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

NCT02635386 | Completed Phase 3 Results DMC

• 2 other identifiers: RP15-008AZ ESR-14-10725
• Study Type: interventional
• Target: 119
• Locations: 1 country
• Sites: 1

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.

Conditions

Polycystic Ovary Syndrome; Obesity

Keywords

PCOS; GLP1 agonists; SGLT2 inhibitors

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (22)

• Absolute Body Weight

  24 weeks of treatment

• Body Mass Index (BMI)

  24 weeks of treatment

• Change in Percent Body Weight

  Change from baseline (time 0) to study end (24 weeks)

• Central Adiposity (Waist Circumference)

  24 weeks of treatment

• Waist-to-Hip Ratio (WHR)

  24 weeks of treatment

Study Arms (5)

Exenatide once weekly (EQW )

EXPERIMENTAL

EQW- 2 mg subcutaneous (SC) injection once every seven days for 24 weeks

Drug: Exenatide once weekly (EQW )

Dapagliflozin (DAPA)

EXPERIMENTAL

DAPA-10 mg oral pill once daily in am for 24 weeks

Drug: Dapagliflozin (DAPA)

EQW plus DAPA

EXPERIMENTAL

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

Dapagliflozin plus Glucophage (MET ER)

EXPERIMENTAL

Combination DAPA / MET ER-10 mg /2000 mg oral pill daily with food for 24 weeks

Drug: Dapagliflozin plus Glucophage (MET ER)

Phentermine /Topiramate (PHEN/ TPM) ER

ACTIVE COMPARATOR

Combination Phentermine /Topiramate ER -7.5 mg/46mg pill once daily in am for 24 weeks

Drug: Phentermine /Topiramate (PHEN/ TPM) ER

Interventions

Exenatide once weekly (EQW ) DRUG

2 mg SC injection every 7 days

Also known as: • Bydureon, • Long acting glucagon like peptide 1 (GLP1) agonist

Exenatide once weekly (EQW )

Dapagliflozin (DAPA) DRUG

One pill (10 mg) by mouth daily (QD) in am

Also known as: • Farxiga, • SGLT2 inhibitor

Dapagliflozin (DAPA)

EQW plus DAPA DRUG

2 mg SC injection every 7 days One pill (10 mg) by mouth QD in am

Also known as: Bydureon plus Farxiga, Long acting GLP1 agonist plus SGLT2 inhibitor

EQW plus DAPA

Dapagliflozin plus Glucophage (MET ER) DRUG

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

Also known as: Xigduo, •Combination SGLT2 inhibitor and metformin ER

Dapagliflozin plus Glucophage (MET ER)

Phentermine /Topiramate (PHEN/ TPM) ER DRUG

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

Also known as: Qsymia

Phentermine /Topiramate (PHEN/ TPM) ER

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Woman's: lead
• AstraZeneca: collaborator

Study Sites (1)

Woman's Hospital

Baton Rouge, Louisiana, 70817, United States

Location

Related Publications (1)

• Elkind-Hirsch KE, Chappell N, Seidemann E, Storment J, Bellanger D. Exenatide, Dapagliflozin, or Phentermine/Topiramate Differentially Affect Metabolic Profiles in Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2021 Sep 27;106(10):3019-3033. doi: 10.1210/clinem/dgab408.

  PMID: 34097062 DERIVED

MeSH Terms

Conditions

Polycystic Ovary Syndrome; Obesity

Interventions

Exenatide; Glucagon-Like Peptide 1; dapagliflozin; Sodium-Glucose Transporter 2 Inhibitors; Metformin; Qsymia

Condition Hierarchy (Ancestors)

Ovarian Cysts; Cysts; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Gonadal Disorders; Endocrine System Diseases; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs; Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

One limitation of this study is the lack of a placebo only arm. As we were interested in the effects of different treatment regimens for obese women with PCOS, this study was designed to provide all patients with drug therapy. Limitations of the present study further include the absence of gold-standard measures of insulin sensitivity ; instead we used the OGTT using established surrogate measures.. Last, serial assessments were over only 24 weeks of treatment.

Results Point of Contact

• Title: Dr Karen Elkind-Hirsch
• Organization: Woman's Hospital

karen.elkind-hirsch@womans.org

2252315278

Study Officials

• Karen Elkind-Hirsch, PhD

  Woman's Hospital, Louisiana

  PRINCIPAL INVESTIGATOR

• Drake Bellanger, MD

  Woman's Hospital, Louisiana

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Research

Study Record Dates

• First Submitted: December 15, 2015
• First Posted: December 18, 2015
• Study Start: March 22, 2016
• Primary Completion: July 22, 2020
• Study Completion: October 9, 2020
• Last Updated: January 29, 2021
• Results First Posted: January 29, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)