Add-on to Thiazolidinedione (TZD) Failures

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Combination With Thiazolidinedione Therapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Thiazolidinedione Therapy Alone

The purpose of this clinical research study is to learn if BMS-512148 (Dapagliflozin) can help reduce the blood sugar levels in subjects with Type 2 Diabetes who are not well controlled on TZD alone. The safety of this treatment will also be studied

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Dapagliflozin; Drug: Thiazolidinedione (Pioglitazone); Drug: Placebo matching Dapagliflozin

• Study Type: Interventional
• Enrollment (Actual): 972
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, B1708IFF
    • Local Institution
  • Cordoba, Argentina, 5000
    • Local Institution
  • Buenos Aires
    • Ciudad Auton, Buenos Aires, Argentina, C1408INH
      • Local Institution
    • Zarate, Buenos Aires, Argentina, 2800
      • Local Institution
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3K 0Y8
      • Local Institution
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1G 1A7
      • Local Institution
  • Newfoundland and Labrador
    • Mount Pearl, Newfoundland and Labrador, Canada, A1N 1W7
      • Local Institution
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 5R3
      • Local Institution
  • Ontario
    • Sarnia, Ontario, Canada, N7T 4X3
      • Local Institution
    • Toronto, Ontario, Canada, M8V 3X8
      • Local Institution
  • Quebec
    • Mirabel, Quebec, Canada, J7J 2K8
      • Local Institution
• India
  • Hariyana, India, 132001
    • Local Institution
  • Mumbai, India, 400007
    • Local Institution
  • Vellore, India, 632004
    • Local Institution
• Mexico
  • Chihuahua, Mexico, 31020
    • Local Institution
  • Veracruz, Mexico, 91700
    • Local Institution
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44670
      • Local Institution
    • Guadalajara, Jalisco, Mexico, 44100
      • Local Institution
    • Zapopan, Jalisco, Mexico, 45200
      • Local Institution
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64240
      • Local Institution
    • Monterrey, Nl, Nuevo Leon, Mexico, 64400
      • Local Institution
  • Yucatan
    • Merida, Yucatan, Mexico, 97210
      • Local Institution
• Peru
  • Lima, Peru, 17
    • Local Institution
  • Lima, Peru, 09
    • Local Institution
  • Lima, Peru, 31
    • Local Institution
• Philippines
  • Cebu City, Philippines, 6000
    • Local Institution
  • Manila, Philippines, 1000
    • Local Institution
  • Pasig City, Philippines, 1600
    • Local Institution
• Puerto Rico
  • Ponce, Puerto Rico, 00717
    • Local Institution
• Taiwan
  • Changhua, Taiwan, 500
    • Local Institution
  • Taichung, Taiwan, 43303
    • Local Institution
  • Taipei, Taiwan, 110
    • Local Institution
• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group, LLC
    • Ozark, Alabama, United States, 36360
      • Iicr
  • Arizona
    • Phoenix, Arizona, United States, 85051
      • 43rd Medical Associates, P.C.
    • Tempe, Arizona, United States, 85282
      • Clinical Research Advantage Inc / Desert Clinical Res, Llc
    • Tempe, Arizona, United States, 85282
      • Clinical Research Advantage, Inc
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Little Rock Family Practice Clinic
    • Searcy, Arkansas, United States, 72143
      • Searcy Medical Center
  • California
    • Costa Mesa, California, United States, 92626
      • Clinical Innovations, Inc.
    • Greenbrae, California, United States, 94904
      • Marin Endocrine Care And Research, Inc.
    • Lomita, California, United States, 90717
      • Torrance Clinical Research
    • Los Angeles, California, United States, 90023
      • Randall Shue, D.O.
    • Northridge, California, United States, 91325
      • Diabetes Medical Center of California
    • Palm Desert, California, United States, 92260
      • Desert Medical Advances
    • Redlands, California, United States, 92373
      • Avastra Clinical Trials
    • Roseville, California, United States, 95661
      • Sierra Clinical Research
    • San Diego, California, United States, 92117
      • Ritchken & First M.D.'S
    • Santa Ana, California, United States, 92701
      • Advantage Clinical Research
    • Spring Valley, California, United States, 91978
      • Encompass Clinical Research
    • Tustin, California, United States, 92780
      • Diabetes Research Center
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Aurora Family Medicine Center, P.C.
    • Denver, Colorado, United States, 80209
      • Denver Internal Medicine
  • Florida
    • Altamonte Springs, Florida, United States, 32701
      • Central Florida Clinical Trials
    • Chipley, Florida, United States, 32428
      • Health First Clinical Research Group, Inc.
    • Coral Gables, Florida, United States, 33134
      • Clinical Therapeutics Corporation
    • Jacksonville, Florida, United States, 32205
      • Westside Center for Clinical Research
    • Marianna, Florida, United States, 32446
      • Panhandle Family Care Associates
    • Miami, Florida, United States, 33156
      • Baptist Diabetes Associates, PA
    • New Port Richey, Florida, United States, 34652
      • Suncoast Clinical Res Inc.
  • Georgia
    • Stone Mountain, Georgia, United States, 30088
      • Stone Mountain Clinical Research
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Cedar Crosse Research Center
  • Indiana
    • Valparaiso, Indiana, United States, 46383
      • Northwest Indiana Center for Clinical Research
  • Kansas
    • Wichita, Kansas, United States, 67203
      • Professional Research Network of Kansas
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • St. Mary'S Center For Diabetes And Endocrinology
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Endocrine Research Associates
    • Olive Branch, Mississippi, United States, 38654
      • Olive Branch Family Medical Center
    • Rolling Fork, Mississippi, United States, 39159
      • Danny W. Jackson P.A.
  • Nevada
    • Las Vegas, Nevada, United States, 89101
      • Association Of International Professionals
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Physicians Research Center
  • New York
    • Rochester, New York, United States, 14618
      • Finger Lakes Clinical Research
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • Metrolina Internal Medicine
    • Charlotte, North Carolina, United States, 28277
      • The Center For Nutrition & Preventive Medicine, Pllc
    • Lenoir, North Carolina, United States, 28645
      • Northstate Clinical Research
    • Wilmington, North Carolina, United States, 28401
      • New Hanover Medical Research
  • Ohio
    • Dayton, Ohio, United States, 45439
      • Providence Health Partners - Center For Clinical Research
    • Zanesville, Ohio, United States, 43701
      • Physician Research, Inc.
  • Pennsylvania
    • Levittown, Pennsylvania, United States, 19056
      • Family Medical Associates
    • Pittsburgh, Pennsylvania, United States, 15216
      • Banksville Medical, Pc
    • Pottstown, Pennsylvania, United States, 19464
      • Brookside Family Practice & Pediatrics
  • South Carolina
    • Columbia, South Carolina, United States, 29201
      • Columbia Clinical Research, Inc.
    • Taylors, South Carolina, United States, 29687
      • Southeastern Research Associates, Inc.
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Holston Medical Group
  • Texas
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes & Endocrine Center
    • Houston, Texas, United States, 77024
      • Village Family Practice
    • Houston, Texas, United States, 77090
      • Office Of Dr. Michelle Zaniewski Singh
    • San Antonio, Texas, United States, 78229
      • Diabetes & Glandular Disease Research Assoc,, Inc.
  • Virginia
    • Virginia Beach, Virginia, United States, 23454
      • Tidewater Integrated Medical Research
  • Washington
    • Spokane, Washington, United States, 99216
      • William L. Gray, Md

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Males and females, ≥ 18 years old, with type 2 diabetes and with inadequate glycemic control
• All subjects must have central laboratory pre-randomization A1C ≥ 7.0 and ≤ 10.5%
• C-peptide ≥ 1.0 ng/mL (0.34 nmol/L)
• Body Mass Index ≤ 45.0 kg/m²

Exclusion Criteria:

• AST and /or ALT > 2.5 times the upper limit of normal
• Serum total bilirubin > 2 mg/dL (34.2 µmol/L)
• Creatinine kinase > 3.0 times the upper limit of normal
• Symptoms of severely uncontrolled diabetes
• Serum creatinine ≥ 2.0 mg/dL
• Calculated Cr-Clearance < 50 ml/min (calculated by Cockroft-Gault formula)
• Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1	Drug: Dapagliflozin; Tablets, Oral, 5.0 mg, once daily, up to 48 weeks; Other Names: BMS-512148; Drug: Dapagliflozin; Tablets, Oral, 10.0 mg, once daily, up to 48 weeks; Other Names: BMS-512148; Drug: Thiazolidinedione (Pioglitazone); Tablets, ≥ 30 mg, Once daily, up to 48 weeks
Experimental: Arm 2	Drug: Dapagliflozin; Tablets, Oral, 5.0 mg, once daily, up to 48 weeks; Other Names: BMS-512148; Drug: Dapagliflozin; Tablets, Oral, 10.0 mg, once daily, up to 48 weeks; Other Names: BMS-512148; Drug: Thiazolidinedione (Pioglitazone); Tablets, ≥ 30 mg, Once daily, up to 48 weeks
Placebo Comparator: Arm 3	Drug: Thiazolidinedione (Pioglitazone); Tablets, ≥ 30 mg, Once daily, up to 48 weeks; Drug: Placebo matching Dapagliflozin; Tablets, Oral, 0 mg, once daily, up to 48 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])	HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.	From Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the double-blind period.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double-blind period.	From Baseline to Week 24
Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. Mean and standard error for percentage of participants were estimated by modified logistic regression model.	From Baseline to Week 24
Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. In post oral glucose tolerance test (OGTT), glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained on Day 1 and week 24 in the double-blind period.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in waist circumference at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Waist circumference measurements were obtained during the qualification and lead-in periods and on Day 1 and Week 24 of the double-blind period.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Total Body Weight (kg) Among Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the double-blind period.	From Baseline to Week 24

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Astra Zeneca, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Shah M, Stolbov L, Yakovleva T, Tang W, Sokolov V, Penland RC, Boulton D, Parkinson J. A model-based approach to investigating the relationship between glucose-insulin dynamics and dapagliflozin treatment effect in patients with type 2 diabetes. Diabetes Obes Metab. 2021 Apr;23(4):991-1000. doi: 10.1111/dom.14305. Epub 2021 Jan 25.
• Kohan DE, Fioretto P, Johnsson K, Parikh S, Ptaszynska A, Ying L. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016 Jun;29(3):391-400. doi: 10.1007/s40620-016-0261-1. Epub 2016 Feb 19.
• Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012 Jul;35(7):1473-8. doi: 10.2337/dc11-1693. Epub 2012 Mar 23.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): January 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: May 22, 2008
• First Submitted That Met QC Criteria: May 23, 2008
• First Posted (Estimate): May 26, 2008

Study Record Updates

• Last Update Posted (Actual): February 23, 2017
• Last Update Submitted That Met QC Criteria: January 3, 2017
• Last Verified: January 1, 2017

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; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin; Pioglitazone; 2,4-thiazolidinedione
• Other Study ID Numbers: MB102-030