Efficacy and Safety Study of Saxagliptin + Metformin Immediate Release (IR) Versus Metformin IR Alone in Type 2 Diabetes Mellitus

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Phase 3 Trial to Evaluate the Efficacy and Safety of 2.5 mg Saxagliptin, Twice Daily, in Combination With Metformin IR in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin IR Alone

The purpose of this study is to compare the reduction in hemoglobin A1C (A1C) for participants taking saxagliptin in combination with metformin immediate release (IR) versus metformin IR alone.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Saxagliptin plus metformin IR; Drug: Placebo plus metformin IR

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Ludwigshafen, Germany, 67067
    • Local Institution
  • Magdeberg, Germany, 39112
    • Local Institution
  • Pirna, Germany, 01796
    • Local Institution
  • Saarbrucken, Germany, 66119
    • Local Institution
  • Saarlouis, Germany, 66740
    • Local Institution
  • Tann, Germany, 36142
    • Local Institution
  • Wuestensachsen, Germany, 36115
    • Local Institution
• Hungary
  • Balatonfured, Hungary, 8230
    • Local Institution
  • Budapest, Hungary, 1036
    • Local Institution
  • Eger, Hungary, 3300
    • Local Institution
  • Szigetvar, Hungary, 7900
    • Local Institution
  • Zalaegerszeg, Hungary, 8900
    • Local Institution
• Puerto Rico
  • Ponce, Puerto Rico, 00716
    • Local Institution
  • San Juan, Puerto Rico, 00909
    • Local Institution
  • San Juan, Puerto Rico, 00920
    • Local Institution
  • San Juan, Puerto Rico, 00926
    • Local Institution
• United States
  • California
    • Concord, California, United States, 94520
      • John Muir Physician Network Clinical Research Center
    • Fountain Valley, California, United States, 92708
      • Southland Clinical Research Center, Inc.
    • Lomita, California, United States, 90717
      • Torrance Clinical Research
    • San Diego, California, United States, 92117
      • Ritchken & First M.D.'S
  • Florida
    • Altamonte Springs, Florida, United States, 32701
      • Central Florida Clinical Trials, Inc.
    • Chipley, Florida, United States, 32428
      • Family Care Associates Of Nw Florida
    • Coral Gables, Florida, United States, 33134
      • Clinical Therapeutics Corporation
    • Miami, Florida, United States, 33145
      • NextPhase Clinical Trials, Inc.
  • Georgia
    • Perry, Georgia, United States, 31069
      • Middle Georgia Drug Study Center, Llc
  • Louisiana
    • Slidell, Louisiana, United States, 70458
      • Louisiana Heart Center Research
  • Mississippi
    • Rolling Fork, Mississippi, United States, 39159
      • Jackson Clinic
  • Ohio
    • Akron, Ohio, United States, 44319
      • Community Health Care Of Manchester
    • Bellbrook, Ohio, United States, 45305
      • Midwest Regional Research, Inc.
    • Kettering, Ohio, United States, 45429
      • Wells Institute for Health Awareness
    • Newark, Ohio, United States, 43055
      • Newark Physician Associates
  • Oklahoma
    • Oklahoma, Oklahoma, United States, 73170
      • Integris Family Care South
    • Yukon, Oklahoma, United States, 73099
      • Integris Family Care Yukon
  • Oregon
    • Eugene, Oregon, United States, 97404
      • Williamette Valley Clinical Studies
  • Pennsylvania
    • Fleetwood, Pennsylvania, United States, 19522
      • Integrated Medical Group Pc/Fleetwood Clinical Research
  • South Carolina
    • Taylors, South Carolina, United States, 29687
      • Southeastern Research Associates, Inc
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
  • Texas
    • Houston, Texas, United States, 77024
      • Village Family Practice
    • Pearland, Texas, United States, 77584
      • Southwest Clinical Research Centers, Llc
    • San Antonio, Texas, United States, 78229
      • Jolene K. Berg, Md., Dgd Research, Inc.
  • Virginia
    • Virginia Beach, Virginia, United States, 23454
      • Tidewater Integrated Medical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 2 diabetes
• 18-78 years of age
• Taking stable twice daily (BID) dosing of metformin IR (at least 1500 mg) for at least 8 weeks
• A1C: 7-10%
• C-peptide: ≥ 0.8 ng/mL
• Body mass index (BMI): ≤45 kg/m^2

Exclusion Criteria:

• Women of childbearing potential unable or unwilling to use acceptable birth control
• Women who are pregnant or breastfeeding
• Fasting plasma glucose (FPG) >270 mg/dL
• Significant cardiovascular history
• Symptoms of poorly controlled diabetes
• History of diabetic ketoacidosis or hyperosmolar nonketotic coma
• Insulin therapy within one year of screening
• Cardiovascular even within the prior 6 months
• New York Heart Association Stage III/IV congestive heart failure and/or known left ventricular ejection fraction <=40%
• Significant history of renal or hepatic disease
• History of a psychiatric disorder, alcohol or drug abuse within the previous year
• Treatment with potent CYP3A4 inhibitors or inducers
• Immunocompromised participants
• Active liver disease or clinically significant abnormal hepatic, renal , endocrine, metabolic, or hematological screening tests

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Saxagliptin plus metformin IR	Drug: Saxagliptin plus metformin IR; Tablets, Oral, 2.5 mg, Twice daily, 12 weeks; Other Names: Onglyza; BMS-477118
Placebo Comparator: Placebo plus metformin IR	Drug: Placebo plus metformin IR; Tablets, Oral, Placebo, Twice daily, 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Hemoglobin A1C (A1c) and Change From Baseline to Week 12	Mean change was adjusted for baseline.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Baseline and Change From Baseline in Fasting Plasma Glucose (FPG)	Mean change was adjusted for baseline.	Baseline, Week 12
Percentage of Participants Achieving a Therapeutic Glycemic Response (A1C < 7.0%) at Week 12	Adjusted for baseline. Calculated using the method by Zhang et al. (Zhang M, Tsiatis A, Davidian M. Improving efficiency of inference in randomized clinical trials using auxiliary covariates. Biometrics. Published online on January 11, 2008; Digital Object Identifier: 10.1111/j.1541-0420.2007.00976.x.)	Week 12
Percentage of Participants Achieving a Therapeutic Glycemic Response (A1C <= 6.5%) at Week 12	Adjusted for baseline. Calculated using the method by Zhang et al. (Zhang M, Tsiatis A, Davidian M. Improving efficiency of inference in randomized clinical trials using auxiliary covariates. Biometrics. Published online on January 11, 2008; Digital Object Identifier: 10.1111/j.1541-0420.2007.00976.x.)	Week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participant Adverse Event (AE), Related AE, Serious Adverse Event (SAE), Related SAE, and Discontinued Due to AEs Summary	AE = any new untoward medical occurrence/worsening of a pre-existing medical condition which does not necessarily have a causal relationship with this treatment.SAE = any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in development of drug dependency or drug abuse, is an important medical event. Treatment-related=Possible, Probable, or Certain relationship to drug.	Week 1 to Week 12; AEs are included up to the last treatment day + 1 day or the last visit in the double-blind (DB) period. SAEs are included up to the last of 1) the last treatment day + 30 days or 2) the last visit day + 30 days in the DB period.
Participants With Reported Hypoglycemia AEs During Double-Blind Treatment Period	Hypoglycemic Events are based upon the Saxagliptin Predefined List of Events, which included hypoglycemia, blood glucose decreased, and hypoglycemic unconsciousness.	Week 1 to Week 12; AEs are included up to the last treatment day + 1 day or the last visit in the DB period. SAEs are included up to the last of 1) the last treatment day + 30 days or 2) the last visit day + 30 days in the DB period.
Participants With Confirmed Hypoglycemia	Confirmed hypoglycemia was defined by a fingerstick glucose value <= 50 mg/dL with associated hypoglycemia symptoms.	Week 1 to Week 12; AEs are included up to the last treatment day + 1 day or the last visit in the DB period. SAEs are included up to the last of 1) the last treatment day + 30 days or 2) the last visit day + 30 days in the DB period.
Participant Electrocardiogram (ECG) Status at Baseline and Week 12	Abnormal ECGs were defined as those not within the normal limits for the participant, according to the investigator. 'Shifted Normal to Abnormal' and 'Shifted Abnormal to Normal' references a change from measurements at Baseline to those at Week 12.	Baseline, Week 12
Baseline and Mean Change From Baseline in Participant Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Baseline values reference the measurement for the cohort of participants evaluated at the given time point.	Baseline, Week 4, Week 8, Week 12
Baseline and Mean Change From Baseline in Participant Heart Rate (HR)	Baseline values reference the measurement for the cohort of participants evaluated at the given time point.	Baseline, Week 4, Week 8, Week 12
Participants Experiencing Changes From Baseline in Laboratory Parameters That Met the Marked Abnormality Criteria	A laboratory value was considered a marked abnormality if it is outside the pre-defined criteria for marked abnormality and the on-treatment value was more extreme (farther from the limit) than the baseline value. ULN=upper limit of normal; LLN=lower limit of normal.	Baseline, Week 12
Participants Experiencing Changes From Baseline in Urinalysis Parameters That Met the Marked Abnormality Criteria	Marked abnormality criteria were urine protein: if pre-Rx=o use >=2, if pre-Rx =0.5 or 1 use >=3, if pre-Rx =2, use >=4; urine blood: if pre-Rx=0, use >=2, if pre-Rx=0.5 or 1, use >=3, if pre-Rx=2, use >=4; Urine red blood cell count (RBC): if pre-Rx=o use >=2, if pre-Rx =0.5 or 1 use >=3, if pre-Rx =2, use >=4; urine white blood cell count (WBC): if pre-Rx=o use >=2, if pre-Rx =0.5 or 1 use >=3, if pre-Rx =2, use >=4.	Baseline, Week 12

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• White JL, Buchanan P, Li J, Frederich R. A randomized controlled trial of the efficacy and safety of twice-daily saxagliptin plus metformin combination therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapy. BMC Endocr Disord. 2014 Feb 24;14:17. doi: 10.1186/1472-6823-14-17.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: April 21, 2009
• First Submitted That Met QC Criteria: April 21, 2009
• First Posted (Estimate): April 22, 2009

Study Record Updates

• Last Update Posted (Estimate): June 1, 2015
• Last Update Submitted That Met QC Criteria: May 8, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Saxagliptin
• Other Study ID Numbers: CV181-080; EUDRACT #: 2009-010224-25