Saxagliptin + Metformin Compared to Saxagliptin or Metformin Monotherapy in PCOS Women With Impaired Glucose Homeostasis

NCT02022007 | Completed Phase 3 Results DMC

• 2 other identifiers: RP13-013BMS CV181-354
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The objective of the present proposal is to compare the clinical, endocrine and metabolic effects of therapy with combination saxagliptin and metformin to saxagliptin and metformin monotherapy in women with PCOS and prediabetic hyperglycemia (IFG, IGT or IFG/IGT). Saxagliptin is an oral dipeptidyl peptidase IV (DPP-4) inhibitor whose mechanism of action is to prolong the duration of blood glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) levels by inhibiting their degradation and thereby augmenting insulin secretion. This study will serve as a pilot investigation to open perspectives for future studies to explore the potential of combining anti-diabetic drugs with different mechanisms of action in in patients with PCOS and impaired glucose regulation (IGR), especially ones for whom standard treatment with metformin is less effective.

Conditions

Polycystic Ovary Syndrome; Disorder of Glucose Regulation

Keywords

PCOS; IGT; DPP-4 inhibitor

Outcome Measures

Primary Outcomes (2)

• Glucose Metabolism

  Glucose metabolic secretory status after drug treatment (normal, impaired or diabetic). We used the American Diabetes Association (ADA) definition of impairment which is fasting glucose greater than 100 mg/dL and/or 2 hour glucose greater than 140 mg/dL.

  16 weeks

• Oral Disposition Index

  Post-treatment in insulin-sensitivity-secretion index . The insulin secretion-sensitivity index (IS-SI) provides an estimate of β-cell compensation relative to the prevailing insulin resistance, not absolute insulin secretion. It is derived by applying the concept of the disposition index (DI) to measurements obtained during the 2-h OGTT. The IS-SI, a surrogate measure of the DI derived from the OGTT (IGI multiplied by the SIOGTT\], was calculated as the product of acute β-cell response \[IGI\] and Matsuda index (SIOGTT) based on the existence of the predicted hyperbolic relationship between these two measures

  16 weeks

Secondary Outcomes (9)

• Fasting Glucose

  16 weeks

• Mean Blood Glucose During the OGTT

  16 weeks

• Matsuda Index of Insulin-Sensitivity (SI OGTT)

  16 weeks

• Pancreatic ß-cell Compensatory Function

  16 weeks

• Body Mass Index at 16 Weeks

  16 weeks

Other Outcomes (1)

• Number of Participants With No Clinically Significant Changes in Liver Enzyme Levels or Positive Pregnancy Tests

  16 weeks

Study Arms (3)

Metformin XR

ACTIVE COMPARATOR

Metformin 2000 mg daily (QD) for 16 weeks

Drug: Metformin XR

Saxagliptin

ACTIVE COMPARATOR

Saxagliptin 5 mg QD for 16 weeks

Drug: Saxagliptin

Saxagliptin-Metformin XR

EXPERIMENTAL

Saxagliptin-Metformin XR (combination pill) 5mg Saxagliptin/2000 mg Metformin XR QD for 16 weeks

Drug: Saxagliptin-Metformin XR

Interventions

Metformin XR DRUG

Start 2 pills (2 pills of 500 mg =1000mg XR) for 3 weeks Increase to 4 pills as tolerated (4 pills of 500 mg XR =2000 mg XR) for remainder of study

Also known as: Glucophage XR, Biguanide-insulin sensitizer

Metformin XR

Saxagliptin DRUG

Start 1 pill (5 mg)) for 3 weeks Remain at 1 pill (5mg dose) for remainder of study

Also known as: Onglyza, DPP-4 inhibitor

Saxagliptin

Saxagliptin-Metformin XR DRUG

Start 1 pill (2.5 mg/ 1000mg XR) for 3 weeks Increase to 2 pills as tolerated (5mg/2000 mg XR) for remainder of study

Also known as: Kombiglyze XR, Combination DPP-4 inhibitor and Glucophage XR

Saxagliptin-Metformin XR

Eligibility Criteria

• Age: 18 Years - 42 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Females 18 years to 42 years of age with polycystic ovary syndrome(NIH PCOS criteria) with prediabetic hyperglycemia determined by an 75 gram oral glucose tolerance test (OGTT). Study subjects will be inclusive of PCOS women with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both (IFG/IGT).
• Written consent for participation in the study

You may not qualify if:

• Presence of significant systemic disease, heart problems including congestive heart failure, history of pancreatitis, or diabetes mellitus (Type 1 or 2)
• Any hepatic diseases in the past (viral hepatitis, toxic hepatic damage, jaundice of unknown etiology), gallstones, abnormal liver function tests or renal impairment (elevated serum creatinine levels or abnormal creatinine clearance)
• Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital adrenal hyperplasia or hyperprolactinemia
• Significantly elevated triglyceride levels (fasting triglyceride \> 400 mg %)
• Untreated or poorly controlled hypertension (sitting blood pressure \> 160/95 mm Hg)
• Use of hormonal medications, drugs known to affect gastrointestinal motility, lipid-lowering (statins, etc.) and/or anti-obesity drugs or medications that interfere with carbohydrate metabolism (such as isotretinoin, hormonal contraceptives, gonadotropin releasing hormone (GnRH) analogues, glucocorticoids, anabolic steroids, C-19 progestins) for at least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finasteride, spironolactone, flutamide) for at least 4 weeks
• Prior history of a malignant disease requiring chemotherapy
• Known hypersensitivity or contraindications to use of insulin sensitizers such as metformin or thiazolidinediones
• History of hypersensitivity reaction to saxagliptin or other DPP-4 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions)
• Current use of metformin, thiazolidinediones, glucagon-like peptide -1 receptor agonists, DPP-4 inhibitors, or weight loss medications (prescription or OTC) Patients must stop use of insulin sensitizers or antidiabetic medicines such as metformin for at least 4 weeks or thiazolidinediones, GLP1 agonists or DPPIV inhibitors for 8 weeks.
• Prior use of medication to treat diabetes except gestational diabetes
• Use of drugs known to exacerbate glucose tolerance
• Eating disorders (anorexia, bulimia) or gastrointestinal disorders
• Suspected pregnancy (documented negative serum pregnancy test), desiring pregnancy during the study treatment interval, 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 or history of alcoholism

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, Paterson MS, Seidemann EL, Gutowski HC. Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: a single-blind, randomized, pilot study. Fertil Steril. 2017 Jan;107(1):253-260.e1. doi: 10.1016/j.fertnstert.2016.09.023. Epub 2016 Oct 27.

  PMID: 28228317 DERIVED

MeSH Terms

Conditions

Polycystic Ovary Syndrome

Interventions

Metformin; saxagliptin; Dipeptidyl-Peptidase IV Inhibitors

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

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs

Limitations and Caveats

Study limitations were the small number of patients and the short interval (16 weeks) of drug treatment. Surrogate measures derived from the OGTT were used to estimate insulin sensitivity and secretion. .

Results Point of Contact

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

karen.elkind-hirsch@womans.org

225-231-5275

Study Officials

• Karen Elkind-Hirsch, Ph.D.

  Woman's Hospital, Louisiana

  PRINCIPAL INVESTIGATOR

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 17, 2013
• First Posted: December 27, 2013
• Study Start: March 1, 2014
• Primary Completion: August 1, 2016
• Study Completion: October 1, 2016
• Last Updated: June 28, 2017
• Results First Posted: June 28, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)