Clinical trial NCT01548651
Conditions: Impaired Glucose Tolerance
Sponsor: Baylor College of Medicine
Start date: 2012-02-01; Completion date: 2017-08-25
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to examine the effect of saxagliptin, an anti-diabetes medication, on hepatic and myocardial fat content and monocyte inflammation in patients with Impaired Glucose Tolerance (IGT).

Detailed description:
Obese, insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD). The fatty liver is insulin resistant. Individuals with a fatty liver are more likely to have excess intra-abdominal fat as well as a reduction in circulating plasma adiponectin levels. A new class of antidiabetes medications known as dipeptidyl peptidase 4 (DPP-4) inhibitors (sitagliptin, saxagliptin) which enhance the circulating half life of Glucagon-like peptide-1 (GLP-1), an incretin hormone that enhances insulin secretion/ lowers glucose levels, have been approved to treat type 2 diabetes. More recently, it has been shown that these dipeptidyl peptidase 4 inhibitors can also decrease liver fat and inflammation in animal models of obesity by increasing circulating levels of GLP-1. It has been shown that GLP-1 enhances liver fat oxidation, reduces liver fat synthesis, and increases adiponectin levels in animal models in vivo.

Recent reports suggest that NAFLD is associated with an increased risk of cardiovascular disease independent of associated cardiovascular risk factors. Furthermore type 2 diabetics and subjects with impaired glucose tolerance are characterized by an increase in both hepatic and myocardial fat and left ventricular (LV) dysfunction, particularly diastolic dysfunction. Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus as well as impaired glucose tolerance. However, the effect of saxagliptin therapy on liver and myocardial fat content, as well as LV systolic and diastolic function in patients with impaired glucose tolerance (IGT) or type 2 diabetes has not been previously studied. Recently, it has been demonstrated that myocardial triglyceride content is increased in type 2 diabetic patients and is associated with impaired left ventricular diastolic function, independently of age, body mass index (BMI), heart rate, visceral fat, and diastolic blood pressure. More recently, it has been shown that that obese normal glucose tolerant subjects, obese subjects with IGT, and type 2 diabetic subjects have increased myocardial fat compared to lean subjects. Thus, both IGT and type 2 diabetic subjects have increased myocardial steatosis and defects in LV function. GLP-1 has been shown to improve myocardial function and cardiac output in conscious chronically instrumented canine models of cardiac injury or heart failure. GLP-1 increased cardiac output and reduced left ventricular end diastolic pressure in association with reduced systemic vascular resistance, and it improved myocardial insulin sensitivity and myocardial glucose uptake in dogs with rapid pacing-induced dilated cardiomyopathy. However, no previous study has examined the effect of saxagliptin on myocardial fat or LV function in IGT or type 2 diabetic patients. Finally, the effect of saxagliptin on vascular inflammation and monocyte Nuclear Factor-KappaB (NFkappaB) remains to be studied. Patients with Impaired Glucose Tolerance (IGT)/ Impaired Fasting Glucose (IFG) have insulin resistance as a well established defect. Furthermore, as stated previously, both myocardial and hepatic steatosis as well as defects in LV function are well characterized in obese, insulin resistant patients with IGT. However, the effect of DPP IV inhibitors on hepatic and myocardial steatosis and monocyte inflammation in insulin resistant patients with IGT have not been previously studied.

Arms: arm 1: Placebo 5 mg orally daily for 6 months arm 2: Saxagliptin 5 mg orally daily for 6 months
Interventions: intervention 1: Saxagliptin intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will be randomized to receive either Saxagliptin 5mg daily orally or placebo for 6 months. All subjects will receive baseline measurements of fasting plasma glucose, free fatty acids, plasma adipocytokines, plasma levels of inflammatory markers and C Reactive Protein (CRP), Intracellular Adhesion Molecule (ICAM), vascular cell adhesion molecule (VCAM), plasma lipids, and glucose tolerance (75 gram oral glucose tolerance test) as well as measurement of liver and myocardial fat content and left ventricular systolic and diastolic function with magnetic resonance imaging/spectroscopy. All subjects will also undergo measurements of monocyte inflammatory proteins at baseline. All subjects will undergo repeat measurements of fasting plasma glucose, Free Fatty Acids, inflammatory markers and adipocytokines, oral glucose tolerance test, monocyte inflammation, as well as hepatic/myocardial fat content determination and left ventricular function at the end of the 6 months. intervention 2: Subjects will be randomized to receive either Saxagliptin 5mg daily orally or placebo for 6 months. Prior to randomization, all subjects will receive baseline measurements of fasting plasma glucose, free fatty acids, plasma adipocytokines, plasma levels of inflammatory markers and CRP, ICAM, VCAM, plasma lipids, and glucose tolerance (75 gram oral glucose tolerance test) as well as measurement of liver and myocardial fat content and left ventricular systolic and diastolic function with magnetic resonance imaging/spectroscopy. All subjects will also undergo measurements of monocyte inflammatory proteins at baseline. All subjects will undergo repeat measurements of fasting plasma glucose, Free Fatty Acids, inflammatory markers and adipocytokines, oral glucose tolerance test, monocyte inflammation, as well as hepatic/myocardial fat content determination and left ventricular function at the end of the 6 month treatment period.

Protocol documents:
Prot_SAP_000.pdf: 
 
Saxagliptin IST Protocol Shell 
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PROTOCOL 
 
 
 
 
TITLE PAGE 
 
Effect of Saxagliptin Treatment on Myocardial Fat Content, Left Ventricular 
Function, and Monocyte Inflammation in Patients with Impaired Glucose 
Tolerance 
 
 
 
NCT01548651 
 
 
 
 
 
 
 
 
 
[Protocol Version/Date:1.1/ dated 7-24-2014] 
 
 
 


                                               TABLE OF CONTENTS 
TITLE PAGE .................................................................................................... 1 
TABLE OF CONTENTS .................................................................................. 2 
PROTOCOL SYNOPSIS .................................................................................. 4 
1 
INTRODUCTION ...................................................................................... 6 
1.1 
Summary of Results of Investigational Program .......................... 7 
1.1.1 Clinical Toxicology ............................................................... 7 
1.1.2 Summary of Efficacy Results in Subjects with 
Type 2 Diabetes Mellitus ..................................................... 8 
1.1.3 Summary of Safety Results in Subjects with 
Type 2 Diabetes Mellitus ..................................................... 9 
1.1.3.1 .............................................................................................. 
Adverse Events of Special Interest ..................................... 11 
1.2 
Overall Risk/Benefit Assessment ................................................... 12 
1.3 
Research Hypothesis ....................................................................... 13 
1.4 
Study Rationale............................................................................... 13 
2 
STUDY OBJECTIVES .............................................................................. 18 
2.1 
Primary Objective ........................................................................... 18 
2.2 
Secondary Objectives ...................................................................... 18 
3 
ETHICAL CONSIDERATIONS ................................................................ 18 
3.1 
Good Clinical Practice ..................................................................... 18 
3.2 
Institutional Review Board/Independent Ethics 
Committee ....................................................................................... 19 
3.3 
Informed Consent ........................................................................... 19 
4 
INVESTIGATIONAL PLAN ..................................................................... 20 
4.1 
Study Design and Duration ............................................................ 20 
4.2 
Study Population ............................................................................ 27 
4.2.1 Inclusion Criteria ................................................................. 27 
4.2.2 Exclusion Criteria ................................................................... 28 
4.2.3 Discontinuation of Subjects from Treatment ...................... 30 
4.3 
Data Safety Monitoring Plan ......................................................... 30 
5 
TREATMENTS .......................................................................................... 31 
5.1 
Study Treatment: Saxagliptin ........................................................ 31 
5.1.1 Identification ........................................................................ 31 
5.1.2 Packaging and Labeling ....................................................... 32 
5.1.3 Storage, Handling, and Dispensing ..................................... 32 
5.2 
Drug Ordering and Accountability ................................................. 32 
5.2.1 Initial Orders ........................................................................ 32 
5.2.2 Re-Supply ............................................................................. 32 
5.3 
Method of Assigning Subjects to a Treatment ............................... 32 
5.4 
Selection and Timing of Dose for Each Subject ............................. 33 
5.5 
Blinding/Unblinding ....................................................................... 33 
5.6 
Concomitant Treatments ................................................................ 33 


5.6.1 Prohibited and/or Restricted Treatments ........................... 33 
5.6.2 Other Restrictions and Precautions .................................... 33 
5.7 
Treatment Compliance ................................................................... 34 
6 
STUDY ASSESSMENTS AND PROCEDURES ...................................... 34 
6.1 
Time and Events Schedule ............................................................. 34 
6.2 
Study Materials .............................................................................. 37 
6.3 
Safety Assessments ......................................................................... 37 
6.4 
Efficacy Assessments ...................................................................... 37 
6.4.1 Primary Efficacy Assessment .............................................. 37 
6.4.2 Secondary Efficacy Assessments ......................................... 37 
7 
ADVERSE EVENT REPORTING ............................................................. 38 
7.1 
Adverse Events ............................................................................... 38 
7.1.1 Serious Adverse Events ....................................................... 38 
7.1.2 Adverse Events of Special Interest ...................................... 39 
7.1.3 Nonserious Adverse Events ................................................. 39 
7.2 
Assignment of Adverse Event Intensity and 
Relationship to Investigational Product ........................................ 39 
7.3 
Collection and Reporting ................................................................ 40 
7.3.1 Serious Adverse Events and Adverse Events of 
Special Interest .................................................................... 40 
7.3.2 Handling of Expedited Safety Reports ................................ 41 
7.3.3 Nonserious Adverse Events ................................................. 42 
7.4 
Laboratory Test Abnormalities ...................................................... 42 
7.5 
Pregnancy ........................................................................................ 43 
7.5.1 Requirements for Pregnancy Testing .................................. 43 
7.5.2 Reporting of Pregnancy ........................................................ 43 
7.6 
Overdose .......................................................................................... 44 
7.7 
Other Safety Considerations ............................................................ 44 
8 
STATISTICAL CONSIDERATIONS ........................................................ 45 
9 
STUDY MANAGEMENT 
9.1 
Compliance with the Protocol and Protocol Revisions .................. 46 
9.2 
Records Retention ........................................................................... 47 
9.3 
Destruction of Investigational Product .......................................... 47 
10 GLOSSARY OF TERMS ............................................................................ 48 
11 LIST OF ABBREVIATIONS ..................................................................... 49 
12 REFERENCES .......................................................................................... 50 
APPENDIX 1: None  
 


 
 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Effect of Saxagliptin Treatment on Myocardial Fat Content, Left 
Ventricular Function, and Monocyte Inflammation in Patients 
with Impaired Glucose Tolerance 
Site Numbers & Names: 
Baylor College of  Medicine, Houston, TX 
Research Hypothesis: 
We hypothesize that saxagliptin therapy (compared to placebo) 
would be associated with a reduction in myocardial and hepatic 
fat content, an improvement in left ventricular (LV) function, and 
a reduction in monocyte inflammation in patients with impaired 
glucose tolerance. 
 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Saxagliptin 5 mg or placebo PO daily for 6 months 
Study Objectives: 
• Primary: 
• Secondary: 
The primary objective is to examine the effects of saxagliptin 
on myocardial and hepatic fat content in patients with impaired 
glucose tolerance (IGT). 
The secondary objective is to examine the effect of saxagliptin 
on left ventricular systolic and diastolic function and monocyte 
inflammation in patients with IGT. 
Study Design: 
Patients with IGT or prediabetes will be randomized to receive 
saxagliptin or placebo in a double blind placebo controlled single 
center trial. 
Accrual Goal: 
(Total number of subjects) 
40 patients 
Accrual Rate: 
(Number of subjects 
expected per month) 
3 patients per month 
FPFV: 
LPFV: 
Follow Up: 
(dd-mm-yy) 
December 1, 2011 
December 1, 2012 
 
31-05-2013 
 
Correlative Studies: 
(PK/PD, etc.) 
- 
Inclusion Criteria: 
Patients between the age of 30 and 70 years with IGT. 


 
 
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Exclusion Criteria: 
Patients with type 1 or type 2 diabetes and patients on any anti-
hyperglycemic medications 
Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Changes in myocardial and hepatic fat, LV function and 
monocyte inflammation following saxagliptin versus placebo 
treatment for 6 months. 
Statistics: 
Between 
groups 
(i.e., 
saxagliptin 
therapy 
vs. 
placebo) 
comparisons will be made using two-way analysis of variance 
(ANOVA). Pre and post treatment within a group will be 
analyzed using paired t-tests. Simple correlation analysis will be 
performed with Pearson’s correlation coefficients to examine the 
relationship between hepatic fat and myocardial fat and LV 
function. Multivariate analysis will be performed where 
appropriate to examine the impact of simultaneous changes 
(glucose levels) in experimental parameters on hepatic fat.  All 
statistical analysis will be performed using SAS (Cary, NC).  
Sample size is calculated using SigmaPlot software (San Jose, 
CA). For the two major outcome variables i.e. myocardial fat and 
hepatic fat, the sample size of ~ 16 patients per treatment group 
(total of 32 patients) will have >90% power to detect a difference 
in the means of 20%, assuming a standard deviation of 15%, 
and with alpha= 0.025. Given that we expect about 10-15% of 
the patients enrolled may not complete the 6 month study, we 
would like to enroll 36 patients so that 32 patients may complete 
the study. 


 
 
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1 
INTRODUCTION 
Type 2 diabetes mellitus (T2DM) is a progressive disease and is associated with long-
term microvascular complications such as retinopathy, nephropathy, and neuropathy as 
well as cardiovascular morbidity and mortality. Intensive treatment to reduce plasma 
glucose to normal levels can minimize the risk of developing these complications (1). 
Currently available therapeutic agents are associated with side effects including 
hypoglycemia, weight gain, edema and changes in blood lipid profile. Agents with new 
mechanisms of action for the treatment of T2DM are being studied, and inhibition of 
dipeptidyl peptidase IV (DPP-IV) is emerging as a new therapeutic approach for 
treatment of type 2 diabetes. Bristol-Myers Squibb (BMS) and Astra-Zeneca (AZ) have 
jointly developed saxagliptin, a novel DPP-IV inhibitor, as a once daily oral therapy for 
the treatment of hyperglycemia in patients with T2DM. 
Saxagliptin (BMS-477118) is a synthetic, potent, reversible, orally active DPP-IV 
inhibitor. DPP-IV is an enzyme that selectively cleaves dipeptides from the N-terminus 
of oligopeptides with proline or alanine in the penultimate position. DPP-IV converts the 
key insulinotropic hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP) from active to inactive form, and is responsible for their 
short-half-lives in vivo. Inhibitors of DPP-IV increase levels of endogenous intact GLP-1 
and GIP in a glucose-dependent manner, thereby potentiating their physiological actions, 
augmenting postprandial insulin secretion, and improving the glycemic profile in patients 
with T2DM. Because of the glucose-dependent mechanism of action, DPP-IV inhibitors 
are expected to present low risk of hypoglycemia. 
Several lines of evidence indicate that preservation of active GLP-1 by treatment with a 
DPP-IV inhibitor will improve the insulin secretion pattern from pancreatic β-cells, 
enhance postprandial glucose control, and result in long-term improvements in both 
fasting and postprandial glycemia (2). Furthermore, experimental data suggest DPP-IV 
inhibitors may protect and/or promote pancreatic β-cell function and capacity as well as 
have pleiotropic effects on glucose homeostasis and/or pancreatic β-cell function (2). 
Possible mechanisms include inhibiting inactivation of GIP and effects on other relevant 
targets, such as decreasing the levels of the ‘counter-regulatory’ hormone glucagon.  
Saxagliptin has been tested in a large developmental program including six Phase 3 
studies and in over 4000 patients. Saxagliptin has shown statistically significant lowering 


 
 
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in all parameters of glucose control (glycated hemoglobin [A1C], fasting plasma glucose 
[FPG], and postprandial glucose [PPG]) either as monotherapy or in combination with 
metformin, glyburide or thiazolidinedione. Further studies are intended to evaluate the 
safety and efficacy of saxagliptin in comparison with commonly used strategies of 
treatment in clinical practice. 
1.1 
Summary of Results of Investigational Program 
1.1.1 
Clinical Toxicology 
In clinical pharmacology studies, 620 subjects have received at least 1 single oral dose 
(1-400 mg) of saxagliptin.  
Saxagliptin is rapidly and completely absorbed after oral administration, with maximum 
plasma concentration usually attained within 2 hours after dosing. It is primarily 
metabolized by hydroxylation to a pharmacologically active metabolite, BMS-510849, 
approximately 2-fold less potent than saxagliptin. BMS-510849 systemic exposure values 
are between 2 to 7 times higher than those of saxagliptin on a molar basis. The 
pharmacokinetics of saxagliptin and BMS-510849 appear linear and do not change with 
repeated daily dosing of saxagliptin doses up to 400 mg once daily for 2 weeks (i.e., 
80 times the expected usual clinical dose of 5 mg). Evidence from in vitro experiments 
suggest that cytochrome P450 3A4 and 3A5 (CYP3A4 and 3A5) are the major enzymes 
responsible for the metabolism of saxagliptin and conversion to BMS-510849. 
Saxagliptin and BMS-510849 do not appear to inhibit or induce the major CYP enzymes 
or P-glycoprotein. 
Approximately 24% and 36% of the dose was excreted into the urine as unchanged 
saxagliptin and BMS-510849, respectively. Renal excretion is a major elimination 
pathway for systemic saxagliptin and BMS-510849. In humans, following a single 50 mg 
dose of 14C-saxagliptin, 24%, 36%, and 75% (on average) of the dose was excreted in the 
urine as saxagliptin, BMS-510849, and total radioactivity respectively (CV181004) (3). 
These data suggest that saxagliptin was extensively absorbed from the gastrointestinal 
tract, and that BMS-510849 is a major metabolite of saxagliptin in humans. The average 
renal clearance of saxagliptin (~230 mL/min) was greater than the average estimated 
glomerular filtration rate (~120 mL/min), suggesting saxagliptin undergoes active renal 
excretion by as yet unidentified transporter(s). For BMS-510849, renal clearance values 
were comparable to estimated glomerular filtration rate. A total of 22% (on average) of 


 
 
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the administered radioactivity was recovered in feces representing the fraction of the 
saxagliptin dose excreted in bile and/or unabsorbed drug from the gastrointestinal tract. 
BMS-510849 was the predominant saxagliptin-related compound in human feces (8.4% 
of the dose), indicating that approximately one-fifth of the total amount of BMS-510849 
formed is excreted via the bile in healthy subjects. 
Saxagliptin may be administered without regard to meals. No dosage adjustment is 
considered necessary in elderly subjects on the basis of age. Body mass index (BMI), 
T2DM, gender, age, race, hepatic impairment, and mild renal insufficiency had no 
clinically meaningful effects on the pharmacokinetics of saxagliptin or BMS-510849. In 
subjects with moderate to severe renal impairment, and end stage renal disease (i.e., 
creatinine clearance <50 mL/min), area under curve (AUC) values for saxagliptin and/or 
BMS-510849 were generally greater than 2-fold higher than the AUC values in healthy 
subjects.  
Co-administration of saxagliptin with the following drugs had no meaningful effect on 
the pharmacokinetics of saxagliptin, BMS-510849, or the other drug tested: metformin, 
glyburide, pioglitazone, digoxin, or simvastatin. Co-administration of saxagliptin and 
ketoconazole or diltiazem dosed to steady-state resulted in up to 1.6- and 2.5-times 
increase in saxagliptin maximum observed concentration (Cmax) and area under curve 
extrapolated to infinity [AUC(INF)] values, respectively, and up to an 8-times decrease in 
the exposure to BMS-510849. However, the systemic exposures to the total active 
moieties of saxagliptin (saxagliptin + BMS-510849 corrected for relative differences in 
potency of DPP-IV inhibition) were not meaningfully altered by diltiazem or 
ketoconazole. Co-administration of saxagliptin with gastric acid controllers: aluminum 
and magnesium hydroxides + simethicone, famotidine or omeprazole did not 
meaningfully alter the pharmacokinetics of saxagliptin or BMS-510849. 
More detailed information on clinical pharmacokinetics of saxagliptin may be found in 
the Investigator Brochure (Sections 5.1 and 5.2) (3). 
1.1.2 
Summary of Efficacy Results in Subjects with Type 2 Diabetes 
Mellitus 
Saxagliptin Phase 2b and Phase 3 worldwide clinical development program in T2DM 
included eight studies in which over 4600 subjects combined with the results from 
clinical pharmacology studies support the oral dose of saxagliptin 5 mg once daily as the 


 
 
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usual clinical dose in a wide range of subjects with T2DM, as either monotherapy, add-on 
combination therapy with metformin, a thiazolidinedione (TZD), or a sulfonylurea (SU), 
or initial combination therapy with metformin. 
In the Phase 2b dose-ranging study, administration of saxagliptin 5 mg was associated 
with significant inhibition of plasma DPP-IV activity at the trough of the dosing interval 
as well as clinically meaningful decreases in A1C, fasting plasma glucose (FPG), and 
postprandial serum glucose. The results from the short-term periods of the Phase 3 
studies confirmed clinically meaningful benefits of saxagliptin 5 mg on A1C, as well as 
FPG, postprandial glucose, insulin, C-peptide, and glucagon levels. In the monotherapy 
studies (CV181011 and CV181038), add-on combination therapy studies (CV181014, 
CV181013, CV181040 with metformin, TZD, glyburide, respectively), and initial 
combination study with metformin (CV181039), treatment with saxagliptin produced 
statistically significant reductions in A1C relative to control. A greater percentage of 
subjects treated with saxagliptin achieved target glycemic goals including A1C levels 
< 7% compared with subjects treated with placebo or active comparator. The saxagliptin 
5 mg groups achieved greater reductions from baseline in A1C than the saxagliptin 
2.5 mg groups in five of the six core Phase 3 studies (one of the core studies, 
Study CV181039, did not have a 2.5 mg treatment group). There was no consistent 
evidence for an incremental efficacy benefit for 10 mg beyond that seen for the 5 mg 
dose.  
Saxagliptin treatment consistently demonstrated a beneficial antihyperglycemic effect 
across subgroups of demographic and baseline diabetes characteristics. 
1.1.3 
Summary of Safety Results in Subjects with Type 2 Diabetes 
Mellitus 
Once-daily, orally administered saxagliptin was safe and well-tolerated at doses of up to 
400 mg QD for 2 weeks, 100 mg QD for 6 weeks, 40 mg QD for 12 weeks, and at doses 
of 2.5, 5, and 10 mg QD for up to 102 weeks. In an extensive Phase 2b/3 program, the 
majority of reported adverse events (AEs) was of mild intensity and did not require 
treatment discontinuation. The safety profile was generally consistent with placebo or 
comparator when saxagliptin was given as monotherapy, as add-on combination 
treatment to metformin, SU, or TZD, and as initial therapy in combination with 
metformin. Although the rate of certain AEs was higher in subjects who received 


 
 
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saxagliptin 10 mg compared with those who received 2.5 and 5 mg, saxagliptin 10 mg 
was also safe and well tolerated, providing a safety margin for the saxagliptin 5 mg dose. 
The placebo-controlled pooled safety analysis, which included the two monotherapy 
studies (CV181011 and CV181038), and the add on combination studies (CV181014, 
CV181013, CV181040 with metformin, TZD, glyburide, respectively), demonstrated that 
the overall incidence of AEs in subjects treated with saxagliptin 5 mg was similar to 
placebo (72.2% vs. 70.6%). The majority of reported AEs was of mild intensity and did 
not require treatment discontinuation. There was no discernible difference in the clinical 
AE profile between the saxagliptin 2.5 mg and 5 mg doses. The most frequently reported 
AEs (incidence ≥ 5%) in active vs. placebo group were upper respiratory tract infection 
(7.7% vs. 7.6%), headache (7.0% vs. 5.9%), nasopharyngitis (6.0% vs. 6.8%), urinary 
tract infection (5.8% vs. 6.1%), diarrhea (5.2% vs. 6.1%), and back pain (3.9% vs. 5.1%). 
In the combination study with metformin (CV181-039) headache (7.9% in saxagliptin, 
5.2% in metformin) and diarrhea (6.4% in saxagliptin, 7.3% in metformin) were the most 
frequently reported AEs (incidence ≥ 5%). 
In the placebo-controlled pooled safety analysis the frequency of serious adverse events 
(SAEs) was identical (3.4%) for the saxagliptin 5 mg and placebo groups. The 
frequencies of SAEs were comparable for the saxagliptin 5 mg plus metformin and 
metformin monotherapy groups (2.5% and 2.4%, respectively) in the combination with 
metformin study (CV181039). 
The frequency of AEs leading to discontinuation from study therapy was generally low 
for all treatment groups. In the placebo-controlled pooled safety analysis, the overall 
frequency of AEs leading to discontinuation of study medication was comparable 
between the saxagliptin 2.5 mg and placebo groups (2.2% and 1.2%, respectively), but 
was greater for subjects in the saxagliptin 5 and 10 mg groups (3.3% and 3.9%, 
respectively). The most frequently reported AEs (> 1 subject) leading to study 
discontinuation, which were numerically higher in subjects who received saxagliptin 
compared with placebo were: lymphopenia, increased blood creatine kinase (CK), 
increased blood creatinine, nausea, and eye pain. Rates of discontinuation for rash were 
similar in subjects who received saxagliptin and placebo, whereas the rate of 
discontinuation for AEs of increased weight, depression, and angina pectoris were higher 
in subjects who received placebo compared with saxagliptin. 


 
 
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Overall, death was an infrequent event and occurred with comparable frequencies in the 
saxagliptin and comparator groups. In the Phase 2/3 studies, a total of 16 subjects died 
during the short-term and long-term periods (as of January, 2008): 2 (0.2%) subjects each  
in the saxagliptin 2.5 and 5 mg groups, 3 (0.3%) subjects in the saxagliptin 10 mg group, 
5 (0.5%) subjects in the placebo group, and 4 (1.2%) subjects in the metformin 
monotherapy group. 
1.1.3.1 Adverse Events of Special Interest 
Hypoglycemia: Treatment with saxagliptin led to rates of hypoglycemia that were 
generally similar compared with placebo. This is consistent with the mechanism of action 
of DPP-IV inhibitors, which exert their insulinotropic effects on the β-cell in a 
glucose-dependent manner. In the add-on to sulphonylurea (SU) study, the rate of 
hypoglycemia was numerically higher in subjects who received 2.5 or 5 mg of saxagliptin 
added on to an intermediate dose of glyburide compared with up-titration of glyburide 
monotherapy plus placebo. 
Skin-related AEs: The frequency of skin-related AEs was generally comparable between 
subjects who received saxagliptin 5 mg and placebo. Overall, evaluation of the Phase 3 
clinical data has not revealed any signals that correlate to the skin findings during 
non-clinical toxicology studies in the monkey, including reversible erosive and/or 
ulcerative skin lesions with scab formation. 
Local edema: The proportion of subjects with AEs of localized edema, an event of 
special interest given reports of symptomatic edema of the hands and feet in subjects who 
received another member of the DPP-IV-inhibitor class, was generally similar in subjects 
who received saxagliptin and placebo with the exception of the add-on to TZD study, 
where there was a higher rate of events constituting localized edema compared to placebo 
in subjects treated with saxagliptin 5 mg. The majority of these events in the saxagliptin 
5 mg plus TZD group were for pedal edema with no imbalance seen for events of hand 
edema. Across the clinical program, the majority of events of localized edema was of 
mild-to-moderate intensity and did not lead to study discontinuation. 
Lymphopenia: The frequency of investigator reported AEs of lymphopenia was similar 
for subjects who received saxagliptin and placebo. Mean lymphocyte counts remained 
stable and within normal limits with daily dosing up to 102 weeks. Overall, a small 
decrease in mean absolute lymphocyte count was observed at a dose of saxagliptin 5 mg 


 
 
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and above. At the 5 mg dose, the mean decrease was approximately 100 cells/μL relative 
to placebo (from baseline absolute lymphocyte count of approximately 2200 cell/μL) 
based on a pooled analysis of the 5 placebo-controlled clinical studies including 
saxagliptin as monotherapy, and as add-on therapy to metformin, TZD and SU. While the 
clinical significance of the decreases in lymphocyte count relative to placebo is not 
known, the decreases were not associated with clinically relevant AEs. 
Platelet counts: Results from the Phase 3 clinical studies demonstrated no clinically 
meaningful or consistent effect on platelet counts.  
In the five-pooled monotherapy and placebo-controlled combination studies, the 
frequencies of AEs in the system organ class (SOC) Infection and Infestations were 
comparable in the saxagliptin 2.5 mg, saxagliptin 5 mg, and placebo groups (36.4%, 
35.9%, and 34.8% respectively); a higher frequency of AEs was observed in the 
saxagliptin 10 mg group (40.1%). There was no evidence for an association of saxagliptin 
treatment with an increased risk of elevated liver function tests or serum creatinine. 
Effect on QTc interval: In the clinical pharmacology program, results from a thorough 
QTc study at daily doses of saxagliptin up to 40 mg QD and analyses from other studies 
at daily doses up to 400 mg QD demonstrated an absence of an effect of saxagliptin and 
BMS-510849 on QTc interval in humans.  
1.2 
Overall Risk/Benefit Assessment 
The efficacy of saxagliptin for the treatment of subjects with T2DM was demonstrated in 
a single Phase 2b study and confirmed in 6 double-blind, placebo- or active- controlled 
clinical studies. In these studies, 4673 subjects (4607 subjects randomized and treated and 
66 subjects treated in the open-label (OL) cohort of CV181011) received at least one dose 
of study medication, including 3422 receiving saxagliptin and 1251 receiving either 
placebo or metformin plus rescue medication if necessary. Treatment with saxagliptin 
2.5, 5, and 10 mg was demonstrated to be generally safe and well tolerated. The overall 
frequencies of AEs for saxagliptin 2.5 and 5 mg were comparable to placebo. Also, the 
initial combination study with metformin showed that the safety profile of saxagliptin 
5 mg plus metformin was generally comparable to either agent used as monotherapy.  
Evaluation of the clinical efficacy and clinical safety data, discussed in Sections 1.1.2 and 
1.1.3, indicate an acceptable risk/benefit profile at the dose of saxagliptin 5 mg daily, as a 
monotherapy, and also in combination with metformin XR 1500 mg. Type 2 diabetes 


 
 
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mellitus is a progressive disease, and a combination of 2 agents with complimentary 
mechanisms of action, such as metformin and saxagliptin, may offer considerable 
therapeutic advantage. 
1.3 
Research Hypothesis 
We hypothesize that  saxagliptin therapy (compared to placebo) would be 
associated with a reduction in myocardial and hepatic fat content, an 
improvement in left ventricular function, and a reduction in monocyte 
inflammation in patients with impaired glucose tolerance. 
 
1.4 
Study Rationale 
Obese, insulin resistant individuals have an excess of fat in the liver which is not 
attributable to alcohol or other known causes of liver disease, a condition defined as 
nonalcoholic fatty liver disease (NAFLD) (4). The fatty liver is insulin resistant. 
Individuals with a fatty liver are more likely to have excess intra-abdominal fat as well as 
a reduction in circulating plasma adiponectin levels (4-9). We have previously shown that 
type 2 diabetes and its associated NAFLD is characterized by increased hepatic fat 
content, and hepatic and peripheral (muscle)  insulin resistance (6,8). Treatment with 
PPAR-gamma agonists (thiazolidinediones) reduces hepatic fat content, improves hepatic 
insulin sensitivity, and is associated with a three-fold increase in plasma adiponectin in 
patients with type 2 diabetes (6,8).   DPP4-deficient rats (10), characterized by high 
levels of active GLP-1 due to an inactive DPP4 enzyme, display reduced hepatic 
triglycerides, accompanied by down-regulation of lipogenesis enzymes and parallel up-
regulation of carnitine palmitoyltransferase-1, a key enzyme in fatty acid beta-oxidation. 


 
 
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Mechanistically, GLP-1 increased AMP-Activated-Protein-Kinase (AMPK) activity in 
hepatocytes, resulting in reduced hepatic lipogenesis. Furthermore, DPP4- rats expressed 
lower levels of hepatic proinflammatory and profibrotic cytokines in response to nutrient 
stimuli (10).These results are similar to our own studies in DIO mice treated with 
exendin-4. We demonstrated that a single injection of an adenovirus exendin-4 
expression vector to diet-induced obese mice reduced hepatic fat and enzymes involved 
in hepatic fatty acid synthesis independent of changes in insulin and glucagon (11). 
 Recent reports suggest that NAFLD is associated with an increased risk of 
cardiovascular disease independent of associated cardiovascular risk factors (12,13). 
Furthermore type 2 diabetics and subjects with impaired glucose tolerance are 
characterized by an increase in both hepatic and myocardial fat and left ventricular (LV) 
dysfunction, particularly diastolic dysfunction (14-17). Myocardial steatosis is an 
independent predictor of diastolic dysfunction in type 2 diabetes mellitus as well as 
impaired glucose tolerance (15, 17, 18). Pioglitazone therapy reduces myocardial fat and 
improves LV function (16); however, it is associated with fluid retention and an increased 
risk of pulmonary edema in those with pre-existing LV failure. However, the effect of 
saxagliptin therapy on liver and myocardial fat content, as well as LV systolic and 
diastolic function in patients with IGT or type 2 diabetes has not been previously studied. 
The pathophysiology of diabetic cardiomyopathy is complex, and the exact mechanisms 
of disease remain partly unknown. Increasing evidence is emerging that lipid oversupply 
to cardiomyocytes, which may lead to lipotoxic injury, plays a role in the development of 


 
 
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diabetic cardiomyopathy (14). Increased fatty acid (FA) fluxes arising from the 
disproportionate amount of insulin resistant (visceral) adipose tissue lead to excessive FA 
delivery and uptake in the heart. This FA uptake exceeds the oxidizing requirements of 
the organ, giving rise to fatty acyl-CoA esters, diacylglycerol, and ceramide as 
intermediates. Increasing evidence exists that accumulation of these FA intermediates 
causes mitochondrial dysfunction and reactive oxygen species, giving rise either directly 
to cell damage and apoptosis or indirectly through the induction of inflammatory 
cascades, which leads to myocardial dysfunction. In animal models, antisteatotic 
treatment with thiazolidinediones reduced myocardial triglyceride accumulation and 
ceramide content, and prevented myocardial dysfunction. Recently, it has been 
demonstrated that myocardial triglyceride content is increased in uncomplicated T2DM 
and is associated with impaired left ventricular diastolic function, independently of age, 
BMI, heart rate, visceral fat, and diastolic blood pressure (15).  More recently, Iozzo et al 
(17) have shown that obese normal glucose tolerant subjects, obese subjects with IGT, 
and type 2 diabetic subjects have increased myocardial fat compared to lean subjects 
(Figure 1). In multiple regression analysis, myocardial fat was independently related with 
cardiac output and work in these subjects (17). Furthermore, Bajraktari et al (18) have 
shown that both type 2 diabetics and subjects with IGT have left ventricular diastolic 
dysfunction and that insulin resistance is an independent correlate of diastolic 
dysfunction. Thus, both IGT and type 2 diabetic subjects have increased myocardial 
steatosis and defects in LV function. 


 
 
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Figure 1.  
GLP-1 has been shown to improve myocardial function and cardiac output in conscious 
chronically instrumented canine models of cardiac injury or heart failure. GLP-1 
increased cardiac output and reduced left ventricular end diastolic pressure in association 
with reduced systemic vascular resistance, and it improved myocardial insulin sensitivity 
and myocardial glucose uptake in dogs with rapid pacing-induced dilated 
cardiomyopathy (19). A clinical study showed that GLP-1 improves left ventricular 
ejection fraction and functional status in patients with congestive heart failure, without 
affecting heart rate or blood pressure, suggesting a mechanism other than direct inotropic 
or chronotropic effects (20). Early studies demonstrated the presence of transcripts for 
GLP-1Rs in the heart (21), but only recently has the cellular distribution of the receptors 
been localized. Ban et al. (22) identified GLP-1Rs via immunohistochemistry in 
cardiomyocytes and coronary and vascular endothelial cells as well as smooth muscle in 
mice. Recent studies in rodents suggest that some of the cardiovascular effects of native 


 
 
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GLP-1 may be mediated by a mechanism independent of the known GLP-1R (22). 
However, no previous study has examined the effect of saxagliptin on myocardial fat or 
LV function in IGT or type 2 diabetic patients. 
Finally, the effect of saxagliptin on vascular inflammation and monocyte NFkappaB 
activity remains to be studied. We have previously shown in vitro (23) that exenatide 
inhibits FFA-induced inflammation and NFkappaB activity in cultured skeletal muscle 
cells (L6 Myotubes). However, no previous study has examined the effect of GLP-
1/saxagliptin on monocyte inflammation in patients with type 2 diabetes or impaired 
glucose tolerance.  
Patients with Impaired Glucose Tolerance (IGT)/ Impaired Fasting Glucose (IFG) have 
insulin resistance as a well established defect. Hepatic insulin resistance is well 
established as the product of basal hepatic glucose production and fasting plasma insulin 
levels (basal hepatic insulin sensitivity index) is increased significantly compared with 
non-diabetic control subjects even though the fasting (and following a 75 gram OGTT) 
hyperglycemia is mild. Furthermore, as stated previously, both myocardial and hepatic 
steatosis as well as defects in LV function are well characterized in obese, insulin 
resistant patients with IGT. However, the effect of DPP-IV inhibitors on hepatic and 
myocardial steatosis and monocyte inflammation in insulin resistant patients with IGT 
have not been previously studied.   
 


 
 
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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to examine the effects of saxagliptin on myocardial and 
hepatic fat content in patients with impaired glucose tolerance (IGT). 
2.2 
Secondary Objectives 
  The secondary objective is to examine the effect of saxagliptin on left ventricular 
systolic and diastolic function and monocyte inflammation in patients with IGT 
 
3 
ETHICAL CONSIDERATIONS 
3.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, 
the safety or physical or mental integrity of the subjects of the study or the scientific 
value of the study. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks. This study will not use the 
services of study personnel where sanctions have been invoked or where there has been 
scientific misconduct or fraud (eg, loss of medical licensure; debarment).  


 
 
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3.2 
Institutional Review Board/Independent Ethics 
Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment 
materials/process (eg, advertisements), and any other written information to be provided 
to subjects. The investigator should also provide the IRB/IEC with a copy of the 
Investigator Brochure or product labeling, information to be provided to subjects, and any 
updates. The investigator should provide the IRB/IEC with reports, updates, and other 
information (eg, expedited safety reports, amendments, and administrative letters) 
according to regulatory requirements or institution procedures. 
3.3 
Informed Consent 
Investigators must ensure that subjects (or, in those situations where consent cannot be 
given by subjects, the legally acceptable representative) are clearly and fully informed 
about the purpose, potential risks, and other critical issues regarding clinical studies in 
which they volunteer to participate. Freely given written informed consent must be 
obtained from every subject (or, in those situations where consent cannot be given by 
subjects, the legally acceptable representative) before clinical study participation, 
including informed consent for any screening procedures conducted to establish subject 
eligibility for the study. 
Investigators must: 
1) Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. 
The language must be non-technical and easily understood.  
2) Allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study. 
3) Obtain an informed consent signed and personally dated by the subject or the 
subject's legally acceptable representative and by the person who conducted the 
informed consent discussion.  
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information. 
5) If informed consent is initially given by a subject’s legally acceptable representative 
or legal guardian, and the subject subsequently becomes capable of making and 


 
 
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communicating their informed consent during the study, then consent must 
additionally be obtained from the subject. 
6) Revise the informed consent whenever important new information becomes available 
that is relevant to the subject's consent. The investigator, or a person designated by 
the investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented.  
The consent form must also include a statement that BMS and regulatory authorities have 
direct access to subject records. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
Subjects: 
40 obese subjects with impaired glucose tolerance (IGT) or prediabetes, 
(fasting plasma glucose between 100-125 mg/dl, or 2 hour post 75 gram 
OGTT plasma glucose between 140-199 mg/dl, or HbA1c 5.7-6.4% ) who 
are free of other major organ system disease will be studied. Subjects 
will range in age from 30   to 70 years and in body mass index from 30-
35 kg/m2.  Subjects who have previously received or are taking 
metformin, 
DPP-IV 
inhibitors, 
exenatide, 
liraglutide, 
or 
a 
thiazolidinedione for treatment of IGT will be excluded. Patients on 
statins and other lipid lowering therapy will be included provided they 
are on a stable dose of lipid lowering therapy for at least 3 months prior 
to enrollment. The dose of the lipid lowering therapy will not be changed 
for the entire duration of the study. The fasting plasma glucose must be  
≤125 mg/dl, 2 hour post 75 gram OGTT plasma glucose must be less 


 
 
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than 200 mg/dl, and HbA1C must be < 6.5% to be included in the study. 
Subjects with clinically significant cardiac, hepatic, or renal disease will 
not be studied. Subjects will be recruited from the Endocrine/Diabetes/ 
Obesity Clinic at the Baylor Clinic. All subjects will be recruited by 
direct contact from Dr. Mandeep Bajaj or one of the co-investigators. 
Study Design:  All subjects will participate in an initial screening visit 
(medical history and physical exam, urinanalysis, EKG, CBC, liver 
function tests (LFTs), serum creatinine, lipid profile, HbA1c; and a 
fasting and 2 hour plasma glucose (during a 75 gram OGTT).  During 
the 2 hour OGTT (75 grams), glucose, insulin, c-peptide, and FFA 
determinations will be made at baseline (fasting) and every 15-30 
minutes and insulin sensitivity will be calculated by the Matsuda Index. 
In addition, plasma triglycerides will be measured at baseline and at 120 
minutes during the OGTT. 
Following determination of eligibility, 40  IGT or prediabetes subjects 
will be randomized (double blind) to participate in one of the following 
two treatment arms (i) saxagliptin 5 mg daily PO for 26 weeks or (ii) 
Placebo PO daily for 26 weeks (control arm). Two weeks prior to 
randomization, subjects will meet with a dietitian and will be instructed 
to consume a weight-maintaining diet containing 50% carbohydrate, 
30% fat, and 20% protein. During the week prior to start of the study all 
subjects will receive: (i) baseline measurements of FPG, plasma 
adiponectin (HMW and total adiponectin), CRP, IL-1, IL6, TNF-alpha, 
MMP-9, ICAM, VCAM, Fibroblast Growth Factor 21 (FGF21), fasting 


 
 
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plasma lipids, postprandial plasma triglyceride level (at 2 hours 
following a mixed meal), and HbA1c; (ii) monocyte isolation from 
peripheral (venous) whole blood  and quantification of monocyte TLR2, 
TLR4, SOCS-3, MYD88, NFkappaB (P65) and IkB-alpha, and IkB-beta 
protein as well as expression levels of CD36, MCP-1, MMP-9,VCAM1, 
ICAM1 and JNK. We will also measure of plasma lipopolysaccharide 
(LPS) and LPS- binding protein (LPS-BP) concentrations. Plasma 
samples used for LPS determination will be stored in LPS-free glass 
tubes to prevent loss of endotoxin to plastic tube walls. All materials for 
the assay will be rendered LPS-free; and (iii) liver and myocardial fat 
content with magnetic resonance (MR) spectroscopy and determination 
of left ventricular systolic and diastolic function by MR imaging as 
detailed below.  
During the entire 6 month treatment period, subjects will return to the 
Clinical Research Center every 4 weeks at 0800 h following an overnight 
fast for measurement of FPG, body weight, and blood pressure. A urine 
pregnancy test will also be performed at each visit. On each visit, dietary 
adherence will be reinforced by the dietician. Fasting plasma lipids and 
postprandial triglyceride levels, HbA1c, and LFTs will be measured at 3 
months and at the end of the 6 month study period. At the end of the 
treatment period of six months all subjects will also undergo a repeat 75 
gram OGTT (for measurements of baseline FPG, and plasma glucose, 
FFA, c-peptide and insulin during OGTT as well as 2 hour plasma 
triglyceride measurements as described previously), plasma adiponectin, 


 
 
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CRP, IL-1, IL6, TNF-alpha, MMP-9, ICAM, VCAM, Fibroblast Growth 
Factor 21 (FGF21), FFA, insulin, LPS and LPS-BP.   Liver and 
Myocardial fat and LV function as well as monocyte studies for 
inflammatory pathways as detailed previously will be repeated after 26 
weeks of therapy. 
Measurement of Liver Fat Content (MR Spectroscopy) 
Localized 1H nuclear magnetic resonance spectra of the liver will be 
obtained on a 3.0 Tesla magnetic resonance imaging scanner  
(Department of Radiology, St Lukes Episcopal Hospital and Texas Heart 
Institute, Houston) using a standard body coil in transmitter and 
receiver mode. An initial T1-weighted spin-echo anatomical magnetic 
resonance scan for liver MRS localization will be performed with the 
following parameters: repetition time/echo time• = 130 msec/15 
msec•160 degrees; slice thickness = 7 mm; field of view = 44 cm x 45 cm; 
number of excitations = 1; and an image matrix = 100 x 256. The slice 
with the largest gross dimensions of the liver will be chosen for the MRS 
study. MRS for water and fat quantification will be accomplished by 
using a point resolved spectroscopy sequence as described previously (3). 
The imaging parameters for point resolved spectroscopy sequence are as 
follows: repetition time/echo time• = 1500 msec/54 msec•90 degree; 
number of averages = 2; and data points = 512. A 3 cm x 3 cm x 3 cm 
volume (voxel) will be selected in the left, right anterior, and right 
posterior hepatic lobes for scanning to provide a more generalized 
distribution of fat within the liver. During the measurements, the 


 
 
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subject will be supine within the bore of the magnet. The total scan time 
is approximately 60 min. During the MRS examinations, identical areas 
of the liver are scanned in the pre- and post-treatment MRS studies of 
the same subject by the use of anatomical landmarks visualizing images.  
   After line broadening, phase and baseline correction, the peak area of 
the water at 4.77 ppm, and fat resonance (Sf) at 1.4 ppm will be 
measured. Quantification of the fat content will be done by comparing 
the area of the Sf with that of the unsuppressed water. Spectroscopic 
data will be processed using the operating system software. Hepatic fat 
percentage will be calculated by dividing (100 x Sf) by the sum of Sf and 
peak area of the water. This technique is highly reproducible, with a 
coefficient of variation less than 2% when the same subjects were 
studied on eight separate days.    
Measurement of Cardiac Myocardial Triglyceride Content with 
Dual Gating 
The MR studies will be performed on a commercial MR scanner (3.0 
tesla) equipped with 1H MR Spectroscopic capabilities.  The 
participating subjects will undergo MR scanning in the morning after 
fasting overnight.  A 5-10 ml size voxel will be carefully positioned over 
the interventricular septum based on the four-chamber and the short-
axis images acquired at end-systole.  Based on a high-temporal 
resolution cine image acquired previously, the MR spectroscopy will be 
timed to occur during systole, and MR spectra will be acquired using the 
following acquisition parameters: sequence type: Point resolved 


 
 
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spectroscopy sequence (PRESS);  TE: 25 ms; TR > 3000 msec; 1024 
acquisition points acquired using 1 kHz spectral bandwidth, and 128 
NSA.  The long TR ensures a more complete recovery of the myocardial 
triglyceride signals.  The cardiac MR spectroscopy sequence is both 
cardiac gated (vectorcardiography (VCG) gating), as well as respiratory 
gated to combat the adverse effects of both cardiac pulsation as well as 
bulk motion of the heart caused by respiratory motion. Gating 
(respiratory and cardiac gating) improves the reproducibility of cardiac 
MR spectra. During the MRI/MRS, we will also measure LV systolic and 
diastolic function. 
MRI Measurement of Left Ventricular Function 
Systolic LV Function:  A series of scout images of the thoracic cavity 
along multiple axes will be obtained.  Following these scout scans, a 
series of cardiac cine Steady State Free Precession (SSFP) images will be 
obtained along the conventional two-chamber and four-chamber 
orientations with the following acquisition parameters: TR/TE/flip: 3-3.2 
ms/1.5-1.6 ms/; slice thickness: 8 mm; temporal resolution: 40-50 ms; 
acquired in-plane spatial resolution: 2 x 2 mm; breath-hold duration: 6-8 
heart-beats per slice.  Based on these two long-axis orientation slices, a 
series of contiguous short-axis slices were acquired to cover from the left-
ventricular apex to the base at 8 mm intervals in a series of breath-holds.  
The endocardial contours will be manually traced by an experienced 
observer at end-diastole and end-systole to delineate the LV volume in 
diastole (EDV) and systole (ESV).  From the knowledge of EDV, and 


 
 
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ESV, LV ejection fraction (LVEF) will be calculated as the normalized 
difference between EDV and ESV, or (EDV-ESV)/EDV. 
Diastolic LV function: MRI flow measurements: Diastolic LV function 
will be obtained by measuring the blood-flow across the mitral-valve 
using a cardiac-gated phase-contrast MR sequence.  A 5 mm slice 
oriented orthogonal to the mitral valve plane (positioned with the help of 
the four-chamber and the  left-ventricular outflow tract (LVOT) views) 
will be acquired with the following parameters:  TR/TE: 4.6 ms/15 ms; 
flip angle; in-plane acquired voxel size: 1.6 x 1.8 mm; reconstructed voxel 
size: 1.2 x 1.2 mm; velocity encoding value (Venc value): 100-125 cm/s; 
number of acquisitions: 2.   The acquisition will be retrospectively 
cardiac gated to ensure that the entire diastolic period is captured.   
MRI flow analysis: The flow data will be analyzed using a commercial 
post-processing workstation.  The characteristic diastolic flow data will 
be quantified by calculating the peak filling rates during the early filling 
phase (E), and the active filling phase (A). 
High temporal resolution cine MR imaging:  
Using a combination of a state-of-the-art RF hardware (32 channel RF 
system), and fast imaging techniques (Sensitivity Encoding or SENSE), 
a high temporal resolution cine MR images (~ 6 ms/cardiac phase) of the 
LV will be acquired in a series of breath-holds. A total of three short-axis 
slices will be acquired with a temporal resolution of 5-6.5 ms using the 
following acquisition parameters: TR/TE/flip: 2.7-3.1 ms/1.5-1.6 ms; 
acquired voxel size: 2.5 x 2.5 x 8 mm; reconstructed voxel size: 1.76 x 


 
 
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1.76 x 8 mm; half-scan factor: 0.625; number of phase encoding steps 
acquired per heart-beat (turbo-field echo factor): 2; acquired temporal 
resolution: 5.5 – 6.2 ms/cardiac phase; SENSE factor: 3; total scan time: 
18-20 hb/slice. From the high-temporal resolution cine images, the LV 
cavity will be segmented using a segmentation algorithm.   Metrics 
quantifying diastolic function such as IVRT will be calculated using 
custom-built software. A series of blood-pressure measurements will be 
obtained throughout imaging at 5 minute intervals. 
 
4.2 
Study Population 
For entry into the study, the following criteria MUST be met.  
4.2.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Before any study procedures are performed, subjects will have the details of the 
study described to them, and they will be given a written informed consent 
document to read. Then, if subjects consent to participate in the study, they will 
indicate that consent by signing and dating the informed consent document in the 
presence of study personnel. 
2) Target Population 
a) Subjects with a diagnosis of Impaired Glucose Tolerance or Prediabetes i.e. 
fasting plasma glucose between 100-125 mg/dl, or 2 hour post 75 gram OGTT 
plasma glucose between 140-199 mg/dl, or HbA1c 5.7-6.4% as per revised ADA 
criteria (24) 
b) Age and Reproductive Status 
c) Men and women, ages 30 to 70 years.  
i) Women of childbearing potential (WOCBP) must be using an acceptable 
method of contraception to avoid pregnancy throughout the study in such a 
manner that the risk of pregnancy is minimized. 
ii) Women must have a negative serum or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the 
start of investigational product.  


 
 
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iii) Women must not be breastfeeding. 
 
Women of childbearing potential include any female who has experienced 
menarche and who has not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not 
postmenopausal. Post menopause is defined as:  
• Amenorrhea ≥ 12 consecutive months without another cause and a 
documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL, or 
• Women with irregular menstrual periods and a documented serum follicle 
stimulating hormone (FSH) level > 35 mIU/mL, or 
NOTE: FSH level testing is not required for women ≥ 62 years old with 
amenorrhea of ≥ 1 year. 
• Women on hormone replacement therapy (HRT). 
Women who are using oral contraceptives, other hormonal contraceptives 
(vaginal products, skin patches, or implanted or injectable products), or 
mechanical products such as an intrauterine device or barrier methods 
(diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing 
abstinence or where their partner is sterile (eg, vasectomy) should be considered 
to be of childbearing potential. 
 
d) Patients must have been on a stable dose of allowed chronic medications such as 
statins and other lipid lowering therapy for 90 days prior to entering the study.   
e) Patients must have a BMI between 30-35 kg/m2.  Only subjects whose body 
weight has been stable (±3-4 pounds) over the three months prior to study will be 
included.  
f) Patients must have the following laboratory values: 
               Hematocrit             ≥ 34 vol% 
               S. creatinine               < 1.5 mg/dl in men and 1.4 mg/dl in women 
         AST (SGOT) 
  < 2.5 times upper limit of normal 
               ALT (SGPT) 
  < 2.5 times upper limit of normal 
               Alkaline phosphatase < 2.5 times upper limit of normal 
                
 
 
4.2.2 
Exclusion Criteria 
1) Sex and Reproductive Status 


 
 
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a) WOCBP who are unwilling or unable to use an acceptable method to avoid 
pregnancy for the entire study period. 
b) Women who are pregnant or breastfeeding. 
2) Medical History and Concurrent Diseases 
a) Type 1 or Type 2  diabetes mellitus (FPG > 125 mg/dl) 
b) History of diabetic ketoacidosis or hyperosmolar nonketotic coma 
3) Physical and Laboratory Test Findings 
a) Patients with diabetic gastroparesis will be excluded. 
b) Patients with a history of clinically significant heart disease (New York Heart 
Classification greater than class 2; more than non-specific ST-T wave changes on 
the EKG), peripheral vascular disease (history of claudication), or pulmonary 
disease (dyspnea on exertion of one flight or less; abnormal breath sounds on 
auscultation) will not be studied.  
4) Allergies and Adverse Drug Reactions 
a) Subjects with a history of any serious hypersensitivity reaction to saxagliptin or 
DPP-IV inhibitor. 
5) Prohibited Treatments and/or Therapies 
a) Treatment with strong systemic cytochrome P450 3A4/5 (CYP 3A4/5) inhibitors. 
b) Patients must not be on or have received any antihyperglycemic treatment for 
treatment of IGT at any time. Patients must not be receiving any of the following 
medications: thiazide or furosemide diuretics, beta-blockers, or other chronic 
medications such as hormone replacement therapy with known adverse effects on 
glucose tolerance levels. Patients must not be on systemic glucocorticoids. 
6) Other Exclusion Criteria 
a) Prisoners, or subjects who are involuntarily incarcerated. 
b) Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria. 


 
 
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4.2.3 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and noninvestigational product at 
the discretion of the investigator) for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness 
which, in the opinion of the investigator, indicates that continued participation in 
the study is not in the best interest of the subject. 
• Pregnancy 
− Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (eg, missed or late menstrual period) at any 
time during study participation. Institutional policy and local regulations 
should determine the frequency of on-study pregnancy tests for WOCBP 
enrolled in the study. 
− The investigator must immediately notify BMS if a study subject becomes 
pregnant. The mechanism for reporting pregnancy is described in Section 7.5. 
• Termination of the study by BMS. 
• Loss of ability to freely provide consent through imprisonment or involuntarily 
incarceration for treatment of either a psychiatric or physical (eg, infectious 
disease) illness 
• Inability to comply with the protocol. 
All subjects who discontinue should comply with protocol specified follow-up 
procedures as outlined in Section 6. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent freely 
(ie, is imprisoned or involuntarily incarcerated for the treatment of either a psychiatric or 
physical illness). If a subject was withdrawn before completing the study, the reason for 
withdrawal must be entered on the appropriate case report form (CRF) page. 
4.3 
Data Safety Monitoring Plan 
Protocol and consent form approval has been obtained from the Baylor 
College of Medicine IRB. Request for IND shall submitted to the FDA. Prior 
to screening evaluations, each subject eligible for the study will be given an 
orientation session in which the nature and purpose of the study and the 
risks and benefits will be described.  If an eligible subject agrees to 
participate in the study, he/she will be required to sign an informed consent 
form.  


 
 
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The PI and his team will monitor the study on a daily basis. All treatment 
emergent AEs will be recorded on source documents (i.e. original documents, 
data, and records).  AEs include those reported spontaneously by the subject 
and those noted incidentally or as observed by the investigator or study 
personnel.  All clinically significant abnormalities noted upon physical 
examination, or other diagnostic test results should be reported as an AE, 
except for baseline measurements that may be considered part of the medical 
history.  In addition, all clinically significant AEs that continue at Study 
Termination will be followed up by the investigator and evaluated with 
additional tests if necessary, until the underlying cause is diagnosed or 
resolution occurs.  All AEs will be evaluated for intensity and causal 
relationship with use of the study medication and/or study procedures by the 
investigator and reported to the Baylor IRB. All SAEs will be reported to the 
Baylor IRB and the sponsor within 24 hours. In addition, a safety report will 
be submitted to Baylor IRB annually. Any new information regarding 
saxagliptin will be submitted to Baylor IRB.  
5 
TREATMENTS 
5.1 
Study Treatment: Saxagliptin 
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) in a way 
different from the authorized form, or used for an unauthorized indication, or when used 
to gain further information about the authorized form. In this protocol, the investigational 
product is saxagliptin. 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as noninvestigational products. In this protocol, noninvestigational products 
are: no noninvestigational products will be used in this study 
5.1.1 
Identification 
Saxagliptin 5 mg tablets and placebo tablets are plain, yellow, biconvex, round, film 
coated tablets.  


 
 
Saxagliptin IST Protocol Shell 
32 
 21 July 2010 
5.1.2 
Packaging and Labeling 
 
Saxagliptin film-coated tablets in strengths of 1 mg, 2.5 mg, 5 mg, and 10 mg (as the free 
base) have been developed. The tablets are manufactured from saxagliptin and inactive 
ingredients including lactose, microcrystalline cellulose, croscarmellose sodium, 
magnesium stearate, and film-coating materials (Opadry® II white and Opadry® II 
yellow). The tablets are supplied in high-density polyethylene bottles containing two 
desiccant and charcoal canisters, with cotton coil and tightly closed with a child resistant 
cap.  
5.1.3 
Storage, Handling, and Dispensing 
The investigational product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed only to study 
subjects and only from official study sites by authorized personnel, as dictated by local 
regulations. 
Saxagliptin tablets should be stored at temperatures between 20°C and 25°C (68°F and 
77°F) in tightly closed containers. The investigator is responsible for ensuring that the 
investigational product is stored under the appropriate environmental conditions 
(temperature, light, and humidity), as determined by the sponsor. 
If concerns regarding the quality or appearance of the investigational product arise, do 
not dispense the investigational product, and contact BMS immediately. 
5.2 
Drug Ordering and Accountability 
5.2.1 
Initial Orders 
Contact the BMS protocol manager for information. 
5.2.2 
Re-Supply 
Contact the BMS protocol manager for information. 
5.3 
Method of Assigning Subjects to a Treatment 
 Patients will be randomized to one of the two treatment groups i.e. saxagliptin or 
placebo. Randomisation numbers (patient numbers) will be assigned strictly sequentially 


 
 
Saxagliptin IST Protocol Shell 
33 
 21 July 2010 
as patients become eligible for randomisation. Randomization will be computer-
generated by the research pharmacy, and the investigators will be blinded to the treatment 
assignments. The research pharmacy will provide the randomisation number and the 
appropriate bottle numbers. 
 
5.4 
Selection and Timing of Dose for Each Subject 
The recommended dose of saxagliptin is 5 mg once daily. Saxagliptin can be taken with 
or without food. We shall administer saxagliptin 5 mg once daily PO for 6 months. 
5.5 
Blinding/Unblinding 
Blinding is critical to the integrity of this clinical study. However, in the event of a 
medical emergency or pregnancy in a subject, in which knowledge of the 
investigational product is critical to the subject's management, the blind for that 
subject may be broken by the treating physician.  
Before breaking the blind of an individual subject's treatment, the investigator should 
have determined that the information is necessary, ie, that it will alter the subject's 
immediate management. In many cases, particularly when the emergency is clearly not 
investigational product-related, the problem may be properly managed by assuming that 
the subject is receiving active product without the need for unblinding. 
5.6 
Concomitant Treatments 
5.6.1 
Prohibited and/or Restricted Treatments 
The co-administration of saxagliptin and strong CYP3A4/5 inhibitors such as 
ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, and telithromycin may result in increased plasma concentrations of 
saxagliptin and should be avoided. 
5.6.2 
Other Restrictions and Precautions 
Saxagliptin should not be used in patients with type 1 diabetes mellitus or for the 
treatment of diabetic ketoacidosis.   


 
 
Saxagliptin IST Protocol Shell 
34 
 21 July 2010 
5.7 
Treatment Compliance 
Treatment compliance will be monitored by drug accountability as well as the patient’s 
medical record. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Time and Events Schedule 


 
 
Saxagliptin IST Protocol Shell 
35 
 21 July 2010 
 
Table 1: Time and Event Schedule for Protocol [Insert Protocol Number] 
 
 
 
 
 
 
Procedure 
 
Visit 1 
(Screening) 
 
Visit 2 
(OGTT) 
 
Visit 3 
(Pre randomization) 
 
Visit 4 
(Randomization) 
 
Visit 
5 
 
Visit 
6 
 
Visit 
7 
 
Visit 
8 
 
Visit 
9 
 
Visit 
10 
 
Visit 
11 
Study week 
-4 
-2 
-1 
0 
2 
6 
10 
14 
18 
22 
26 
Obtain Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Review Concomitant 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examination 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Run 12-Lead 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Diet Counseling 
 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test (a) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
CBC, Lipids, LFTs, 
Serum Creatinine 
X 
 
 
 
 
 
 
X 
 
 
X 
FPG 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
 
X 
 
 
 
 
X 
 
 
X 
OGTT 
 
X 
 
 
 
 
 
 
 
 
X 


 
 
Saxagliptin IST Protocol Shell 
36 
 21 July 2010 
Insulin/Cytokines/FFA 
 
 
X  
 
 
 
 
 
 
 
X 
Monocyte isolation 
 
 
X 
 
 
 
 
 
 
 
X 
MRI Studies 
 
 
X 
 
 
 
 
 
 
 
X 
Randomize 
 
 
 
X 
 
 
 
 
 
 
 
Study drug 
 
 
 
Start 
x 
x 
x 
x 
x 
x 
Stop 
Medication Compliance 
Check 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Assess for Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
   
   
   
   
   
6.2 
Study Materials 
Bristol-Myers Squibb (BMS) will provide saxagliptin at no cost for this study. 
6.3 
Safety Assessments 
Study drug toxicities will be assessed continuously. Adverse events will be evaluated on a 
continuous basis while the patient is on study and until 30 days after the last dose of study drug. 
Patients should be followed until all treatment-related adverse events have recovered to baseline 
or are deemed irreversible by the principal investigator. Patients will report every 4 weeks while 
on the study drug and a complete safety assessment including a complete history and physical 
and fasting blood glucose will be performed to evaluate for the following specific adverse events  
- Headache, URI, nasopharyngitis 
-Nausea, abdominal discomfort, gastroenteritis 
-Hypersensitivity-related reactions including skin rash (rare) 
-Hypoglycemia (mild to moderate). Treatment with saxagliptin led to rates of hypoglycemia that 
were generally similar compared with placebo. This is consistent with the mechanism of action 
of DPP-IV inhibitors, which exert their insulinotropic effects on the β cell in a glucose dependent 
manner. Severe hypoglycemia has not been reported in patients on saxagliptin monotherapy.  
 
 
6.4 
Efficacy Assessments 
6.4.1 
Primary Efficacy Assessment 
The primary efficacy objective is to determine whether treatment with saxagliptin compared with 
placebo will result in a reduction in hepatic and myocardial fat in patient with IGT. 
6.4.2 
Secondary Efficacy Assessments 
The secondary efficacy objective is to determine whether treatment with saxagliptin compared 
with placebo will result in an improvement in left ventricular systolic and diastolic function and 
a reduction in monocyte inflammation in patients with IGT. 


 
 
38 
7 
ADVERSE EVENT REPORTING 
7.1 
Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
7.1.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if 
it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
note below for exceptions) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event, defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (eg, 
medical, surgical) to prevent one of the other serious outcomes listed above. Examples of 
such events include but are not limited to intensive treatment in an emergency department 
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result 
in hospitalization. Potential drug induced liver injury (DILI) is also considered an 
important medical event (see Section 7.7 for the definition of potential DILI) 
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, 
pathogenic or non-pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these 
events must be handled as SAEs for data transmission purposes (See Section 7.5.2 for reporting 
pregnancies). 


 
 
39 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
• admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative). 
7.1.2 
Adverse Events of Special Interest 
In this study, the following adverse events are to be reported to BMS, regardless of whether these 
reports are classified as serious or unexpected: 
1. liver test abnormalities accompanied by jaundice or hyperbilirubinemia 
2. opportunistic infections associated with the use of saxagliptin, and 
3. pancreatitis 
4. anaphylaxis 
5. angioedema and  
6. Stevens’ Johnson syndrome. 
7.1.3 
Nonserious Adverse Events 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
7.2 
Assignment of Adverse Event Intensity and Relationship to 
Investigational Product 
All adverse events, including those that are serious, will be graded by the investigator as follows: 
7. 
Mild (Grade 1): awareness of event but easily tolerated 
8. 
Moderate (Grade 2): discomfort enough to cause some 
interference with usual activity 
9. 
Severe (Grade 3): inability to carry out usual activity 
10. 
Very Severe (Grade 4): debilitating; significantly incapacitates 
subject despite symptomatic therapy. 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used: 


 
 
40 
11. 
Related: There is a reasonable causal relationship to 
investigational product administration and the adverse event. 
12. 
Not Related: There is not a reasonable causal relationship to 
investigational product administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there are facts 
(eg, evidence such as de-challenge/re-challenge) or other arguments to suggest a positive causal 
relationship. 
7.3 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. To prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more adverse events. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment 
required. If treatment for the event was administered, it should be recorded in the medical record. 
The investigator must supply BMS and the IRB/IEC with any additional information requested, 
notably for reported deaths of subjects. 
7.3.1 
Serious Adverse Events and Adverse Events of Special Interest 
Following the subject’s written consent to participate in the study, all SAEs and all AEs of 
Special Interest (defined in Section 7.1.2), whether related or not related to study drug, must be 
collected, including those thought to be associated with protocol-specified procedures. All SAEs 
must be collected that occur during the screening period and within 30 days of discontinuation of 
dosing. If applicable, SAEs must be collected that relate to any later protocol-specified procedure 
(eg, a follow-up skin biopsy). The investigator should report any SAE occurring after these time 
periods that is believed to be related to study drug or protocol-specified procedure.   
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
All SAEs, whether related or unrelated to saxagliptin, and all pregnancies must be reported to 
BMS (by the investigator or designee) within 24 hours of study personnel becoming aware of the 
event. If only limited information is initially available, follow-up reports are required. The 
original SAE form must be kept on file at the study site. 


 
 
41 
All SAEs should be reported via confirmed facsimile (fax) transmission, or scanned and reported 
via electronic mail to:  
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number:  609-818-3804 
For studies conducted under an Investigator IND, any event that is both serious and unexpected 
must be reported to the Food and Drug Administration (FDA) as soon as possible and no later 
than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) after the 
investigator’s or institution’s initial receipt of the information. The investigator must provide 
BMS with a copy of all adverse events filed with the FDA. SAEs should be reported on 
MedWatch Form 3500A, 
which 
can 
be 
accessed 
at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.Safety@bms.com 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the 
same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. All pregnancies must be followed to 
outcome. 
7.3.2 
Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are 
suspected (related to the investigational product) and unexpected (ie, not previously described in 
the Investigator Brochure). In the European Union, an event meeting these criteria is termed a 
Suspected Unexpected Serious Adverse Reaction (SUSAR). BMS will send investigators an 
expedited safety report (ESR) to notify them of such an event. 


 
 
42 
Other important findings that BMS may report as ESRs include increased frequency of a 
clinically significant expected SAE, an SAE considered associated with study procedures that 
could modify the conduct of the study, lack of efficacy that poses significant hazard to study 
subjects, clinically significant safety findings from a nonclinical (eg, animal) study, important 
safety recommendations from a study data monitoring committee, or the decision by BMS to end 
or temporarily halt a clinical study for safety reasons. 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the 
Investigator Brochure. Where required by local regulations or when there is a central IRB/IEC 
for the study, BMS will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. When BMS has a written 
agreement with a local IRB/IEC, BMS will directly submit ESR(s). The investigator should also 
comply with the IRB/IEC procedures for reporting any other safety information. 
In addition, BMS will report suspected serious adverse reactions (whether expected or 
unexpected) to the relevant health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
7.3.3 
Nonserious Adverse Events 
The collection of nonserious AE (NSAE) information should begin at initiation of study drug. 
NSAE information should also be collected from the start of a placebo lead-in period or other 
observational period intended to establish a baseline status for the subjects. 
NSAEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious (see Section 7.3.1). Follow-up is also required for NSAEs that cause interruption or 
discontinuation of study drug, or those that are present at the end of study treatment as 
appropriate. All identified NSAEs must be recorded and described on the NSAE page of the 
CRF.  
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study. 
7.4 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. When reporting a test result that constitutes an adverse event, the clinical term 
should be used; for example, the event should be reported as “anemia” not “low hemoglobin.” 
Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be captured on the NSAE CRF page or SAE 
Report Form as appropriate: 


 
 
43 
• Any laboratory test result that is clinically significant or meets the definition of an SAE. 
• Any laboratory abnormality that required the subject to have study drug discontinued or 
interrupted. 
• Any laboratory abnormality that required the subject to receive specific corrective 
therapy. 
7.5 
Pregnancy 
WOCBP must use an effective method of birth control during the course of the study, in such a 
manner that the risk of failure is minimized. 
7.5.1 
Requirements for Pregnancy Testing 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving 
saxagliptin. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units 
of HCG. If the pregnancy test is positive, the subject must not receive saxagliptin and must not 
continue in the study. 
In addition, all WOCBP must be instructed to contact the investigator and/or other study 
personnel immediately if they suspect they might be pregnant (eg, missed or late menstrual 
period) at any time during study participation. 
7.5.2 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
The investigator must immediately notify the BMS Medical Monitor of this event and complete 
and forward a Pregnancy Surveillance Form to BMS within 24 hours and in accordance with 
SAE reporting procedures described in Section  7.3.1 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.  


 
 
44 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
7.6 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 7.3.1 for reporting details). 
Once-daily, orally administered saxagliptin has been shown to be safe and well tolerated, with no 
clinically meaningful effect on QTc interval or heart rate at doses up to 400 mg daily for 2 weeks 
(80 times the recommended human dose). In the event of an overdose, appropriate supportive 
treatment should be initiated as dictated by the patient’s clinical status. Saxagliptin and its major 
metabolite are removed by hemodialysis (23% of dose over 4 hours). 
7.7 
Potential Drug-Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI event. All 
occurrences of potential DILIs, meeting the defined criteria, must be reported as 
SAEs (7.3.1 for reporting details). 
Potential drug induced liver injury is defined as  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to 
be hepatotoxic. 
7.8 
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 


 
 
45 
procedures are required by the protocol, should also be recorded as a nonserious or serious AE, 
as appropriate, and reported accordingly. 
8 
STATISTICAL CONSIDERATIONS 
8.1 Sample size determination  
Sample size is calculated using SigmaPlot software (San Jose, CA). For the two major outcome 
variables i.e. myocardial fat and hepatic fat, the sample size of ~ 16 patients per treatment group 
(total of 32 patients) will have >90% power to detect a difference in the means of 20%, assuming 
a standard deviation of 15%, and with alpha= 0.025.  Given that we expect about 20% of the 
patients enrolled may not complete the 6 month study, we would like to enroll 40 patients so that 
32 patients may complete the study. 
8.2 Population for analysis 
All patients used in the analyses of the primary and secondary objectives will belong to the 
intention-to-treat (ITT) population. This population is defined as all randomised patients. The 
patients will be analysed according to the treatment group to which they were randomized. 
8.3 Endpoint Definitions:  
Primary Efficacy Endpoint:is defined as the effect of saxagliptin compared with placebo on 
reduction in hepatic and myocardial fat. 
Secondary Efficacy endpoint: is defined as the effect of saxagliptin compared with placebo on 
improvement in left ventricular systolic and diastolic function and a reduction in monocyte 
inflammation. 
Safety endpoints: The number and percent of patients with an AE will be summarised for each 
treatment group. In addition, the number and percent of patients with a predefined marked 
abnormality in clinical laboratory tests will be summarised by treatment group. 
8.4 Analyses 
8.4.1 Demographic and baseline characteristics : Demographic and baseline characteristics will 
be summarised using summary statistics based on the ITT data set, for each treatment group as 
well as for all patients combined. Key baseline characteristics will be summarised. No statistical 
test will be performed for comparison of any baseline measurement among treatment groups. 
Demographic and baseline characteristics will be summarised for the total study population. 
 
8.4.2 Efficacy Analysis: Between groups comparisons will be made using two-way analysis of 
variance (ANOVA.) to analyze changes in hepatic/myocardial fat following saxagliptin 


 
 
46 
treatment in comparison to placebo (primary efficacy analysis). Secondary efficacy analysis will 
include the effect of saxagliptin (versus placebo) on LV function and monocyte inflammation. 
Pre and post treatment within a group will be analyzed using paired t-tests. Simple correlation 
analysis will be performed with Pearson’s correlation coefficients to examine the relationship 
between hepatic fat and myocardial fat/ LV function . Spearman Rank Correlation will be used 
for data which is not normally distributed. All statistical analysis will be performed using SAS 
(Cary, NC). 
8.4.3 Safety Analysis 
Safety is evaluated by the following endpoints: 
o Incidence of overall AEs and AEs of special interest 
Other safety endpoints: 
o Changes from baseline in laboratory tests, pulse, BP,  and body weight. 
o Incidence of hypoglycaemic events. 
 
  9. Compliance with the Protocol and Protocol Revisions 
The study must be conducted as described in the final IRB/IEC-approved protocol. 
Documentation of approval, signed by the IRB/IEC chairperson or designee, must be sent to the 
BMS protocol manager. 
All protocol amendments and revisions to the informed consent must be submitted to the BMS 
protocol manager and to the IRB/IEC. No protocol amendments will be implemented until 
written approval has been given by the IRB/IEC, except when necessary to eliminate an 
immediate hazard to study subjects. Administrative letters should also be sent to the BMS 
protocol manager and IRB/IEC; however, they do not require approval.  
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior 
to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change 
must be submitted to: 
• IRB/IEC for review and approval/favorable opinion 
• Bristol-Myers Squibb 
• Regulatory Authority(ies), if required by local regulations. 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS. 
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 


 
 
47 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.  
9.1Records Retention 
The investigator will retain, in a confidential manner, all data pertinent to the study for all treated 
subjects as well as those entered as control subjects. The investigator will retain source 
documents and accurate case histories that record all observations and other data pertinent to the 
investigation (eg, the medical record) for the maximum period required by applicable regulations 
and guidelines or following institutional procedures. If the investigator withdraws from the study 
(eg, relocation or retirement), the records must be transferred to a mutually agreed upon 
designee, such as another investigator or an IRB. Written documentation of such transfer must be 
provided to BMS. 
The investigator will ensure that a current record of disposition of investigational product is 
maintained at each study site where the investigational product is inventoried and disposed. 
Records or logs must comply with applicable regulations and guidelines and should include: 
13. 
amount received and placed in storage area 
14. 
amount currently in storage area 
15. 
label identification number or batch number and use date or 
expiry date 
16. 
dates and initials of person responsible for each inventory 
entry/movement 
17. 
amount dispensed to and returned by each subject, including 
unique subject identifiers 
18. 
amount transferred to another area/site for dispensing or storage 
19. 
non-study disposition (eg, lost, wasted, broken) 
20. 
amount destroyed at study site, if applicable 
21. 
amount returned to the sponsor, if applicable. 
9.2 Destruction of Investigational Product  
If the study drugs are to be destroyed on site, it is the investigator’s responsibility to ensure that 
arrangements have been made for disposal, and that procedures for proper disposal have been 
established according to applicable regulations, guidelines, and institutional procedures. 
Appropriate records of the disposal must be maintained.  


 
 
48 
GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product) 
 


 
 
49 
LIST OF ABBREVIATIONS 
A1C 
Glycosylated Hemoglobin 
AE 
Adverse Event 
BMS 
Bristol-Myers Squibb 
CYP3A4 
Cytochrome P450 3A4 
DPP-IV 
Dipeptidyl peptidase IV 
ESR 
Expedited Safety Report 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
GIP 
Glucose dependent insulinotropic peptide 
HCG 
Human Chorionic Gonadotropin 
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
IST 
Investigator-Sponsored Trial 
MWG 
Mean Weighted Glucose 
NSAE 
Non-Serious Adverse Event 
PPG 
Post-Prandial Glucose 
SAE 
Serious Adverse Event 
SU 
Sulfonylurea 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TDZ 
Thiazolidinedione 
WOCBP 
Women of Child-Bearing Potential 
 


 
 
50 
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