Conditions: Polycystic Ovary Syndrome Obesity
Keywords: PCOS GLP1 agonists SGLT2 inhibitors
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 119
Healthy volunteers: yes

Brief summary:
This is a randomized, single-blind, parallel 5 treatment group 24-week trial designed to directly compare the therapeutic effects of exenatide once weekly (EQW), dapagliflozin (DAPA), EQW plus DAPA, combined DAPA/metformin extended release (XR) and the weight loss medication, phentermine/topiramate extended release (PHEN/TPM ER) on metabolic and endocrinological parameters in overweight/obese non-diabetic women with PCOS. In this study, we will examine the efficacy of these therapies on metabolic parameters, body weight and body composition, anthropometric measurements, and reproductive function in a well-defined group of pre-menopausal overweight/obese, non-diabetic women with PCOS, focusing on their relationship to insulin resistance and obesity. We hope to determine which treatment(s) addressing the multifaceted disturbances of individual subgroups emerge as the preferable therapy.

Detailed description:
Polycystic ovary syndrome is a heterogeneous condition characterized by disordered reproductive and metabolic function which accounts for the myriad of clinical features including androgen excess, chronic anovulation, insulin resistance adiposity, and dyslipidemia. This syndrome is highly prevalent, affecting between 8 and 18% of the female population, depending on the diagnostic criteria used. Hyperandrogenism, ovarian dysfunction and metabolic abnormalities - the main determinants of PCOS - all appear to be involved in a synergistic way in the pathophysiology of PCOS. Women with PCOS are more likely to be obese: between 38 and 88% of women with PCOS are overweight or obese, although PCOS can also manifest in lean women. Obesity, particularly abdominal obesity, plays a central role in the development of PCOS, and exacerbates the reproductive and metabolic dysfunction. Rather than absolute body weight, it is the distribution of fat that is important with central (visceral) adiposity being a risk factor. Visceral adipose tissue is more metabolically active than subcutaneous fat and the amount of visceral fat correlates with insulin resistance and hyperinsulinemia. Weight gain is also often an important pathogenic factor, with PCOS usually becoming clinically manifest in women with a presumable genetic predisposition for PCOS who subsequently gain weight. Therefore, environmental (particularly dietary) factors are important. However, BMI is also influenced by genetic factors such as the fat mass and obesity-associated protein, and obesity is a highly heritable condition. Therefore, the weight gain responsible for the manifestation of PCOS in many women with this condition is itself influenced by genetic factors. Ethnicity, genetic background, personal and family history, degree of obesity must all be taken into account because they might aggravate or even trigger metabolic disturbances women with PCOS. Moreover, the incidence of glucose intolerance, dyslipidemia, gestational diabetes, and type 2 diabetes (DM2) is increased in women with PCOS at all weight levels and at a young age. PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women. The exact factors responsible for this excess risk in women with PCOS have not been identified; family history of DM 2, obesity, insulin resistance, beta cell (ß-cell) secretory dysfunction, and hyperandrogenism are possible candidates. With better understanding of its pathophysiology, the metabolic consequences of the syndrome are now evident. Therefore, these patients need to be followed up even after their presenting complaint has been adequately resolved.

Lifestyle modification is a key component for the improvement of reproductive function for overweight, anovulatory women with PCOS. Even a modest weight loss 5% of total body weight can restore ovulation in overweight women with PCOS. Features of PCOS (e.g., hirsutism, testosterone levels, insulin resistance, menstrual cyclicity and ovulation) showed marked improvements, and PCOS frequently resolved after substantial weight loss induced by bariatric surgery. Recently a number of anti-diabetes medications have been approved which facilitate weight loss and improve the underlying insulin resistance. We reported that treatment with the glucagon like peptide -1 (GLP-1) agonist, exenatide for 24 weeks was superior to single agent metformin treatment in improving insulin action and reducing body weight and hyperandrogenism in obese women with PCOS. We further observed exenatide treatment significantly improved first-phase insulin responses to oral glucose administration. Since aberrant first-phase insulin secretion and impaired suppression of endogenous glucose production are major contributors to postprandial hyperglycemia and development of type 2 diabetes, the effects of exenatide once weekly \[EQW (2 mg)\] to target these defects, and normalize glucose excursions are likely to be clinically significant in obese patients with PCOS. Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are the newest class of medications for diabetes management that have not been investigated for use in the women with PCOS. The SGLT2 inhibitor, dapagliflozin \[DAPA (10 mg/day)\] has an insulin-independent action, promotes weight loss, has a low incidence of hypoglycemia, and complements the action of other antidiabetic agents. The loss of glucose with attendant caloric loss contributes to weight loss; in addition, improvements in β cell function have been seen. Because the SGLT2 inhibitors have a distinct mechanism of action that is independent of insulin secretion, the efficacy of this class of drugs is not anticipated to decline in the presence of severe insulin resistance. The weight loss seen with SGLT2 inhibitors is similar to that seen with glucagon-like peptide 1 agonists, and may be more acceptable because they are oral agents. The resulting weight loss will further assist in decreasing insulin resistance, leading to increased glucose disposal thus contributing to an increased insulin secretion-insulin sensitivity (ISSI) index, the primary outcomes measure.

The non-diabetic female with PCOS offers a unique model to study the relationship between insulin resistance and adiposity. Women with PCOS demonstrate abnormal body composition characterized by a greater percent body fat, body fat mass, and increased ratio of fat to lean mass (F/L ratio). Studies using dual-energy X-ray absorptiometry (DEXA) methodology report a higher degree of metabolic dysfunction in patients with PCOS which appears be directly associated with their higher F/L ratio. Given that monotherapy and combined therapy with exenatide once weekly (EQW),and dapagliflozin (DAPA) along with DAPA/ metformin XR therapy are associated with weight loss introduces a confounder to the current study since it prevents distinguishing direct effects of the compounds on β-cell function vs. effects due to reduced adiposity. To control for loss of body mass and provide appropriate intervention in the remaining study arm we propose the use of a comparator weight loss drug alone, combination phentermine (PHEN)/topiramate (TPM) extended release (ER). To avoid the confounding relationship of body fat and insulin resistance, we will enroll only obese non-diabetic women with PCOS. All patients will receive diet and lifestyle counselling, including advice on exercise, according to usual clinical routine commencing during the lead-in period and continuing throughout the study We propose a randomized, single-blind, parallel 5 treatment group 24-week trial designed to directly compare the therapeutic effects of exenatide once weekly (EQW), dapagliflozin (DAPA), EQW plus DAPA, combined DAPA/metformin ER and the weight loss medication, phentermine/topiramate extended release (PHEN/TPM ER) on metabolic and endocrinological parameters in obese non-diabetic women with PCOS.

Arms:
arm 1: EQW- 2 mg subcutaneous (SC) injection once every seven days for 24 weeks arm 2: DAPA-10 mg oral pill once daily in am for 24 weeks arm 3: EQW- 2 mg SC injection once every seven days for 24 weeks DAPA-10 mg oral pill once daily in am daily for 24 weeks arm 4: Combination DAPA / MET ER-10 mg /2000 mg oral pill daily with food for 24 weeks arm 5: Combination Phentermine /Topiramate ER -7.5 mg/46mg pill once daily in am for 24 weeks

Interventions: intervention 1: Exenatide once weekly (EQW ) intervention 2: Dapagliflozin (DAPA) intervention 3: EQW plus DAPA intervention 4: Dapagliflozin plus Glucophage (MET ER) intervention 5: Phentermine /Topiramate (PHEN/ TPM) ER
Intervention descriptions: intervention 1: 2 mg SC injection every 7 days intervention 2: One pill (10 mg) by mouth daily (QD) in am intervention 3: 2 mg SC injection every 7 days One pill (10 mg) by mouth QD in am intervention 4: DAPA/MET ER-5 mg /1000 mg - 1 pill by mouth in am with food for 4 weeks DAPA/MET ER-10 mg /2000 mg - 2 pills in am by mouth with food -final dose intervention 5: PHEN 3.75/TPM ER 23mg - 1 pill by mouth once daily in am for 2 weeks. After 2 weeks, PHEN 7.5mg/TPM ER 46mg- 1 pill by mouth once daily in am

Protocol document:
ICF_000.pdf: 





































Prot_SAP_002.pdf: 
Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page1 
Clinical Trial Number NCT02635386 
Drug Substance 
Dapagliflozin/Bydureon 
Study Number 
ESR-14-10725 
Comparison of dapagliflozin (DAPA) and once-weekly exenatide (EQW), 
co-administered or alone, combination tablet dapagliflozin/ extended 
release metformin (DAPA/MET XR) and the weight loss drug,
combination phentermine (PHEN)/topiramate (TPM) extended release
(ER), on metabolic profiles and body composition in overweight/obese
PCOS women 
Principal Investigators: 
Karen Elkind-Hirsch, M.Sc., PhD 
Martha Paterson, M.D. 
Address 
 
 
Woman's Health Research Department 
 
 
 
Woman’s Metabolic Health Center 
 
 
 
100 Woman’s Way 
 
 
 
Baton Rouge, LA  70817 
 
 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
PCOS 
Polycystic ovary syndrome 
T2DM 
Type 2 diabetes mellitus 
β-cell 
GLP1 
Pancreatic beta cell 
Glucagon-like peptide 1 
SGLT2 
Sodium/glucose cotransporter 2 
OGTT 
Oral glucose tolerance test 
BMI 
Body mass index 
WC 
Waist circumference 
WHR 
Waist to hip ratio 
WHtR 
Waist to height ratio 
DEXA 
Metformin XR 
Dual-energy X-ray absorptiometry 
Metformin extended release 
DAPA 
EQW 
PHEN/TPM ER 
Dapagliflozin 
Exenatide once weekly 
Phentermine/topiramate extended release 
 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page3 
INTRODUCTION 
Background  
Polycystic ovary syndrome (PCOS) is a heterogeneous condition characterized by disordered 
reproductive and metabolic function that accounts for the myriad of clinical features including androgen 
excess, chronic anovulation, hyperinsulinemia, adiposity, and dyslipidemia. This syndrome is highly 
prevalent, affecting between 8 and 18% of the female population, depending on the diagnostic criteria 
used.  Hyperandrogenism, ovarian dysfunction and metabolic abnormalities - the main determinants of 
PCOS – all appear to be involved in a synergistic way in the pathophysiology of PCOS.  Women with 
PCOS are more likely to be obese: between 38 and 88% of women with PCOS are overweight or obese, 
although PCOS can also manifest in lean women.  Obesity, particularly abdominal obesity, plays a central 
role in the development of PCOS, and exacerbates the reproductive and metabolic dysfunction.  Rather 
than absolute body weight, it is the distribution of fat that is important with central (visceral) adiposity 
being a risk factor.  Compared with weight-matched healthy women, those with PCOS have a similar 
amount of total and trunk fat, but a higher quantity of central abdominal fat.  Visceral adipose tissue is 
more metabolically active than subcutaneous fat and the amount of visceral fat correlates with insulin 
resistance and hyperinsulinemia. Weight gain is also often an important pathogenic factor, with PCOS 
usually becoming clinically manifest in women with a presumable genetic predisposition for PCOS who 
subsequently gain weight.  Therefore, environmental (particularly dietary) factors are important.  
However, BMI is also influenced by genetic factors such as the fat mass and obesity-associated protein, 
and obesity is a highly heritable condition.  Therefore, the weight gain responsible for the manifestation 
of PCOS in many women with this condition is itself influenced by genetic factors. Ethnicity, genetic 
background, personal and family history, degree of obesity must all be taken into account because they 
might aggravate or even trigger metabolic disturbances women with PCOS.  Moreover, the incidence of 
glucose intolerance, dyslipidemia, gestational diabetes, and type 2 diabetes (T2DM) is increased in 
women with PCOS at all weight levels and at a young age. Several studies have demonstrated that 
T2DM occurs with increased frequency in women with PCOS so that recently the American Diabetes 
Association and the International Diabetes Federation have identified PCOS as a significant non-
modifiable risk factor associated with type 2 diabetes.  PCOS may be a more important risk factor than 
ethnicity or race for glucose intolerance in young women.  The exact factors responsible for this excess 
risk in women with PCOS have not been identified; family history of T2DM, obesity, insulin resistance, 
beta cell (ß-cell) secretory dysfunction, and hyperandrogenism are possible candidates.  With better 
understanding of its pathophysiology, the metabolic consequences of the syndrome are now evident.  
Therefore, these patients need to be followed up even after their presenting complaint has been 
adequately resolved. 
Multiple metabolic aberrations, such as insulin resistance (IR) and hyperinsulinemia, impaired 
glucose tolerance, visceral obesity, hypertension and dyslipidemia are associated with polycystic ovary 
syndrome.  Current research has shown that the use of diabetes management practices aimed at 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page4 
reducing IR and hyperinsulinemia (such as weight reduction and the administration of antidiabetic 
drugs) in non-diabetic women with PCOS can not only improve glucose and lipid metabolism but can 
also reverse testosterone abnormalities and restore menstrual cycles.  Weight reduction through 
lifestyle modification is strongly advocated for PCOS to alleviate metabolic and cardiovascular risk. 
Lifestyle interventions remain essential to the management of women with PCOS; however, the majority 
of non-diabetic overweight/obese PCOS patients do not reach their therapeutic goals with these 
interventions alone and will require pharmacologic therapies. 
Until a few years ago, the treatment for women with PCOS consisted exclusively of a combination 
of estrogen and progestins.  Over the last years, considering the importance given to insulin resistance in 
the pathogenesis of the syndrome, clinical studies have focused on insulin sensitizing drugs for the 
treatment of women with PCOS, with metformin being the drug most extensively studied in this 
syndrome.  Although no antidiabetic agents have US Food and Drug Administration approval for the 
treatment of PCOS, metformin was preferred due to the fact that it had the safest risk-benefit ratio, and 
could cause weight loss, while thiazolidinediones increased weight as a result of fluid retention.   
Metformin acts by decreasing hepatic gluconeogenesis and free fatty acid oxidation while increasing 
peripheral glucose uptake.  Early studies in PCOS suggested that metformin indirectly reduces insulin 
levels, dyslipidemia and systemic inflammation; however, recent placebo-controlled trials failed to 
demonstrate significant metabolic benefit.  Considerable variability in the metabolic responses to 
metformin has been observed in women with PCOS, attributable to several potential factors such as 
different doses of the drug and genetic background.  Weight loss has been claimed to be a beneficial 
secondary effect of metformin extended release (metformin XR) but the effect is not very consistent.  
Interestingly, most studies have not found any beneficial effects of metformin treatment in obese 
patients with PCOS.  It is possible that the weight loss that often accompanies protracted metformin 
therapy may account for some of the beneficial effects observed in many studies. Irrespective of 
treatment group (after adjustment for baseline BMI and age), only weight loss, but not the use of 
metformin, was associated with a significant improvement in metabolic and reproductive function in 
obese women with PCOS.  Furthermore, a number of studies have substantiated the view that obesity 
may reduce the benefit of metformin treatment. 
Novelty of Study 
The realization that hyperinsulinemia is a key component in the pathogenesis of PCOS provided 
a basis for advances in treatment strategies for women with the disorder. Lifestyle modification, 
including diet and exercise, is considered a cornerstone of the management of women with PCOS 
presenting with obesity, particularly the abdominal phenotype.  PCOS is characterized by a vicious cycle 
whereby androgen excess favors abdominal fat deposition, which in turn aggravates insulin resistance 
and compensatory hyperinsulinism, further enhancing ovarian androgen secretion.  Hence, therapeutic 
strategies ameliorating abdominal adiposity and weight excess may inhibit this vicious cycle, improving 
not only the metabolic co-morbidities of PCOS but also androgen excess and reproductive aberrations 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page5 
for overweight, anovulatory women with PCOS.  Even a modest weight loss of 5% of total body weight 
can restore ovulation in overweight women with PCOS.  Most characteristics of PCOS (e.g., hirsutism, 
testosterone levels, insulin resistance, menstrual cyclicity and ovulation) showed marked improvements, 
and PCOS frequently resolved after substantial weight loss induced by bariatric surgery.  While weight 
loss is the key in the treatments of overweight/obese patients with PCOS, current non-pharmacologic 
management of body weight is hard to achieve.  Thus, in the majority of patients with PCOS 
pharmaceutical intervention is an additional essential therapeutic aid to lifestyle changes.   
The growing body of evidence linking PCOS to an inherited resistance to insulin action, 
aggravated by lifestyle problems such as obesity, poor diet and physical inactivity has led to trials of 
diabetic therapies in patients with the polycystic ovary syndrome.  Currently, a number of anti-diabetes 
medications have been approved that facilitate weight loss and improve the underlying insulin 
resistance.  Glucagon-like peptide 1 (GLP-1) agonists evolved as therapeutic options for the treatment of 
T2DM primarily because of their effects on insulin and glucagon secretion, with weight loss as an 
additional benefit.  Early studies of human GLP-1 showed that continuous peripheral infusion was 
associated with decreased appetite and increased satiety.  Continuous infusion of GLP-1 also was shown 
to improve insulin sensitivity, glycemic control, and β-cell function in individuals with T2DM.  Weight loss 
ranging from 2 to 6 kg has been a consistent finding in studies designed to investigate the glycemic 
benefits of GLP-1 agonists in individuals with T2DM.  Additionally, this therapy has produced progressive 
weight loss in obese people without diabetes.  The mechanisms of weight loss with GLP-1 agonists are 
not fully understood but may include changes in energy expenditure, changes in leptin sensitivity, or 
nausea resulting in decreased food intake.   We found that treatment with the GLP-1 agonist exenatide 
for 24 weeks was superior to single agent metformin treatment in improving insulin action and reducing 
body weight and hyperandrogenism in obese women with PCOS.  Similarly, a recent study showed that a 
12-week treatment with another GLP1 agonist, liraglutide was associated with significantly greater 
weight loss in a subset of obese patients with PCOS and higher metabolic risk profile when compared to 
metformin.  Another preliminary report confirmed that liraglutide had an add-on effect on weight loss in 
obese women with PCOS who had lost <5% body weight during a 6-month pre-treatment with 
metformin.  We further observed exenatide treatment in women with PCOS significantly improved first-
phase insulin responses to oral glucose administration.  Since aberrant first-phase insulin secretion and 
impaired suppression of endogenous glucose production are major contributors to postprandial 
hyperglycemia and development of T2DM, the effects of the long acting GLP-1 agonist, exenatide once 
weekly [EQW (2 mg)], to target these defects, and normalize  glucose excursions are likely to be clinically 
significant in overweight/obese patients with PCOS.  The potential efficacy of a long-acting once-weekly 
GLP-1 agonist has not yet been evaluated in the PCOS population.  We hypothesize that intervention 
with long-acting exenatide once-weekly will result in reduced body weight and improved hormonal and 
metabolic parameters in overweight/obese women with PCOS. 
Sodium/glucose cotransporter 2 (SGLT-2) inhibitors are the newest class of medications for 
diabetes management.  The main advantage of SGLT-2 inhibitors is they have a completely different 
mechanism of action; SGLT2 inhibitors work primarily to lower the renal threshold to glucose, leading to 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page6 
increased glucose in the urine and reduced glucose levels in the blood.  In addition, this inhibitory action 
can induce mild osmotic diuresis and increase urinary excretion of glucose with modest caloric 
elimination leading to weight loss.  Dapagliflozin is a highly potent selective and reversible inhibitor of 
SGLT2 that improves fasting and post-prandial plasma glucose levels.  Orally administered dapagliflozin 
is rapidly absorbed generally achieving peak plasma concentrations within 2 h with a half-life of 12-13 
hours; so that once-daily dosing is appropriate.  In addition to the beneficial effects related to improved 
glycemic control, dapagliflozin induces weight loss via caloric loss from glycosuria; i.e., by passing 
glucose out of the body, the accompanying calories in the excreted glucose are also passed out.   
Consistent with this, 3-6 months treatment with dapagliflozin has been associated with weight losses of 
2–3 kg.  The weight loss seen with SGLT2 inhibitors is similar to that seen with GLP-1 agonists, and may 
be more acceptable because they are oral agents.  In addition, dapagliflozin treatment has recently been 
shown to improve insulin resistance and B-cell function in patients with T2DM by correcting 
hyperglycemia, i.e., reversal of glucotoxicity.  . Because the SGLT2 inhibitors have a distinct mechanism 
of action that is independent of insulin secretion, the efficacy of this class of drugs is not anticipated to 
decline in the presence of severe insulin resistance.  In prior study trials, the SGLT 2 inhibitor 
dapagliflozin appears to be safe, effective and lead to weight loss. The reduction in central adiposity may 
be an advantage in non-diabetic patients with PCOS who have associated insulin resistance.  This drug 
class has not been investigated for use in the women with PCOS.  Weight reduction has a beneficial 
effect on hyperinsulinemia, hyperandrogenism and increased SHBG production in overweight/obese 
women with PCOS supporting that dapagliflozin may be an effective alternative for in this group of 
patients.  
The potentially beneficial role of long-acting GLP1 receptor agonist, exenatide once weekly in 
combination with the SGLT2 inhibitor, dapagliflozin in PCOS has not yet been evaluated. SGLT-2 
inhibitors are type 2 diabetes drugs with an action independent of insulin, whereas GLP-1 agonists are 
"insulin dependent." Both seem to invoke weight loss as a secondary outcome, but it is not known 
whether this is additive, given the differing mechanisms of action of the two drug classes.  Early data 
suggests there are additive weight loss effects. A small UK study observed that adding a sodium glucose 
cotransporter 2 (SGLT-2) inhibitor to therapy for T2DM patients who are already taking a glucagon like 
peptide 1 (GLP-1) agonist can result in additive weight loss.  There was twice as much weight loss in 
those taking both agents compared with those taking just one of the medications.  This clinical profile 
suggests that co-administration of DAPA and exenatide once-weekly (EQW) would have additional 
weight loss benefits and be useful therapeutic intervention for the treatment of overweight/obese 
women with PCOS.   
The single fixed-dose combination of SGLT2 inhibitor, dapagliflozin and metformin extended 
release (XR) will also provide two complementary therapeutic approaches and allow for another 
innovative option for treating women with PCOS.  The new combination is indicated for use as an 
adjunct to diet and exercise in adults in whom treatment with both dapagliflozin and metformin is 
appropriate.  Metformin reduces hepatic glucose production and to a lesser extent, increases peripheral 
glucose uptake.  Dapagliflozin causes the kidney resorption of glucose in the kidney by blocking a renal 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page7 
protein called human sodium-glucose cotransport 2 (SGLT-2) resulting in increased urinary glucose 
excretion, with a consequent lowering of plasma glucose levels as well as weight loss.   In addition to the 
beneficial effects related to improved glycemic control, the SGLT2 inhibitors have a number of non-
glycemic effects that make them desirable agents for combination treatment with other antidiabetic 
agents.  The SGLT2 inhibitor, dapagliflozin has an insulin-independent action, promotes weight loss, has 
a low incidence of hypoglycemia, and complements the action of other antidiabetic agents In PCOS, 
metformin has become an established treatment.  While metformin has been shown to be effective in 
reducing fasting insulin and total testosterone concentrations in overweight women with PCOS, it had 
no consistent effect on weight loss or waist circumference.  The potential therapeutic add-on effect of 
treatment with dapagliflozin has not been evaluated in the subpopulation of overweight/obese women 
with PCOS.  The fixed-dose combination of metformin plus dapagliflozin should be more convenient 
than taking the drugs separately and an oral pill a more acceptable route of administration for some 
patients. 
The non-diabetic female with PCOS offers a unique model to study the relationship between 
insulin resistance and adiposity.  Women with PCOS demonstrate abnormal body composition 
characterized by a greater percent body fat, body fat mass, and increased ratio of fat to lean mass (F/L 
ratio).  Studies using DEXA methodology report a higher degree of metabolic dysfunction in patients 
with PCOS which appears be directly associated with their higher F/L ratio.  Given that monotherapy and 
combined therapy with exenatide once weekly (EQW), and dapagliflozin (DAPA) along with DAPA/ 
metformin XR therapy are associated with weight loss introduces a confounder to the current study 
since it prevents distinguishing direct effects of the compounds on β-cell function vs. effects due to 
reduced adiposity.  To control for loss of body mass and provide appropriate intervention in the 
remaining study arm we propose the use of a comparator weight loss drug alone, combination 
phentermine (PHEN)/topiramate (TPM) extended release (ER).  Combination phentermine 
(PHEN)/topiramate (TPM) extended release (ER) is a is a fixed combination oral weight-loss medication 
comprised of immediate-release phentermine hydrochloride and extended-release topiramate  
approved by the U.S. Food and Drug Administration in 2012 as an adjunct to lifestyle modification for 
long-term treatment of overweight and obesity.  Phentermine, a sympathomimetic drug, has been 
widely used as short-term appetite suppressant. Topiramate is an antiepileptic drug.  The anorectic 
effect of phentermine is mediated by catecholamine release in the hypothalamus.  The exact 
mechanism underlying the weight loss action of topiramate is not known; however, it may be associated 
with a combination of features such as an effect on sodium channels, enhancement of γ-aminobutyric 
acid (GABA) activated chloride channels, and inhibition of carbonic anhydrase isoenzymes.  This fixed 
combination uses lower doses of phentermine (titration dose at 3.75 mg, recommended dose at 7.5 mg) 
than as a single agent. Topiramate is an ER formulation.  Its dose in the fixed combination (titration dose 
at 23 mg, recommended dose at 46 mg) is lower than that when it is used for migraine prophylaxis or to 
control seizures.  Both medications reduce appetite and in addition, topiramate produces a sense of 
satiety (feeling of fullness), and in some people, induce a negative energy balance.  PHEN/TPM ER has 
been shown to improve cardiometabolic parameters and prevent progression to T2DM in patients with 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page8 
prediabetes and/or metabolic syndrome.  This treatment will allow us to examine the independent 
impact of reduction in body weight on improved insulin sensitivity in this non-diabetic patient 
population. 
Study Rationale 
We propose a randomized, single-blind, parallel 5 treatment group 24-week trial designed to 
directly compare the therapeutic effects of exenatide once weekly (EQW), dapagliflozin (DAPA), EQW 
plus DAPA, combined DAPA/metformin XR and the weight loss medication, phentermine/topiramate 
extended release (PHEN/TPM ER) on metabolic and endocrinological parameters in overweight/obese 
non-diabetic women with PCOS.  To avoid the confounding relationship of body fat and insulin 
resistance, we will enroll only overweight/obese non-diabetic insulin-resistant women with PCOS.  All 
patients will receive diet and lifestyle counseling, including advice on exercise, according to usual clinical 
routine commencing during the lead-in period and continuing throughout the study.  In this study, we 
will examine the efficacy of these therapies on metabolic parameters, body weight and body 
composition, anthropometric measurements, and reproductive function in a well-defined group of pre-
menopausal overweight/obese, non-diabetic women with PCOS, focusing on their relationship to insulin 
resistance and obesity.  We hope to determine which treatment(s) addressing the multifaceted 
disturbances of individual subgroups emerge as the preferable therapy. 
There is a growing need to develop pharmacologic interventions to improve metabolic function 
in women with PCOS.  Use of the combination of GLP-1 agonists/SGLT2 inhibitors, compared to either of 
the individual components as monotherapy or dapagliflozin combined with metformin, will likely induce 
greater weight loss.  The resulting weight loss will further assist in decreasing insulin resistance leading 
to increased glucose disposal thus contributing to an increased insulin secretion-insulin sensitivity (ISSI) 
index, the primary outcomes measure.  More germane to the current application is the fact that all 
therapies are associated with weight loss, which in and of itself introduces a confounder to the current 
study since it prevents distinguishing direct effects of the compounds on β cell function vs. effects due 
to a reduction in adiposity.  To control for weight loss due to exenatide once-weekly, dapagliflozin, 
exenatide once-weekly plus dapagliflozin and combination dapagliflozin/metformin XR, as well as 
provide appropriate intervention in the remaining arm requires use of a weight loss drug alone.  There 
are very limited data on weight loss with phentermine/topiramate extended release in non-diabetic 
females with PCOS treated with this agent.  The use of DEXA technology that is simple, operator 
independent, safe, accurate and cost-effective will be used to assess fat quantity and distribution. 
 
Benefit/Risk and Ethical Assessment 
 
GLP-1 receptor agonists are peptides that mimic native GLP-1, binding to its receptors to elicit 
the same effects, but at much higher pharmacological levels than the physiological profiles.  The most 
common treatment-related adverse effects of GLP-1 receptor agonists are gastrointestinal in nature and 
include nausea, vomiting, and diarrhea, which are usually mild and tend to subside over time.  Other 
documented but infrequent concerns with GLP-1 receptor agonists include injection site reactions and, 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
Page9 
particularly with exenatide extended-release, the development of transient small nodules around 
injection sites related to the microsphere technology of delivery.  When looking at the benefit–risk 
assessment, the GLP-1 receptor agonists demonstrate clinical advantages such as reduced risk for drug-
related hypoglycemia and often favorable effects on body weight. 
Dapagliflozin is an SGLT2 inhibitor that works by targeting and helping to stop sodium-glucose 
transport proteins from allowing glucose that has been filtered out of the blood by the kidneys to be 
reabsorbed back into the blood.  Its efficacy and safety has been studied in multiple randomized 
controlled trials including an add-on to metformin compared with a placebo.  Clinical trials with 
dapagliflozin have demonstrated that treatment in healthy subjects results in continuously excreted 
glucose in the absence of hyperglycemia.  The increased glucose excretion with the SGLT2 inhibitors 
leads to increased urogenital infections.  Genital mycotic infections, increased urination and urinary 
tract infection are the most common side effects associated with dapagliflozin.  In clinical studies, 
subjects receiving SGLT2 inhibitors compared with placebo were reported to have an increase in the 
rate of genital and urinary tract infections with a greater percentage of women diagnosed than men.  
These fungal infections were reported to subside spontaneously or to respond to local antifungal 
treatment.  Genital mycotic infections and urinary tract infections were usually mild to moderate and 
responsive to treatment, and they rarely resulted in discontinuation of therapy.  Studies have also 
shown that some adverse events related to osmotic diuresis (e.g., polyuria) are greater with SGLT2 
inhibitors than with placebo but these agents remain well tolerated and beneficial.  Currently available 
data on dapagliflozin, the most clinically advanced of the SGLT2 inhibitors, has demonstrated efficacy 
and consistent safety across a wide range of patient populations.  In addition, the asymptomatic clinical 
presentation of subjects with familial renal glycosuria despite multiple generations of the disease 
suggests that chronic inhibition of renal glucose reabsorption and the associated chronic glycosuria may 
not be associated with adverse effects.  Based on the efficacy of SGLT2 inhibition on weight reduction 
and safety, the benefits of this treatment far outweigh the risk of increased urogenital infections that 
can be minimized by meticulous genital hygiene. 
The side effect profile in patients treated with PHEN/TPM ER is well tolerated and consistent 
among all phase III and post-marketing reports.  The most commonly reported treatment-related 
adverse events (AEs) in clinical trials include paraesthesia, dizziness, dysgeusia (altered taste), insomnia, 
constipation, and dry mouth. The majority of reported adverse events have been mild and 
discontinuation of study drug due to AEs was rare.  In clinical studies, PHEN/TPM ER showed a significant 
weight loss across all doses studied that exceed both FDA efficacy benchmarks for weight loss. 
PHEN/TPM ER is a safe and effective medication in managing weight loss as adjunct therapy to diet and 
exercise for the obese or overweight patient with at least one weight-related comorbidity.   Benefits 
may extend to improve and reduce the risk of cardiovascular disease in obese and overweight patients 
with co-morbidities.  PHEN/TPM ER is contraindicated in pregnancy because of concerns about the 
teratogenicity of topiramate.  Topiramate is associated with oral clefts if used during pregnancy.  It 
requires a negative pregnancy test before treatment and monthly thereafter.   


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Study Number ESR-14-10725 
Edition Number 3 
 
 
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Women with PCOS are at substantially increased risk of T2DM.  Compared with the general 
population, these women are more likely to be overweight or obese.  Taken together, the data support 
increased abdominal fat as the strongest factor associated with declining B-cell compensation for insulin 
resistance in PCOS women at high risk for Type 2 DM.  Although no pharmacological agent is without 
some risk, DAPA, EQW, combination DAPA/metformin XR, and PHEN/TPM ER appear to have wide 
margins of safety when used appropriately.  The robust clinical benefits observed with these 
pharmacologic agents may confer a significant advantage to improve outcomes in patients at high risk of 
developing type 2 diabetes.  
STUDY OBJECTIVES 
Primary Objective:  
• 
The primary aim of this study is to compare the efficacy of dapagliflozin, exenatide once-weekly, 
dapagliflozin plus exenatide once-weekly, combination dapagliflozin/metformin XR and 
phentermine/topiramate extended release in improving the oral disposition index (product of 
Matsuda index and insulinogenic index; SIOGTT x Δinsulin30–0 min to glucose30–0 min)], modeled 
from a simple 2-h oral glucose tolerance test (OGTT) in obese non-diabetic female subjects with 
polycystic ovary syndrome (PCOS). 
 
Secondary Objective(s) 
• 
We will further examine the impact of the administration of these pharmacotherapies on insulin 
sensitivity, first phase insulin response, glycemic parameters determined with a 75-g OGTT, total 
fat mass and fat distribution evaluated by DEXA and other anthropometric parameters, 
cardiometabolic markers (lipid fractions and blood pressure) and reducing hyperandrogenism in 
non-diabetic PCOS women using the following parameters: 
• 
Surrogate measures of insulin action derived from OGTT [insulin sensitivity index 
(HOMA-IR, Matsuda index), corrected early insulin secretory response (insulinogenic 
index/HOMA-IR)   
• 
Fasting and 2 hour glucose levels after an OGTT 
• 
Plasma lipid fractions 
• 
Liver enzymes 
• 
Blood pressure 
• 
Anthropometric parameters, including body mass index [BMI], absolute body weight, 
waist circumference, waist: hip ratio, waist-height ratio and trunk fat mass and truck 
fat/extremities fat ratio by DEXA, 
• 
Free androgen index (total testosterone and SHBG) and DHEAS 
• 
Menstrual diaries 


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Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
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Safety Measures: 
Safety and tolerability will be assessed by collating data on adverse events (AEs), laboratory tests, 
physical examinations, and vital signs.  Patients will be educated about the side effects and use of 
exenatide extended-release and the injection delivery system.  Patients will be asked about the most 
common adverse events related to exenatide such as headache, nausea, dyspepsia and vomiting if not 
volunteered.  In addition, patients will be actively questioned at each study visit to assess signs, 
symptoms, and reports suggestive of genital infection and of urinary tract infection (UTI). These 
responses and those obtained spontaneously will be categorized in the database using a predefined list 
suggestive of vulvovaginitis, and related genital infection and UTI.  If patients become pregnant during 
the study, all medications will be stopped immediately. 
This protocol and the associated Informed Consent as well as any addenda or amendments, must 
be reviewed and approved by the Woman’s Hospital Institutional Review Board (WHIRB) review 
committee prior to the start of the study.  All revisions to this Protocol are considered “protocol 
amendments; these must be approved in advance, in writing, by the WHIRB.  Every patient will have 
given her written informed consent prior to participating in the study.  Prior to participation in this trial, 
each subject will have an opportunity to ask questions and will sign (and date) a written Informed 
Consent, which must be witnessed.  The signed consent forms will be filed with the investigator's study 
charts for each subject.  Any subject may voluntarily withdraw from the study at any time without 
prejudicing treatment. 
 
STUDY PLANS AND PROCEDURES 
 
Randomized, Single-blind, Parallel, Prospective Study Trial 
All patients will randomly be assigned to one of 5 investigation product treatment groups-– 
exenatide once weekly (EQW), dapagliflozin (DAPA), EQW plus DAPA, combined DAPA/metformin XR 
and the weight loss medication, phentermine/topiramate extended release (PHEN/TPM ER); all subjects 
will be allocated to one of these 5 groups based on computer-generated random numbers using a block 
randomization method.  The pharmacy will “single-blind” all the treatment arms to the primary 
investigators by filling color-coded bags (A, B, C, D, E) with 1 of 5 medications-A) exenatide once weekly 
(EQW), B) dapagliflozin, C) EQW plus DAPA, D) DAPA/metformin XR and E) PHEN/TPM ER and dispensing 
open-label medications to study patients in color-coded bags with instructions on how to take the 
medicine. 
Treatment Regimen 
Overweight/obese non-diabetic women with PCOS will be treated for 24 weeks with exenatide 
once weekly (EQW), dapagliflozin (DAPA), dapagliflozin plus exenatide once weekly, combination 
dapagliflozin/metformin XR or the weight loss medication, phentermine/topiramate extended release 
(PHEN/TPM ER). (See separate page with Figure 1 flowchart). 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
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Inclusion Criteria 
1. Non-diabetic women (18-45 years) 
2. PCOS- NIH criteria hyperandrogenism and irregular menses 
3. Overweight/obese (BMI >25<45)  
4. Written consent for participation in the study 
 
Exclusion Criteria 
1. Presence of significant systemic disease, heart problems including congestive heart failure, 
unstable angina or acute myocardial infarction, current infectious liver disease, acute stroke 
or transient ischemic attacks,  history of pancreatitis, or diabetes mellitus (Type 1 or 2) 
2. Any hepatic diseases in the past (infectious liver disease, viral hepatitis, toxic hepatic 
damage, jaundice of unknown etiology) or severe hepatic insufficiency and/or significant 
abnormal liver function tests defined as aspartate aminotransferase (AST) >3x upper limit of 
normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN 
3. Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60 
mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage 
renal disease. 
4. Uncontrolled thyroid disease (documented normal TSH), Cushing’s syndrome, congenital 
adrenal hyperplasia or hyperprolactinemia 
5. Significantly elevated triglyceride levels (fasting triglyceride > 400 mg/dL) 
6. Untreated or poorly controlled hypertension (sitting blood pressure > 160/95 mm Hg) 
7. Use of hormonal medications, lipid-lowering (statins, etc.), anti-obesity drugs or weight loss 
medications (prescription or OTC) and medications known to exacerbate glucose tolerance 
(such as isotretinoin, hormonal contraceptives, GnRH agonists, glucocorticoids, anabolic 
steroids, C-19 progestins) stopped for at least 8 weeks. Use of anti-androgens that act 
peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finesteride, 
spironolactone, flutamide) stopped for at least 4 weeks 
8. Prior history of a malignant disease requiring chemotherapy 
9. Patients at risk for volume depletion due to co-existing conditions or concomitant 
medications, such as loop diuretics should have careful monitoring of their volume status 
10. History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, 
confirmed by a follow-up sample at next scheduled visit. 
11. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, 
angioedema, exfoliative skin conditions 
12. Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide, 
liraglutide) 
13. Use of metformin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 
inhibitors or weight loss medications (prescription or OTC) stopped for at least 4 weeks. 
14. Prior use of medication to treat diabetes except gestational diabetes 
15. Eating disorders (anorexia, bulimia) or gastrointestinal disorders 
16. Suspected pregnancy (documented negative serum β-hCG test), desiring pregnancy in next 6 
months, breastfeeding, or known pregnancy in last 2 months 
17. Active or prior history of substance abuse (smoke or tobacco use within past 3 years) or 
significant intake of alcohol 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
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18. Having a history of bariatric surgery 
19. Patient not willing to use barrier contraception during study period (unless sterilized or have 
an IUD) Debilitating psychiatric disorder such as psychosis or neurological condition that 
might confound outcome variables 
20. Inability or refusal to comply with protocol 
21. Current participation or participation in an experimental drug study in previous three 
months 
 
 
Method 
Following written consent, all study patients will undergo the following clinical, metabolic and 
laboratory evaluations before and during treatment (see separate page with Figure 2 study schedule).  
All study subjects will be assigned an individual study identifier that includes the study acronym, patient 
initials, and unique number.  All blood samples will be obtained and results identified and reported using 
this unique study identifier.  A full physical examination will be performed and vital signs (blood 
pressure, respiration and temperature) determined.  Trained personnel using standardized protocols at 
the baseline and follow-up examination will obtain anthropometric measurements and blood 
specimens.  Absolute body weight, height, waist and hip circumference, body fat distribution (waist/hip 
{WHR}) and waist/height ratio ({WHtR}) and blood pressure (BP) will be determined.  Body weight will 
be measured to the nearest 0.1 kg using a calibrated digital scale with participants in light clothing and 
no shoes.  Height will be measured to the nearest centimeter.  The total body adiposity (total fatness), 
defined as the accumulation of body fat without regard to regional distribution, will be expressed as BMI 
and calculated as weight (kg)/ height (m) 2.  The circumference measurements will be taken in the 
upright position using a 15-mm width flexible metric tape held close to the body but not tight enough to 
indent the skin.  Waist circumference (WC) will be measured at the narrowest level midway between 
the lowest ribs and the iliac crest and hip circumference measured at the widest level over the buttocks 
while the subjects are standing and breathing normally.  The WHR and WHtR will be calculated for 
measure of body fat distribution. 
All patients will randomly be assigned to one of 5 investigation product treatment groups-– 
exenatide once weekly (EQW), dapagliflozin (DAPA), EQW plus DAPA, combined DAPA/metformin XR 
and the weight loss medication, phentermine/topiramate extended release (PHEN/TPM ER); all subjects 
will be allocated to one of these 5 groups based on computer-generated random numbers using a block 
randomization method.   Oral glucose tolerance tests (OGTTs) with glucose (G) and insulin (I) measured 
at 0, 30, 60, and 120 after glucose load to assess diabetes, fasting (FBG) and mean blood glucose (MBG) 
concentrations, insulin resistance and pancreatic ß-cell function will be determined prior to 
randomization and at 20-24 weeks after full doses of study medications are reached.  Mean blood 
glucose (MBG) concentrations will be calculated by summing glucose values obtained at 0,30,60 and 120 
minutes during the OGTT and dividing by 4.  At the initial lab evaluation, creatinine and calculated eGFR, 
TSH, prolactin and ß-hCG will be determined for study inclusion.  Baseline blood samples will also be 
analyzed for lipid profiles and liver enzymes.  A baseline blood sample will also be used to measure an 


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Study Number ESR-14-10725 
Edition Number 3 
 
 
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androgen profile (total testosterone [T], dehydroepiandrosterone sulfate [DHEAS], sex hormone-binding 
globulin [SHBG]), a lipid panel (total cholesterol, high-density lipoprotein [HDL-C], low-density 
lipoprotein [LDL-C], and triglycerides [TRG] and liver enzymes. 
Body composition analyses will be performed using dual-energy x-ray absorptiometry (DEXA) 
(Hologic Discovery A model, software version 12.5; Hologic, Inc., Waltham, MA) at the start and 
completion of the study trial.  For the scan, the participants will be asked to change into a hospital gown 
and asked to lie supine on on the table with hands by the side palms facing down away from the thighs 
and look at the ceiling to maintain head position.  DEXA can estimate 3 body compartments consisting of 
fat mass, lean body mass, and bone mass.  The relative attenuation of two different x-ray energies by 
body tissues produces a three-component model comprising total fat mass (FM), total lean mass (LM 
including fluid and muscle), and total body bone mineral content (BMC) and density.  DEXA also has the 
ability to determine body composition in defined regions such as the arms, legs, and trunk. DEXA 
measurements are based in part on the assumption that the hydration of fat-free mass remains 
constant at 73%.  Total body fat mass [FM]) and fat content of head, trunk and extremities (arms+ legs) 
is provided by the software. Default software readings provide lines positioned to divide the body into 
six compartments, i.e. head, trunk, arms and legs. The trunk is defined by a horizontal line below the 
chin, vertical lines between trunk and arms and oblique lines passing through the colli femuri.  The 
region below this lower border of the trunk, including both legs and the hip region is called lower body 
region. For each region of the whole body, fat and lean body mass and BMC are determined. .  Standard 
software options are used to calculate the total fat-free mass (FFM), fat mass (FM) vs. lean mass (LM).   
 
For a better description of the sex specific fat distribution the fat distribution index (FDI) will be 
calculated as:  
FDI = Upper body fat mass in kg/Lower body fat mass in kg 
 
A fat distribution index below 0.9 indicates a gynoid fat distribution, i.e. the fat mass of the lower body 
surpassed the fat mass of the upper body. A fat distribution index >1.1 defines an android fat 
distribution. In this case the amount of fat tissue of the abdominal region surpassed the fat mass of the 
lower body. An FDI between 0.9 and 1.1 is classified as an intermediate stage of fat distribution. We will 
use the FDI for further quantification of the fat distribution compared to the widely used waist to hip 
ratio.  The WHR describes body shape and silhouette while the FDI provides the quantitative amount of 
fat distribution.  Nevertheless we have to be aware that the FDI describes not the ratio of abdominal fat 
to gluteal-femoral fat, but the ratio between upper body fat, including abdominal fat and breast fat 
mass, and lower body fat. 
All patients will receive the same counseling concerning the benefits of lifestyle modification 
through diet and exercise.  The patients will be also encouraged to increase daily exercise (such as 
walking, using stairs), although this will not be formally assessed.  The participants will receive further 
encouragement to adhere to the regime during follow-up phone calls.  Side effects of the treatment and 
reason for any withdrawals from the study will be recorded.  


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Study Number ESR-14-10725 
Edition Number 3 
 
 
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After 24 weeks of treatment, all clinical and laboratory tests will be repeated. All 
anthropometric parameters and physical including vital signs and DEXA will again be performed and 
calculations will be repeated for post-treatment effects.  In addition, the patient’s record of menstrual 
cycle frequency- (#menses during study period [24 weeks]) will be reviewed and recorded.  All side-
effects will also be recorded and summarized for the 24 week-treatment period. During the whole study 
period, compliance to the treatment will be documented. Questioning regarding the occurrence of 
adverse events and use of concomitant medication will take place throughout the trial.  
All investigational products (study drugs) will be stored under appropriate storage conditions 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. The investigator is responsible for ensuring that the investigational product is 
stored under the appropriate environmental conditions (temperature, light, and humidity), as noted in 
the product labeling: AstraZeneca and Vivus will provide Investigational product. The packing, labeling, 
and distribution of all medications are the sponsors’ responsibility.  Labels will be prepared in 
accordance with Good Manufacturing Practice (GMP) and local regulatory guidelines for labeling.   
Study Drug Records - It is the responsibility of the investigator to ensure that the unblinded 
study coordinator maintains a current disposition record of investigational product. Records or logs 
must comply with applicable regulations and guidelines and should include: 
• 
amount received and placed in storage area; amount currently in storage area 
• 
label ID number or batch number  
• 
amount dispensed to and returned by each subject, including unique subject identifiers 
• 
non-study disposition (e.g., lost, wasted)  
• 
amount destroyed at study site 
• 
dates and initials of person responsible for Investigational Product dispensing/ 
accountability. 
The pharmacy will “single-blind” all the treatment arms to the physicians and clinical 
coordinators (open-label study drugs to study patients) by color-coded bags (A, B, C, D, E) with 1 of 5 
medications-A) exenatide once weekly (EQW) (Bydureon), B) dapagliflozin (Farxiga), C) EQW plus DAPA 
(Bydureon plus Farxiga), D) DAPA/metformin XR (Xigduo)  and E) PHEN/TPM ER (Qsymia), and 
dispensing open-label medications to study patients in color-and letter coded bags with instructions on 
how to take the medicine.  
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 will be maintained. 
 
Study Endpoints and Assessments 
 


Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
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Primary Endpoint 
The primary efficacy endpoint is improvement in the oral disposition index as determined with 
the insulin secretion-insulin sensitivity (ISSI) index (β-cell compensatory function from an OGTT) which is 
analogous to the disposition index obtained from an IVGTT). The ISSI is defined as the product of insulin 
action (Matsuda index- SIOGTT) and insulin secretion (insulinogenic index) derived from the OGTT (SIOGTT x 
Δinsulin30–0 min to glucose30–0 min).  Improving ß-cell compensatory function (increasing insulin 
sensitivity and enhancing insulin release after an oral glucose load) is reflective of improvement and/or 
delays in declining glucose tolerance.  
 
Secondary Endpoints 
Secondary outcome measures include mean blood glucose (MBG), fasting (HOMA) and glucose-
stimulated insulin sensitivity (SIOGTT ) and early pancreatic ß-cell response (IGI/HOMA-IR), glycemic 
parameters (fasting blood glucose [FBG] and 2 hour post OGTT glucose), free androgen index (total 
testosterone and SHBG) and DHEAS. plasma lipid fractions, trunk fat mass and truck fat/extremities fat 
ratio by DEXA, anthropometric endpoints include percent change in body weight from baseline to week 
12, absolute change in body weight and change in BMI, body fat distribution [waist circumference (WC), 
(waist/hip ratio [WHR] and waist/height ratio (WHtR)], and blood pressure (BP) from baseline to weeks 
12 and 24 and menstrual cycle rates (menstrual cyclicity is determined by # menses/24 weeks pre- and 
post-treatment. 
 
Biological Sampling Procedures 
 
Laboratory Measures  
Hormonal and metabolic parameters will be measured at baseline and 16 week follow-up 
following an overnight fast.  Blood samples will be obtained in the fasting state and ½, 1 and 2 h after a 
standardized 75-g oral glucose load.  Blood samples will be centrifuged, divided into aliquots, and stored 
at –70°C until assayed.  Plasma glucose levels will be determined with a glucose analyzer using the 
glucose oxidase method (Glucose Reagent Kit, Bayer Newbury, UK).  Serum insulin will be determined in 
all samples in duplicate by microparticle enzyme immunoassay (Abbott AxSYM System, Abbott 
Laboratories, Abbott Park, IL).  Levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) 
and triglycerides will be determined in the initial basal sample using standard enzymatic colorimetric 
assays on an automated clinical chemistry analyzer whereas low-density lipoprotein cholesterol (LDL-C) 
will be calculated according to the Friedewald equation.  Serum creatinine, liver enzymes, AST, and ALT 
will be measured using standard automated kinetic enzymatic assay.  Circulating levels of TSH, prolactin, 
ß human chorionic gonadotropin (ßhCG), testosterone, sex-hormone binding globulin (SHBG) and DHEAS 
will be measured using a two-site sandwich immunoassay with direct chemiluminometric technology 
(Diagnostic Products, Los Angeles, CA).  The intra- and interassay coefficients of variation are less than 7 
and 11%, respectively, over the sample concentration range.   


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Edition Number 3 
 
 
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Assessment of insulin sensitivity and secretion 
Indexes of insulin sensitivity and secretion using the serum glucose and insulin concentrations 
obtained in the fasting state and during the 2hr OGTT with INS will be computed by several measures 
previously validated in women.  Fasting and glucose-stimulated insulin sensitivity will be estimated by 
homeostasis model assessment of insulin sensitivity (HOMA-IR) and by Matsuda's insulin sensitivity 
index (SIOGTT).  Early pancreatic β-cell response will be estimated as the insulinogenic index (IGI) derived 
from the ratio of the increment of insulin to that of glucose 30 minutes after a glucose load (insulin 30 
min − insulin 0 min/glucose 30 min − glucose 0 min) corrected for by the relative level of insulin 
resistance (IGI/HOMA-IR).  An estimation of β-cell compensatory function, the insulin secretion-
sensitivity index (IS-SI) will be derived by applying the concept of the disposition index to measurements 
obtained during the 2-h OGTT and calculated as the index of insulin secretion factored by insulin 
resistance (ΔINS/ΔPG 30 x Matsuda SIOGTT) from the OGTT.  
Collateral Research 
Several other endpoints will be assessed at each study visit.  Baseline blood samples will also be 
collected for measurement of androgen profiles (DHEAS, total testosterone, SHBG and calculated FAI), 
lipid profiles (cholesterol, HDL and LDL cholesterol, and triglycerides) and liver enzymes (AST/ALT). The 
free androgen index (FAI) is calculated from the total T concentration (nmol/l)/ concentration of SHBG 
(nM/L) x100.  Menstrual cycle frequency before and after medication treatments will be compared.  
Dyslipidemia is defined as the presence of at least one of the mentioned lipid parameters abnormalities. 
Safety assessments 
The safety and tolerability assessments will include incidence and intensity of adverse events, 
withdrawals because of adverse events, physical exams, vital sign measurements and clinical laboratory 
parameters.  Patients will be seen at 12-14 weeks to confirm they are not pregnant by laboratory 
evaluation and required to perform monthly home pregnancy tests. 
 
Statistical Methods and Sample Size Calculations 
A priori sample size analysis was performed using the online calculator provided by the 
Massachusetts 
General 
Hospital 
Mallinckrodt 
General 
Clinical 
Research 
Center 
(http://hedwig.mgh.harvard.edu/sample_size/size.html).  Given there are no previous studies utilizing 
dapagliflozin, exenatide once-weekly or combination treatments for women with PCOS, sample size 
analysis was based on the assumption that the smallest mean difference between treatment groups is 
20% with an with an average SE of 2.2% [average SD of 9.8%]; the sample size with a statistical power of 
0.80 and two-sided P-value <0.05 is calculated to be 20-25 for each group.  Using a 20% drop-out rate, 
the study is designed to recruit 25 patients in each arm to ensure that the number of subjects 
completing the study (22) as derived by the sample size calculation is met 
All analyses will be conducted using SPSS for Windows (version 11.01, SPSS, Inc.; Chicago, Ill).  
The primary outcome measure is comparison of the insulin secretion-insulin sensitivity (ISSI) index (oral 


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Edition Number 3 
 
 
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disposition index) determined from a 75-g OGTT before and after treatment between non-diabetic 
women with PCOS treated with exenatide once weekly (EQW), dapagliflozin (DAPA), EQW plus DAPA, 
combined DAPA/metformin XR or combination phentermine (PHEN)/topiramate (TPM) extended 
release (ER).  The secondary outcome measures include changes in surrogate measures of insulin action 
(HOMA-IR, SIOGTT, IGI/HOMA-IR and oral DI) and glycemic parameters (fasting blood glucose [FBG] and 2 
hour post OGTT glucose) mean blood glucose (MBG), anthropometric parameters (weight and fat 
distribution by DEXA), blood pressure, lipid profiles, liver enzymes, androgen levels (DHEAS, total 
testosterone, SHBG and calculated FAI) and menstrual cyclicity.  Mean blood glucose (MBG) 
concentrations will be calculated by summing glucose values obtained at 0,30,60 and 120 minutes 
during the OGTT and dividing by 4.  The normality of all variables will be checked using the Kolmogorov-
Smirov test.  Continuous variables will be tested for normality of distribution using the Kolmogorov-
Smirov test.  When necessary, non-normally distributed data will be subjected to logarithmic or square 
root transformation to obtain a normal distribution where necessary for subsequent analyses.  Direct 
and indirect estimates of insulin sensitivity and secretion (HOMA, SIOGTT, IGI/HOMA, ß-cell compensatory 
3function, glycemic parameters (FBG, MBG, 2 hour post OGTT glucose level) anthropometric 
measurements (body weight, BMI), fat distribution (WC, WHR and WHtR), BP, androgen and lipid 
profiles will be considered as dependent variables.   
For all analyses, in which the measures are continuous, data from evaluable subjects will be 
submitted to a repeated-measures general linear model (SS/ Drug treatments x repeated measures 
ANOVA) including the arm of drug treatment as the between-subjects effect, and the visit (baseline and 
24 wks.) as the within-subjects effect.  To evaluate the differences in the response to each treatment 
over visits, the interaction effect will be calculated.  For both the primary and secondary outcome 
measures, if a statistically significant interaction effect is found (P 0.05), a contrast analysis will be 
applied to locate the differences between the 5 medication groups.  The pairwise contrasts of the 
average across the within –subject factors (drug treatment x time interaction) will be tested with the 
Bonferonni correction, which adjusts the significance level for multiple comparisons to better control for 
Type I errors. The Bonferroni test uses a straight-forward t test but then evaluates that t at α= .05/c, 
where c is the number of comparisons. This test adjusts the critical value of the test statistic keeping the 
familywise error rate at, or near.05.  The result is that this test is more conservative as the number of 
contrasts increases, which means a larger difference between means, is required for significance and 
each set of comparisons is protected against an increase in the risk of Type 1 errors by the nature of the 
test.  
Dysglycemia occurrence before and after different treatment will be compared with the 
McNemar test (complex chi square for paired data), which formally tests for a change between the 
observed proportions of k related samples.  Menstrual cycle rates before and after treatment will be 
compared with the McNemar test (complex χ2 for paired data), which formally tests for a change 
between the observed proportions of 2 related samples.    
Baseline comparisons between groups (intent-to treat population) will be made by one-way 
ANOVAs and post hoc comparisons performed with the Tukey test to analyze the variation among the 5 


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groups if the ANOVA shows overall baseline differences were significant (p<0.05).  Data will be analyzed 
on the basis of intention to treat and also on completed treatment parameters where relevant.  The 
intent-to-treat population (ITT) is defined as all randomized subjects who received one oral dose of 
medication starting from the evening of day 1.  The evaluable population is defined as all randomized 
subjects who complete treatment through week 20-24 weeks. Results will be reported as mean +/- 
S.E.M unless otherwise noted.  Categorical data will be presented as percentage.   
 
Ethical and Regulatory Requirements 
 
This protocol and the associated Informed consent as well as any addenda or amendments, 
must be reviewed and approved by the Woman’s Hospital Foundation Institutional Review Board 
(WHIRB) review committee prior to the start of the study.  Recruitment materials and advertising must 
be reviewed and approved by the WHIRB prior to use.  All revisions to this Protocol are considered 
“protocol amendments” these must be approved in advance, in writing, by the WHIRB.  Every patient 
will have given her written informed consent prior to participating in the study.  Prior to participation in 
this trial, each subject will have an opportunity to ask questions and will sign (and date) a written 
Informed Consent, which must be witnessed.  The signed consent forms will be filed with the 
investigator's study charts for each subject.  A copy of the informed consent will be provided to the 
subject.  Any subject may voluntarily withdraw from the study at any time without prejudicing 
treatment. 
Good Clinical Practice - This study will be conducted in accordance with Good Clinical Practice 
(GCP), as defined by the International Conference on Harmonization (ICH) and in accordance with the 
ethical principles underlying the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. All potential serious breaches must be 
reported to AstraZeneca (AZ) 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 (e.g., loss of 
medical licensure; debarment).  
Patients starting all oral therapies will be advised that they may have minor gastrointestinal side 
effects.  The most reported common adverse effects of dapagliflozin (Farxiga) are genital mycotic 
infections, lower urinary tract infections (UTIs), and those related to osmotic diuresis.  Patients are 
strongly counseled on the practice of good genital hygiene in order to avoid yeast infections.  That 
means, whenever possible, they should cleanse well after voiding to remove residual glucose.  They are 
also taught to watch for signs-such as itching, burning and redness so they can get treated promptly.  
There is no need to stop the medication, just to treat the infection.  In addition, the tablets contain 
lactose, which may cause discomfort in lactose-intolerant individuals.  The most common side effects of 
metformin are diarrhea, nausea or vomiting, flatulence, indigestion, abdominal discomfort and rarely, a 


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metallic taste in the mouth.  These acute reversible adverse effects occur in 5–20% of patients treated 
with metformin.  The symptoms are dose related and remit if the dose is reduced, sometimes an 
increase in the dose can later be tolerated.  Taking the drug with or after food, and starting therapy with 
low dosages that may be increased slowly can minimize these.  The dose can then be increased slowly at 
intervals of two weeks.  Lactic acidosis is the biguanide-related adverse effect of most concern with an 
estimated incidence of less than 0.01 to 0.08 cases.  Should a patient have lactic acidosis attributable to 
metformin, the drug can be removed by hemodialysis.  Other contraindications to the use of metformin 
include concurrent liver disease and a previous history of lactic acidosis.  Oral therapy will also be 
stopped if the blood lactate concentration is substantially increased by any illness.  Oral therapy will be 
temporarily suspended for all major surgical procedures that involve restriction of fluid intake.   
The United States Food and Drug Administration (FDA) have assigned pregnancy category X to 
phentermine/topiramate (Qsymia).  Data from pregnancy registries and epidemiology studies indicate 
an increased risk in oral clefts (cleft lip with or without cleft palate) with first trimester exposure to 
topiramate, a component of Qsymia.   The US FDA classifies Farxiga and Xigduo as a pregnancy category 
C drugs (i.e., “potential benefit should outweigh the potential risk”).  Women of childbearing potential 
are required to use adequate contraception during use (unless sterilized).  Metformin is classified as a 
US FDA pregnancy category B drug (i.e., "no evidence of risk in humans").  This means that, while there is 
no evidence of teratogenesis or adverse fetal effects, insufficient data exist to state that harm does not 
occur.  Metformin does cross the placenta, prompting a cautious approach to its use in pregnancy.  
There have been several published reports of the use of metformin during pregnancy, predominantly in 
women with insulin resistance and PCOS.  Some clinicians routinely use metformin to treat diabetes in 
pregnant women.  However, most experts believe that if medication is needed to control blood sugar 
during pregnancy, insulin is the drug of choice, not an oral antihyperglycemic agent.  If patients become 
pregnant during the study, all medications will be stopped and the patient will discontinue from the 
study. 
For safety, all subjects who enter the study are evaluable.  Subjects will be monitored for safety 
by assessment of adverse events, physical exams, vital signs and laboratory values.  Continued patient 
safety assessment will be carried out and all adverse events documented and reported to the WHIRB.  
On each visit, compliance with treatment will be checked with questions about the side-effects and a 
subjective evaluation of the tolerability of the administered drug; the patients will also asked about 
incidental missed administrations. 
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. 
 
Adverse Event Procedures    


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An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a 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 (such as an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the 
AE. 
Not related: There is not a reasonable causal relationship between study drug administration 
and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
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.) 
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) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect  
• 
is an important medical event (defined as a medical event(s) 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 [e.g., medical, surgical] to 
prevent one of the other serious outcomes listed in the definition above.) Examples of such events 
include, but are not limited to, intensive treatment in an emergency room 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 6 for the 
definition of potential DILI.) 


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Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is 
an SAE.  
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not always 
serious by regulatory definition, these events must be handled as SAEs. (See Section 4 for reporting 
pregnancies). 
NOTE:  
The following hospitalizations are not considered SAEs:  
− 
a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event) 
− 
elective surgery, planned prior to signing consent 
− 
admissions as per protocol for a planned medical/surgical procedure 
− 
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
− 
medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study. 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 (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
1A. Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, 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.  The investigator should report any SAE that occurs after these time 
periods and that is believed to be related to study drug or protocol-specified procedure.  All SAEs, 
whether related or not related to study drug, and pregnancies must be reported to AZ (or designee) 
within 24 hours. They will also be reported immediately to the Woman’s Hospital Foundation 
Institutional Review Board at (225) 231-5296 and Woman’s Health Research Institute at (225) 231-5275.  
SAEs must be recorded on an SAE Report Form or similar form (e.g. CIOMS, MedWatch); pregnancies on 
an AZ approved Pregnancy Surveillance Form.  Reports are to be transmitted via email or confirmed 
facsimile (fax) transmission. 
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, of 
any serious or unexpected adverse events that occur in accordance with the reporting obligations of 21 
CFR 312.32, and will concurrently forward all such reports to AZ.  A copy of the MedWatch/AdEERs 
report must be faxed to AstraZeneca at the time the event is reported to the FDA.  It is the responsibility 
of the investigator to compile all necessary information and ensure that the FDA receives a report 


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according to the FDA reporting requirement timelines and to ensure that these reports are also 
submitted to AstraZeneca at the same time. 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs form 
indicating the following: 
• 
Investigator Sponsored Study (ISS) 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number 
Investigative site must also indicate, either in the SAE report or the cover page, the causality of events in 
relation to all study medications and if the SAE is related to disease progression, as determined by the 
principal investigator. An SAE report should be completed for any event where doubt exists regarding its 
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.   
Send SAE report and accompanying cover page by way of fax to AstraZeneca’s designated fax line: 1-
866-984-7229 
 
Serious adverse events that do not require expedited reporting to the FDA need to be reported to 
AstraZeneca preferably using the MedDRA coding language for serious adverse events.   
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of the 
randomization code/ code break information or unblind those SAEs which require expedited reporting. 
 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to the 
investigational product.  All SAEs will be documented.  The investigator is responsible for informing the 
IRB and/or the Regulatory Authority of the SAE as per local requirements.  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 AZ (or designee) using the same procedure used for 
transmitting the initial SAE report.  
In cases where the investigator learns of the SAE after its occurrence and resolution, the time and 
circumstances of the event will be recorded.  The reporting requirements will still be followed 
All SAEs should be followed to resolution or stabilization. 
In addition, investigators will also follow 21 CFR 312.32 and notify Vivus, Inc. of Qsymia SAEs within 24 
hours and receive a written report within 48.  In accordance with 21 CFR 312.32, the investigators will 
notify FDA no later than 15 calendar days of all events that are serious, unexpected, and have possible 


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relationship to Qsymia. For unexpected fatal or life-threatening suspected adverse reaction reports 
related to Qsymia, the investigators will notify the FDA no later than 7 calendar days after the 
investigators initial receipt of the information. 
Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
2A. Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. Nonserious AE 
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.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious (see Section 1A). Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug and for those present at the end of study treatment as appropriate. All 
identified nonserious AEs must be recorded and described on the nonserious AE 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. 
2. Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE CRF page or 
SAE Report Form as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE  
• 
Any laboratory test result abnormality that required the subject to have study drug discontinued or 
interrupted 
• 
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy. 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value). 
3. 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 (e.g., 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 (e.g., x-ray studies). Other appropriate pregnancy follow-up 
procedures should be considered if indicated. 


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The investigator must immediately notify AZ (or designee) Medical Monitor of this event and complete 
and forward a Pregnancy Surveillance Form to AZ (or designee) within 24 hours and in accordance with 
SAE reporting procedures described in Section 1A.  
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. 
 
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 1A for reporting details.). 
4. 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 (see Section 1A for reporting details). 
Potential drug induced liver injury is defined as:  
 
AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND  
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND  
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.  
 
5. Adverse Events of Special Interest 
In this study, the following adverse events are to be reported to AZ, 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 dapagliflozin 
3. 
pancreatitis 
4.  
anaphylaxis 
5. 
angioedema 


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6.  
Steven-Johnson’s Syndrome 
When one of these events meets the criteria for a serious adverse event, report the event using SAE 
reporting procedures. When one of these events does not meet the criteria for a serious adverse event, 
report the event within 24 hours as a non-serious event. 
6. Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, x-ray 
filming, any other potential safety assessment required or not required by protocol should also be 
recorded as a nonserious or serious AE, as appropriate, 
 
Discontinuations 
The reason for a subject discontinuing from the study will be recorded in the patient chart.  A 
discontinuation occurs when an enrolled subject ceases participation in the study, regardless of the 
circumstances, prior to completion of the protocol.  The investigator must determine the primary reason 
for discontinuation.  Withdrawal due to adverse event will be distinguished from withdrawal due to 
insufficient response according to the definition of adverse event noted earlier.  The final evaluation 
required by the protocol will be performed at the time of study discontinuation.  The investigator will 
record the reason for study discontinuation, provide or arrange for appropriate follow-up (if required) 
for such subjects, and document the course of the subject’s condition.  They will also to be reported to 
Woman’s Hospital Foundation Institutional Review Board at (225) 231-5296 and Woman’s Health 
Research Institute at (225) 231-5275.  
Subjects MUST discontinue investigational product for any of the following reasons: 
• 
Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• 
Any clinical adverse event, 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 
o Instruct subjects to contact the investigator or study staff immediately if they suspect 
they might be pregnant (e.g., 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 subjects enrolled in the study. 
o The investigator must immediately notify AZ if a study subject becomes pregnant. 
• 
Loss of ability to freely provide consent through imprisonment or involuntary incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness. 
All subjects who discontinue should comply with protocol-specified follow-up procedure. The 
only exception to this requirement is when a subject withdraws consent for all study procedures or loses 
the ability to consent freely (i.e., is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness).  


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Clinical Study Protocol 
Drug Substance Dapagliflozin/Bydureon 
Study Number ESR-14-10725 
Edition Number 3 
 
 
Version 6/29/15 
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