EQW, DAPA, EQW/DAPA, DAPA/MET ER and PHEN/TPM ER in Obese Women With PolycysticOvary Syndrome (PCOS)
Condition: Polycystic Ovary Syndrome; Obesity
MeSH terms: Polycystic Ovary Syndrome; Syndrome
Intervention: Exenatide once weekly (EQW ); Dapagliflozin (DAPA); EQW plus DAPA; Dapagliflozin plus Glucophage (MET ER); Phentermine /Topiramate (PHEN/ TPM) ER
Intervention description: 2 mg SC injection every 7 days; One pill (10 mg) by mouth daily (QD) in am; 2 mg SC injection every 7 days One pill (10 mg) by mouth QD in am; 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; 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
Intervention MeSH terms: Metformin; Dapagliflozin; Exenatide; Topiramate; Sodium-Glucose Transporter 2 Inhibitors; Phentermine; Glucagon; Glucagon-Like Peptide 1
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Enrollment: 119.0
Sex: Female
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: PCOS; GLP1 agonists; SGLT2 inhibitors

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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Non-diabetic women (18-45 years)

          2. PCOS- NIH criteria hyperandrogenism and irregular menses

          3. Obese class I, II, and III (BMI >30<45)

          4. Willing to use effective contraception consistently during therapy which is defined
             as:

               1. an intrauterine device, tubal sterilization, or male partner vasectomy, or

               2. combination of two barrier methods with one being male condom.

          5. 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 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.

          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,
             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

          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, dipeptidyl peptidase 4
             (DPP-4) inhibitors, SGLT2 inhibitors 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 pregnancy 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

         18. Having a history of bariatric surgery

         19. Patient not willing to use two barrier method contraception during study period
             (unless sterilized or have an IUD)

         20. Patients with glaucoma or history of increased intraocular pressure, or use of any
             medications to treat increased intraocular pressure

         21. 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.

         22. Inability or refusal to comply with protocol

         23. Current participation or participation in an experimental drug study in previous three
             months

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