat content. Pharmacologic therapy 
will be stopped if participants HbA1C is less than 7.5%. Participants with HbA1C greater than 7.5% and 
in the triple therapy arm, dapagliflozin (10mg/day) will be added. Participants with HbA1C greater than 
7.5% in the conventional therapy arm will be switched to triple therapy. Patients will be seen every 3 
months for a follow-up visit. Medical history, physical exam, body weight, blood pressure, Fasting blood 
sugar and HBA1c will be measured at each follow-up visit. The OGTT will be repeated at 3 months and 
every 6 months thereafter. Liver fat content and liver fibrosis will be measured with fibroscan annually. 
The 3-month follow-up visits will continue for additional 5 years, to obtain information about the long-
term durability of triple therapy. Liver fat content and liver fibrosis will be measured with fibroscan and 
MRI annually, and  the OGTT will be repeated every 2 years, and all baseline measurements will be 
repeated at 5 years. 
 
Measurement of Hepatic fat content and Liver fibrosis: this measurement is made with fibroscan, which 
uses ultrasound wave sent through the liver from a probe placed on the skin above the liver and connected 
to an ultrasound machine. From the speed by which the ultrasound wave reflected back to the probe and 
the amplitude of the reflected wave, the machine calculates a score that reflects hepatic fat content and the 
degree of fibrosis in the liver. The measurement is non-invasive, lasts 10-15 minutes, does not use 
radiation, and there are no adverse events associated with it.  
 
b. List of Research Procedures or Components (Components can be two or more procedures) (Click here for example) 
(add rows or delete unused rows) (Consider as one component, multiple procedures that may lend themselves to having identical 
risks and benefits described in a single table in c, although exceptions exist to this guidance.) 
 
                          Note that:  
                       A                    +           B  +          C    +D 
# 
Research 
components 
Local Standard 
Practice 
required by the 
research plan  
Research Only (Indicate 
# performed solely for 
research (research 
only) or indicate # 
performed outside 
frequency or timing for 
acceptable local 
practice) 
Total Number 
of 
Research 
Related 
Procedures 
for 36 month 
study 
Follow up 
Visits after 
completing 36 
month study 
Washout 
Phase 
(Patients who 
have 
completed 
6years and 
HbA1C is less 
than 7.5%) 
1 
  OGTT 
 
Research only                 
2 
*OGTT will be 
performed at 
years 3 and 6 
after 
completing 36 
months  
OGTT will be 
performed at 6 
year point and 
then after 2 
years into the 
follow-up 
phase  
2 
DEXA 
 
Research only                 
              2 
At last study 
visit  
 
3 
Carotid intima 
media thickness 
 
Research only                 
2 
Carotid will be 
performed 
years 3 and 6 
after 
completing 36 
months 
1 


 
 
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4 
Ankle-arm blood 
pressure 
 
Research only                 
              2 
Ankle-arm 
blood 
pressure will 
be performed 
at years 3 and 
6 after 
completing 36 
months 
1 
5 
Hyperglycemic 
clamp 
 
Research only                 
              2 
0 
 
6 
Euglycemic 
clamp 
 
Research only                 
              2 
0 
 
7 
Fundus 
examination 
Standard practice 
 
2 
Fundus 
examination 
will be 
performed at 
years 3 and 6 
after 
completing 36 
months 
1 
8 
Initiation of 
pharmacological 
therapy 
Standard practice 
 
 
 
Maintain 
therapy if 
HbA1C is 
greater than 
7.5% (with the 
addition of 
dapagliflozin) 
9 
Follow-up 
 
Research only 
14 
Every 3 
months after 
completing 36 
months in 
years 3-6 
Every 3 
Months there 
will be a follow 
up for 5 years  
10 
FibroScan & 
MRI 
Spectroscopy 
(without 
contrast) 
 
Research only  
 
 
Measured 
annually 
 
 
 
 
 
 
c. Risk:Benefit Analysis 
For each research procedure identified in section 6b above, complete a risk:benefit analysis table. 
(Two tables are provided, copy and paste additional tables as needed) 
 


 
 
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Procedure or component 1 
OGTT 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
Group I  
None 
Group II 
None 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
None 
• 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
• 
none 
None 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
Local reaction at iv site 
Total blood loss for the 
procedure is up to 88 
ml. 
• 
none 
Are all groups exposed to the risks listed above?    X Yes     
No     
N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 


 
 
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Procedure or component 2 
DEXA 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
NONE 
GROUP II 
NONE 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
Radiation exposure (6 
mrems).  Although we 
cannot 
be 
sure 
that 
nothing will happen from 
such a small amount of 
radiation, we know that 
any risk is very small. 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
None 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
none 
none 
Are all groups exposed to the risks listed above?    X Yes     
No     
N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 


 
 
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Procedure or component 3 
Carotid intima media thickness 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
NONE 
GROUP II 
NONE 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
none 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
None 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
none 
none 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 


 
 
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Procedure or component 4 
Measurement  of Ankle-Arm blood pressure 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
NONE 
GROUP II 
NONE 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
none 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
None 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
none 
none 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 


 
 
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Procedure or component 5 
Hyperglycemic clamp 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
NONE 
GROUP II 
NONE 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
none 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
None 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
Local reaction at IV sites 
Total blood loss for the 
procedure is up to 255 
ml. 
 
none 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 21 of 26 
Procedure or component 6 
Euglycemic clamp 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
NONE 
GROUP II 
NONE 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
none 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
None 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
Hypoglycemia 
Local reaction at iv sites 
Total blood loss for the 
procedure is up to 160 
ml. 
none 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 22 of 26 
Procedure or component 7 
Fundus examination 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
NONE 
GROUP II 
NONE 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
none 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
None 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
none 
none 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Procedure or component 8 
Pharmacological Therapy with metformin, and pioglitazone plus exenatide 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 23 of 26 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP I 
This drug combination is likely to reduce your blood sugar  
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
Nausea (exenatide) 
• 
Weight gain (pioglitazone) 
• 
Anemia (pioglitazone) 
Itching where Exenatide 
once weekly (Bydureon) 
was injected  
• Feeling tired (lack of 
energy or tiredness) 
• Injection site events (for 
example: lumps, 
hardening at the site of 
injection, bruising, 
redness of skin, itching, 
rash, and/or pain) 
None 
 
Not serious 
Serious  


 
 
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Page 24 of 26 
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
• 
Abdominal pain (metformin) 
• 
Headache (pioglitazone) 
• 
Flatulence (pioglitazone) 
• 
Vomiting (exenatide 
metformin) 
Hypoglycemia (glyburide) with 
a sulfonylurea) 
Hypoglycemia (with 
metformin and a 
sulfonylurea 
• 
Diarrhea (mertformin, 
exenatide) 
At least 1, but fewer than 
10 patients out of 100 
patients reported: 
• Injection site events (for 
example: bruising, 
bleeding, pain, itching, 
redness of skin, swelling 
and/or small lump where 
Exenatide was injected) 
Dyspepsia 
Gastroesophageal reflux 
disease 
Nasopharyngitis 
Asthenia 
Feeling Jittery 
Decreased appetite 
Dizziness 
Hyperhidrosis 
Fewer than 1 out of 100 
patients reported: 
• Stomach swelling 
• Stomach pain 
• Constipation 
• Gas 
• Burping 
• Abnormal taste sensation 
• 
none 
 
 
Serious  


 
 
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Page 25 of 26 
Rare  
These risks are expected to occur in 
less than 1 subjects out of 100  
Hypoglycemia 
Fewer than 1 out of 1000 
patients reported: 
• Sleepiness 
• Itching 
• Hives 
• Spotty/patchy or swollen 
rash 
• Rapid swelling of the 
tissues around the neck, 
face, mouth, and/or throat 
indicating an allergic 
reaction 
• Hair loss  
• Dehydration (the loss of 
too much water from the 
body), because of nausea, 
vomiting, and/or diarrhea 
• Worsening kidney 
function 
• Inflammation of the 
pancreas 
Fewer than 1 out of 
10,000 patients reported: 
• Hives/itching with 
difficulty breathing and/or 
low blood pressure, 
indicating a severe 
allergic (anaphylactic) 
reaction 
• Thrombocytopenia- a 
condition in which you 
have a low blood platelet 
count. 
 
Heart failure (pioglitazone) 
Bone fracture (pioglitazone) 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 


 
 
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Page 26 of 26 
Procedure or component 9 
Pharmacological therapy, metformin, 
glyburide/Glipizide and insulin 
List each group exposed to this procedure 
on a separate line. 
(e.g., experimental, control, Arm A, Arm B, etc 
Or state All Groups/Subjects 
For each group, list the benefits of this procedure (either the procedure or a 
monitoring procedure likely to contribute to the subject’s well being).  If there are no 
benefits, state “none”. 
GROUP II 
This drug combination is likely to reduce your blood sugar 
For this procedure or component, list the reasonably foreseeable risks 
List the risks according to the probability (likely, less likely or rare) and magnitude (serious or not serious). 
(include: 1) expected adverse events; 2) rare and serious adverse events; 3) all other psychological, social, legal harms) 
 
 
Not serious 
Serious  
Likely 
These risks are expected to occur in 
more than 20 [or insert different #] out 
of 100 subjects. 
• 
Hypoglycemia 
• 
Weight gain 
None 
 
Not serious 
Serious  
Less likely  
These risks are expected to occur in 5 
- 20 [or insert different range]  subjects 
or less out of 100 subjects. 
• 
Abdominal pain 
• 
vomiting 
• 
none 
 
 
Serious  
Rare  
These risks are expected to occur in 
less than 5  [or insert different #] 
subjects out of 100  
none 
none 
Are all groups exposed to the risks listed above?    □  Yes      □No    □ N/A (There is only one group) 
If No, Describe:  [Describe here] 
 
 
 
 
 
7.  Safety Precautions. (The study should at a minimum describe safeguards to address the serious risks listed above.) 
 
 
(1)  Describe the procedures for protecting against or minimizing any potential risks for each of the research procedures 
listed above. 
 
 
PROTECTION OF SUBJECTS.  The PI will review all results on a weekly basis to ensure that the 
timeliness and conformity with established clinical monitoring of the subjects is followed.  
 
1. 
Any subject with clinically significant cardiac, pulmonary, gastrointestinal, or endocrine 
(other than diabetes) disease will be excluded from study. 
2. 
Prior to study, a venous hematocrit will be obtained.  Volunteers with a hematocrit less than 
34 vol % will be excluded from the study. 
3. 
Any serious adverse event will be reported to the IRB within 24 hours. All non-serious 
adverse events will be reported by the investigator to the IRB within 72 hours.  An annual 
report summarizing all adverse events will be submitted to the IRB.  
4. 
The timeliness and accuracy of all information documented in any form and/or records 
pertaining to the study will be maintained. 
5. 
blood sugar level will be measured every 5 minutes during the clamp to prevent the risk for 
hypoglycemia  


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 27 of 26 
6. 
following the initiation of therapy subjects will contacted via phone calls every two weeks to 
ensure that no serious side effects have happened. 
7. 
Subjects will be examined during the follow-up (every 1-3 months) for potential side effects 
and for the quality of their blood sugar control. If severe side effects will appear, drug dose 
will be adjusted accordingly. If blood glucose will not be adequately controlled, therapy will 
be adjusted accordingly. Subjects who will receive full dose therapy in either study arm and 
their A1c remains > 8% will be considered treatment failure and will be returned to their 
doctor for their standard care.  
8. 
During the euglycemic clamp blood sugar will be tested every 5 minutes and glucose infusion 
will be adjusted accordingly to maintain blood sugar at target and prevent hypoglycemia. 
 
 
 
(2)  Where appropriate, discuss provisions for ensuring necessary medical or professional intervention in the event of 
adverse events, or unanticipated problems involving subjects. 
 
If hypoglycemia during the clamp occurs, the study will be stopped and 20% glucose infusion will be started until plasma glucose 
concentration is stabilized 
 
 
(3)  Will the safeguards be different between/among groups?  
Yes     xNo 
 
[If yes, describe here] 
 
 
 
8.  Available Alternative. 
 
 
(1)  Describe alternative treatments and procedures that might be advantageous to the subjects, should they choose not to 
participate in the study.  This should include a discussion of the current standard of care treatment(s). In some cases the only 
alternative may be not to participate in the study.  This section should match the alternative section of the CF (though not written in 
second person like the ICF). 
 
although all drugs used in this study are approved by the FDA for lowering blood sugar and group I will be 
treated according to the ADA recommendations, the participation of patients in this study is completely 
voluntary. Subjects can choose not to participate in the study and be treated with other combination of 
currently approved drugs or other drugs not used in this study (acarbose, DPP 1V inhibitors). 
 
 
9.  Confidentiality. 
 
 
(1)  Specify where the data and/or specimens will be stored and how the researcher will protect both the data and/or 
specimens with respect to confidentiality. 
 
Everything we learn about the subjects will be confidential.  If we publish the results of the study in a 
scientific journal or book, we will not identify them in any way.  The Food and Drug Administration of the 
U.S. Government may also want to see the records. We will not identify any subject by name in any 
publication.  The consent forms will be stored in a locked cabinet in Room at the TDI. Subjects will be 
assigned a study number for identification purposes and the identification code will be  stored in a locked 
cabinet in the PI’s office (Room 3.380s, UTHSCSA). 
Every subject will be assigned a code number, and Data will be stored only on the UTHSCSA computer 
system which is protected with passwords.  
 
 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 28 of 26 
 
(2)  Provide a time table for destroying the data/specimens and identify how they will be destroyed, (this is not necessarily 
the same answer as used in a HIPAA Waiver as that waiver may only apply to some of the information collected during the study) or 
provide rationale for perpetual maintenance. 
 
Data sheets will be saved in un identified manner  
 
 
 
(3)  Specify who will access the identified data/specimens, why they need access and whether they will be authorized to 
remove PHI from the institution.  
PI and co investigators in the study  
 
10.  Payment. 
 
 
(1)  Describe the incentives (e.g., inducements) being offered to subjects for their time during participation in the research 
study. 
 
 For Participants who will have clamps: Participants will receive during the 36 month portion of the study 
the following: Qualification Study Visit:  $20, Study -OGTT & DXA @ $40 each (Before treatment and 
end of treatment) total of $80, INTIMA MEDIA THICKNESS @ $30 each (Before treatment and end of 
treatment) total of $60, INSULIN SECRETION TEST @ $100 each (Before treatment and end of treatment) 
for a total of $200, INSULIN SENSITIVITY TEST  @ $100 each (Before treatment and end of treatment) 
for a total of $200, FOLLOW UP VISITS @ $20 each for total of $280 for all visits, After Treatment phase 
FOLLOW UP VISITS (@ $20 per visit for a  max of 8) for a total of $160, Year 2 After Treatment Phase 
FOLLOW UP VISIT OGTT, DXA, & INTIMA MEDIA THICKNESS for a total of $70. Total amount of 
compensation participant could receive if all procedures and visits are completed  is $1070. 
 
For Participants who will not have a clamp: Participants will receive during the 36 month portion of the 
study and for the follow-up portions are as follows: Qualification Study Visit:  $20, Study -OGTT & DXA 
@ $40 each (Before treatment and end of treatment) total of $80, INTIMA MEDIA THICKNESS @ $30 
each (Before treatment and end of treatment) total of $60, FOLLOW UP VISITS @ $20 each for total of 
$280 for all visits, After Treatment phase FOLLOW UP VISITS (@ $20 per visit for a  max of 8) for a total 
of $160, Year 2 After Treatment Phase FOLLOW UP VISIT OGTT, DXA, & INTIMA MEDIA 
THICKNESS for a total of $70. Total amount of compensation you could receive if completed all procedures 
and visits is $670. 
 
For all participants the compensation during the Follow Up Visits after completing the 36 month treatment 
phase and Washout Phase are as follows: $20 for each follow up visit, $40 for each OGTT, $30 for intima 
media thickness measurement and $30 for the MRI.   
 
 
 
 
Reimbursement for unexpected or unusual expenses related to travel or other circumstances related to study 
participation, but this may not exceed $100. 
 
 
 


 
 
08-456H, DeFronzo, Form C, 12-04-19, AMD.docx 
Page 29 of 26 
 
(2)  If monetary compensation is offered, indicate how much the subjects will be paid and describe the terms and schedule 
of payment.  (It is IRB policy that provision should be made for providing partial payment to subjects who withdraw before the 
completion of the research.  Monetary payments should be prorated or paid in full.)  The Veterans Health Administration prohibits 
payment to human subjects participating in research when the research is integrated with the patient’s medical care and when the 
research makes no special demands on the patient beyond those of standard medical care.  Payment may be permitted, with IRB 
approval, under certain circumstances.  Refer to the Veterans Affairs Research and the UTHSCSA IRB web page to review 
circumstances under which payment is permitted for VA research. 
 
Payments will be made in checks that will be mailed to their home address within 6 weeks of the study date   
 
11.  Costs to Subjects. 
 
 
(1)  Describe any costs for care associated with research (including a breakdown of standard of care procedures versus 
research procedures), costs of test drugs or devices, and research procedure costs that are the subject’s responsibility as a 
consequence of participating in the research. 
 
The cost of all tests performed and medication used in this study will be covered by the investigator. Participants will not be 
asked to cover any cost associated with the procedures or medications of the study  
 
 
(2)  Describe any offer for reimbursement of costs by the sponsor for research related injury care.  (Attach a copy of the 
section of the clinical trial agreement or contract describing research related injury care). 
 
Any injury related to the study will be treated either in the VA hospital (for patients studied in the GCRC of the VA hospital) or at 
the Texas Diabetes Institute. 
 
 
12.  PI-Sponsored FDA-Regulated Research. 
 
 
(1)  If the PI is the IND/IDE holder, the PI is also considered a sponsor.  When the PI assumes a sponsor function, the PI 
must meet the requirements for the sponsor and the investigator.  Describe your (the PI's) experience/knowledge/training (if any) in 
serving as a sponsor. 
 
N/A 
 
 
(2)   Explain what measures you, the PI, will take/have taken to ensure understanding of your responsibilities as both PI 
and sponsor, and how you will ensure compliance with FDA regulations (e.g., detail plans for attending the pre-study visit & review 
of FDA regulations; describe procedures for informing the research team of their responsibilities and a plan for the monitoring 
function). 
 
I have drafted the study protocol, which is consistent with the FDA regulation for treating diabetes.  All study procedures and time 
table will be reviewed with the study team prior to the start of the study. A monthly meeting will be held with all study team to 
update on the study progress and to ensure that all procedures are done in compliance with the study protocol. 
 
IRB policy requires additional CITI training (GCP) for all investigators who are also FDA-regulated sponsors.  If the 
protocol receives IRB approval, the investigator will be required to complete this mandatory training.  Information on the 
training will be included with the IRB approval materials.   
 
 
 


 
 
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Page 30 of 26 
Abstract / Project Summary 
 
Provide a succinct and accurate description of the proposed research. State the purpose/aims. Describe concisely the research 
design and methods for achieving the stated goals. This section should be understandable to all members of the IRB, scientific and 
non-scientific.  This summary will also be needed in future IRB Progress Reports.   
DO NOT EXCEED THE SPACE PROVIDED. 
Abstract  
Type 2 diabetes mellitus (T2DM) is a common metabolic disease that affects 21 million Americans and is 
associated with significant morbidity and mortality secondary to micro- and macrovascular complications. 
Subjects with T2DM manifest insulin resistance in skeletal muscle, liver and adipocytes and impaired insulin 
secretion. Although many therapeutic agents have been developed to target the pathogenic abnormalities in 
subjects with T2DM, the current ADA recommendation for pharmacological therapy in T2DM remains based 
on monotherapy, with dose escalation, followed by sequential addition of oral antidiabetic agents and eventually 
insulin to control blood glucose levels.  Unfortunately, the majority of type 2 diabetic individuals in the US fail 
to achieve the recommended level of glycemic control (HbA1c <6.0%) using this approach. In this study, I 
propose to explore the efficacy of a novel therapeutic approach to attain glycemic control in T2DM subjects. 
This novel approach is based upon the initiation of triple combination therapy at the time of diagnosis with 
agents that target specific pathogenic abnormalities present in T2DM. Two groups of newly diagnosed, drug 
naive T2DM subjects will be studied: (i) Group I will receive triple combination therapy with metformin, 
pioglitazone, and exenatide as initial therapy; (ii) Group II will be started on metformin monotherapy followed 
by sequential addition of a sulfonylurea and then glargine insulin.  The goal of therapy in both groups is to 
reduce the HbA1C < 6.0%. Subjects will be recruited over one year and followed for 2 years (total study duration 
=3 years). The primary outcome will be the difference in HbA1c between Groups I and II. Secondary outcomes 
will include failure to achieve the glycemic goal (HbA1C<6.0%), improvements in insulin resistance, beta cell 
function, markers of inflammation, markers of oxidative stress, and carotid intima media thickness. I hypothesize 
that subjects started on combination therapy at the time of diagnosis of T2DM will have better and more durable 
glycemic control, a lower rate of therapeutic failure, enhanced insulin sensitivity, and improved/preservation of 
beta cell function compared to subjects receiving the “conventional” ADA-recommended stepped-therapeutic 
approach with “standard” medications. I also hypothesize that subjects started on initial combination therapy 
will have: (i) lower levels of inflammatory markers and (ii) reduced carotid IMT. On a long-term basis, one 
would expect the superior metabolic control in T2DM who receive aggressive combination therapy from onset 
to have a lower rate of diabetic complications. 
The results of this study will provide a novel, more progressive therapeutic approach to the treatment of T2DM, 
based upon correction of known pathogenic abnormalities responsible for the disease.      
 
 
 
 
 
 
 


 
 
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Page 31 of 26 
Data Analysis and Statistical Methods 
 
Values are presented as mean 6 SEM. Two-sided t test was used to compare mean diﬀerences between 
treatment arms, and the x2 test was used to test the signiﬁcance of discrete variables. The Cox proportional 
hazards model was used to estimate the inﬂuence of therapy on failure to maintain the treatment goal. The 
model was adjusted for other confounders (namely, age, sex, BMI, disease dura-on, and baseline HbA1c 
level). 
Sample size calculation: 
The study was powered to detect a 0.5% (60.95 SD) HbA1c diﬀerence between the two treatment arms 
based on the HbA1c decrease in the PROactive study (22).We calculated that 76 pa-ents who completed the 
study would be required in each arm to detect signiﬁcant diﬀerence between the two groups at a , 0.05. A 
detailed description of the sample size 
calculation is given in the Supplementary Material.