EQW, DAPA, EQW/DAPA, DAPA/MET ER and PHEN/TPM ER in Obese Women With PolycysticOvary Syndrome (PCOS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Comparison of Dapagliflozin (DAPA) and Once-weekly Exenatide (EQW), Co-administered or Alone, DAPA/ Glucophage (DAPA/MET ER) and Phentermine/Topiramate (PHEN/TPM) ER on Metabolic Profiles and Body Composition in Obese PCOS Women

Conditions
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Polycystic Ovary Syndrome, Obesity

Intervention / Treatment
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* Drug: Exenatide once weekly (EQW )
* Drug: Dapagliflozin (DAPA)
* Drug: EQW plus DAPA
* Drug: Dapagliflozin plus Glucophage (MET ER)
* Drug: Phentermine /Topiramate (PHEN/ TPM) ER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-diabetic women (18-45 years) PCOS- NIH criteria hyperandrogenism and irregular menses Obese class I, II, and III (BMI >30<45) Willing to use effective contraception consistently during therapy which is defined as: an intrauterine device, tubal sterilization, or male partner vasectomy, or combination of two barrier methods with one being male condom. Written consent for participation in the study Exclusion Criteria: 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) 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 Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage renal disease. Patients with a history of nephrolithiasis are also excluded due to increased association with kidney stone formation. Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital adrenal hyperplasia or hyperprolactinemia Significantly elevated triglyceride levels (fasting triglyceride > 400 mg/dL) Untreated or poorly controlled hypertension (sitting blood pressure > 160/95 mm Hg) 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, gonadotropin-releasing hormone 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 (finasteride, spironolactone, flutamide) stopped for at least 4 weeks Prior history of a malignant disease requiring chemotherapy 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 History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit. Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide, liraglutide) Use of metformin, thiazolidinediones, GLP-1 receptor agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, SGLT2 inhibitors stopped for at least 4 weeks. Prior use of medication to treat diabetes except gestational diabetes Eating disorders (anorexia, bulimia) or gastrointestinal disorders Suspected pregnancy (documented negative serum pregnancy test), desiring pregnancy in next 6 months, breastfeeding, or known pregnancy in last 2 months Active or prior history of substance abuse (smoke or tobacco use within past 3 years) or significant intake of alcohol Having a history of bariatric surgery Patient not willing to use two barrier method contraception during study period (unless sterilized or have an IUD) Patients with glaucoma or history of increased intraocular pressure, or use of any medications to treat increased intraocular pressure Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables. Patients with a history of bipolar disorder or psychosis, greater than one lifetime, episode of major depression, current depression of moderate or greater severity (PHQ-9score of 10 or more), presence or history of suicidal behavior or ideation with some intent to act on it, or antidepressant use that has not been stable for at least 3 months will also be excluded. Inability or refusal to comply with protocol Current participation or participation in an experimental drug study in previous three months -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide once weekly (EQW )<br>EQW- 2 mg subcutaneous (SC) injection once every seven days for 24 weeks | Drug: Exenatide once weekly (EQW )<br>* 2 mg SC injection every 7 days<br>* Other names: • Long acting glucagon like peptide 1 (GLP1) agonist;|
| Experimental: Dapagliflozin (DAPA)<br>DAPA-10 mg oral pill once daily in am for 24 weeks | Drug: Dapagliflozin (DAPA)<br>* One pill (10 mg) by mouth daily (QD) in am<br>* Other names: • SGLT2 inhibitor;|
| Experimental: EQW plus DAPA<br>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 | Drug: EQW plus DAPA<br>* 2 mg SC injection every 7 days One pill (10 mg) by mouth QD in am<br>* Other names: Long acting GLP1 agonist plus SGLT2 inhibitor;|
| Experimental: Dapagliflozin plus Glucophage (MET ER)<br>Combination DAPA / MET ER-10 mg /2000 mg oral pill daily with food for 24 weeks | Drug: Dapagliflozin plus Glucophage (MET ER)<br>* 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<br>* Other names: •Combination SGLT2 inhibitor and metformin ER;|
| Active Comparator: Phentermine /Topiramate (PHEN/ TPM) ER<br>Combination Phentermine /Topiramate ER -7.5 mg/46mg pill once daily in am for 24 weeks | Drug: Phentermine /Topiramate (PHEN/ TPM) ER<br>* 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<br>* Other names: Qsymia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oral Disposition (Insulin Sensitivity-insulin Secretion) Index | An estimation of β-cell compensatory function, the insulin secretion-sensitivity index (IS-SI) will be derived by applying the concept of the oral disposition index to measurements obtained during the 2-h OGTT and calculated as the index of insulin secretion factored by insulin sensitivity (ΔINS/ΔPG 30 x Matsuda SIOGTT) from the OGTT. A higher score shows improved pancreatic insulin responsiveness relative to resistance. | 24 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Body Weight | Treatment effect on body weight at 24 weeks of treatment | 24 weeks of treatment | 
| Body Mass Index (BMI) | Treatment efficacy in reducing body mass at 24 weeks of treatment | 24 weeks of treatment | 
| Change in Percent Body Weight | Treatment effect on change in percent body weight from baseline | Change from baseline (time 0) to study end (24 weeks) | 
| Central Adiposity (Waist Circumference) | Treatment effect on loss of central adiposity after 24 weeks | 24 weeks of treatment | 
| Waist-to-Hip Ratio (WHR) | Treatment impact on central adiposity after 24 weeks | 24 weeks of treatment | 
| Waist-to-Height Ratio (WHtR) | Treatment impact on WHtR which is a measure of central adiposity | 24 weeks of treatment | 
| Total Fat Mass (kg) Evaluated by DEXA | Treatment impact on total fat mass by DEXA | 24 weeks of treatment | 
| Total Body Fat (%) by DEXA | Treatment impact on percent total body fat by DEXA | 24 weeks of treatment | 
| Android-Gynoid Ratio (AGR) as Determined by DEXA | treatment impact on measure of central adiposity as determined by android/gynoid ratio | 24 weeks of treatment | 
| Trunk/Leg Fat Ratio by DEXA | Treatment impact on trunk/limb ratio (measure of central adiposity) by DEXA | 24 weeks of treatment | 
| Fasting Blood Glucose | Treatment impact on fasting concentration of glucose in the blood | 24 weeks of treatment | 
| OGTT Mean Blood Glucose (MBG) | Treatment effect on MBG measured during the oral glucose tolerance test | 24 weeks of treatment | 
| Fasting Insulin Sensitivity (HOMA-IR) | Treatment effect on the ratio HOMA-IR which is insulin resistance measure derived from fasting blood glucose and insulin and is calculated by insulin (mU/ml)*glucose (mmol/L)/22,5. The higher thenumber the more insulin resistant. | 24 weeks of treatment | 
| Matsuda Sensitivity Index Derived From the OGTT(SI OGTT) | The SI IOGTT is a measure of peripheral insulin sensitivity derived from the values of Insulin (microunits per milliliter) and Glucose (milligrams per deciliter) obtained from the OGTT and the corresponding fasting values. SI (OGTT) = 10,000/ [(G fasting x I fasting) x (G OGTTmean x I OGTTmean)], where fasting glucose and insulin data are taken from time 0 of the OGTT and mean data represent the average glucose and insulin values obtained during the entire OGTT. The square root is used to correct for nonlinear distribution of insulin, and 10,000 is a scaling factor in the equation. The higher value, the more sensitive to insulin. | 24 weeks of treatment | 
| Corrected First Phase Insulin Secretion (IGI/HOMA-IR) | Treatment effect on insulin secretion from 0 to 30 minutes after glucose load corrected for by fasting insulin sensitivity. A higher score shows improved first phase insulin secretion in response to glucose | 24 weeks of treatment | 
| Total Cholesterol Levels | Treatment effect on blood concentrations of total cholesterol | 24 weeks of treatment | 
| Triglyceride (TRG) Levels | Treatment effect on blood concentrations of triglycerides | 24 weeks of treatment | 
| Total Testosterone Concentrations | Treatment effect on blood concentrations of total testosterone | 24 weeks of treatment | 
| Dehydroepiandrosterone Sulfate (DHEA-S) Levels | Treatment effect on blood concentrations of DHEA-S | 24 weeks of treatment | 
| Free Androgen Index (FAI) | Treatment effect on FAI calculated from total testosterone divided by sex hormone binding globulin (SHBG) levels. A higher score indicates a worse outcome. | 24 weeks of treatment | 
| Systolic Blood Pressure (SBP) | Treatment effect on SBP after 24 weeks of treatment | 24 weeks treatment | 
| Diastolic Blood Pressure (DBP) | Treatment effect on DBP after 24 weeks | 24 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCOS, GLP1 agonists, SGLT2 inhibitors