A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled on Metformin Alone

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

The purpose of this clinical research study is to learn whether dapagliflozin can help reduce blood sugar levels in participants with Type 2 diabetes that is not well controlled on metformin alone. The safety of this treatment will also be studied.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Placebo; Drug: Metformin; Drug: Dapagliflozin

• Study Type: Interventional
• Enrollment (Actual): 915
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1431
    • Local Institution
  • Cordoba, Argentina, 5000
    • Local Institution
  • Buenos Aires
    • Capital Federal, Buenos Aires, Argentina, 1034
      • Local Institution
    • Capital Federal, Buenos Aires, Argentina, 1429
      • Local Institution
    • Capital Federal, Buenos Aires, Argentina, C1056ABJ
      • Local Institution
    • Capital Federal, Buenos Aires, Argentina, C1425AGC
      • Local Institution
    • Ciudad Auton, Buenos Aires, Argentina, C1408INH
      • Local Institution
    • Ciudad Auton., Buenos Aires, Argentina, C1505CWB
      • Local Institution
    • Mar Del Plata, Buenos Aires, Argentina, 7600
      • Local Institution
    • Zarate, Buenos Aires, Argentina, 2800
      • Local Institution
  • Cordoba
    • Villa Carlos Paz, Cordoba, Argentina, 5152
      • Local Institution
• Brazil
  • Rio De Janeiro, Brazil, 20211
    • Local Institution
  • Ceara
    • Fortaleza, Ceara, Brazil, 60021
      • Local Institution
  • Minas Gerais
    • Itajuba, Minas Gerais, Brazil, 37502
      • Local Institution
  • Para
    • Belem, Para, Brazil, 66073
      • Local Institution
  • Rio Grande Do Sul
    • Caxias Do Sul, Rio Grande Do Sul, Brazil, 95070
      • Local Institution
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90020090
      • Local Institution
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035
      • Local Institution
  • Sao Paulo
    • Marilia, Sao Paulo, Brazil, 17519
      • Local Institution
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2R 0X7
      • Local Institution
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 2H4
      • Local Institution
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P4
      • Local Institution
  • New Brunswick
    • Bathurst, New Brunswick, Canada, E2A 4X7
      • Local Institution
  • Newfoundland and Labrador
    • Mount Pearl, Newfoundland and Labrador, Canada, A1N 1W7
      • Local Institution
    • St-John, Newfoundland and Labrador, Canada, A1E 2E2
      • Local Institution
  • Ontario
    • Sarnia, Ontario, Canada, N7T 4X3
      • Local Institution
    • Thornhill, Ontario, Canada, L4J 8L7
      • Local Institution
    • Toronto, Ontario, Canada, M4R 2G4
      • Local Institution
    • Toronto, Ontario, Canada, M9W 4L6
      • Local Institution
  • Prince Edward Island
    • Charlottetown, Prince Edward Island, Canada, C1A 5Y9
      • Local Institution
  • Quebec
    • Drummondville, Quebec, Canada, J2B 7T1
      • Local Institution
    • Granby, Quebec, Canada, J2G 8Z9
      • Local Institution
    • L'Ancienne Lorette, Quebec, Canada, G2E 2X1
      • Local Institution
    • Mirabel, Quebec, Canada, J7J 2K8
      • Local Institution
    • St-Leonard, Quebec, Canada, H1S 3A9
      • Local Institution
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7K 3H3
      • Local Institution
    • Saskatoon, Saskatchewan, Canada, S7K 7H9
      • Local Institution
• Mexico
  • Durango, Mexico, 64710
    • Local Institution
  • Distrito Federal
    • Df, Distrito Federal, Mexico, 11800
      • Local Institution
    • Guadalajara, Distrito Federal, Mexico, 44670
      • Local Institution
    • Zapopan, Distrito Federal, Mexico, 45150
      • Local Institution
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44650
      • Local Institution
    • Guadalajara, Jalisco, Mexico, 44670
      • Local Institution
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64710
      • Local Institution
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Local Institution
    • Monterrrey, Nuevo Leon, Mexico, 64700
      • Local Institution
  • Tamaulipas
    • Tampico, Tamaulipas, Mexico, 89109
      • Local Institution
• United States
  • Arizona
    • Tempe, Arizona, United States, 85282
      • Clinical Research Advantage / Desert Clinical Res, Llc
  • California
    • Encino, California, United States, 91436
      • Medical Group of Encino
    • Fresno, California, United States, 93720
      • Valley Research
    • Los Angeles, California, United States, 90023
      • Randall Shue, D.O.
    • Northridge, California, United States, 91325
      • Diabetes Medical Center Of California
    • San Diego, California, United States, 92117
      • Ritchken & First M.D.'S
    • Spring Valley, California, United States, 91978
      • Encompass Clinical Research
    • Torrance, California, United States, 90505
      • Raikhel, Marina
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Express Care Clinical Res
    • Denver, Colorado, United States, 80209
      • Denver Internal Medicine
    • Golden, Colorado, United States, 80401
      • New West Physicians
  • Florida
    • Altamonte Springs, Florida, United States, 32701
      • Central Florida Clinical Trials, Inc.
    • Chipley, Florida, United States, 32428
      • Family Care Associates Of Nw Florida
  • Minnesota
    • Minneapolis, Minnesota, United States, 56440
      • Health Partners Research Foundation
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Woodlake Research
  • Nevada
    • Las Vegas, Nevada, United States, 89101
      • Nevada Alliance Against Diabetes
  • North Carolina
    • Morehead City, North Carolina, United States, 28557
      • Diabetes & Endocrinology Consultants, PC
  • Ohio
    • Newark, Ohio, United States, 43055
      • Newark Physician Associates
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73159
      • Integris Family Care S. Penn
  • Pennsylvania
    • Carlisle, Pennsylvania, United States, 17013
      • Cumberland Valley Endocrinology Center, Llc
    • Pittsburgh, Pennsylvania, United States, 15216
      • Banksville Medical Pc
  • South Carolina
    • Summerville, South Carolina, United States, 29485
      • Palmetto Clinical Research
    • Taylors, South Carolina, United States, 29687
      • Southeastern Research Assoc
  • Texas
    • Houston, Texas, United States, 77081
      • Texas Center For Drug Development, P.A.
    • San Antonio, Texas, United States, 78229
      • Diabetes & Glandular Disease Research Associates, Inc.
    • San Antonio, Texas, United States, 78229
      • S.A.M. Clinical Research Center
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Optimum Clinical Research
  • Washington
    • Spokane, Washington, United States, 99216
      • Office Of Dr. Gray

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 77 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria

• Males and females, 18 to 77 years old, with type 2 diabetes and inadequate glycemic control
• Participants who have been receiving metformin at a total daily dose ≥1500 mg per day for at least 8 weeks
• C-peptide ≥1.0 ng/mL
• Body mass index ≤45.0 kg/m^2
• Serum creatinine level <1.50 mg/dL for men or <1.40 mg/dL for women.

Key Exclusion Criteria

• Aspartate aminotransferase and/or alanine aminotransferase level >3.0 times the upper limit of normal
• Serum total bilirubin level >2 mg/dL
• Creatinine kinase level >3 times upper limit of normal
• Symptoms of severely uncontrolled diabetes
• Serum creatinine level ≥1.50 mg/dL for men or ≥1.40 mg/dL for women
• Currently unstable or serious cardiovascular, renal, hepatic, hematologic, oncologic, 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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo + Metformin; Participants received dapagliflozin-matching placebo once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Placebo; Dapagliflozin-matching placebo administered as tablets orally once daily for up to 102 weeks; Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks
Experimental: Dapagliflozin, 2.5 mg + Metformin; Participants received dapagliflozin, 2.5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks; Drug: Dapagliflozin; Tablets administered orally as a 2.5-, 5-, or 10-mg dose once daily for up to 102 weeks; Other Names: BMS-512148
Experimental: Dapagliflozin, 5 mg + Metformin; Participants received dapagliflozin, 5 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks; Drug: Dapagliflozin; Tablets administered orally as a 2.5-, 5-, or 10-mg dose once daily for up to 102 weeks; Other Names: BMS-512148
Experimental: Dapagliflozin, 10 mg + Metformin; Participants received dapagliflozin, 10 mg, once daily plus open-label metformin ≥1500 mg per day for up to 102 weeks	Drug: Placebo; Dapagliflozin-matching placebo administered as tablets orally once daily for up to 102 weeks; Drug: Metformin; Open-label metformin administered as ≥1500 mg per day for up to 102 weeks; Drug: Dapagliflozin; Tablets administered orally as a 2.5-, 5-, or 10-mg dose once daily for up to 102 weeks; Other Names: BMS-512148

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 Fasting Plasma Glucose at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Data after rescue medication was excluded from this analysis. 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.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Total Body Weight 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, 3, 4, 6, 8, 12, 16, 20, and 24 of 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.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants With Baseline HbA1c ≥9.0% at Week 24 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. HbA1c was measured as percent of hemoglobin by a central laboratory. The population included those randomized participants who received treatment and had a baseline HbA1c > 9.0%. Data after rescue medication were 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.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Total Body Weight at Week 24 in Participants With Baseline Body Mass Index (BMI) ≥27 kg/m^2 (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, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants 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 for baseline HbA1c. HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication were 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.	From Baseline to Week 24
Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 1 (Last Observation Carried Forward [LOCF])	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured 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.	From Baseline to Week 1
Adjusted Percentage of Participants Achieving Hemoglobin A1c (HbA1C) ≤6.5% 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. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.	From Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Hypoglycemia Events, Related AEs, Death as Outcome, Serious AEs (SAEs), Related SAEs, SAEs Leading to Discontinuation, AEs Leading to Discontinuation, and Hypoglycemia Events Leading to Discontinuation	AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or missing relationship to study drug. Events captured from baseline to last dose plus 4 days for AEs and plus 30 days for SAEs during the double-blind 12-week period. Data after rescue included.	From Baseline to end of Long-term Period (Week 102)
Number of Participants With Laboratory Test Results Meeting the Criteria for Laboratory Abnormality	BUN=blood urea nitrogen; preRX=pretreatment; ULN=upper limit of normal; AST=aspartate aminotransferase; ALT=alanine aminotransferase; ALP=alkaline phosphatase. Phosphorus, inorganic (low): ages 17-65 years, ≤1.8 mg/dL; ages≥66 years, ≤2.1 mg/dL. Phosphorus, inorganic (high): ages 17-65 years, ≥5.6 mg/dL; ages≥66 years, ≥5.6 mg/dL. Phosphorus, inorganic (low) ≤1.8 mg/dL if age 17-65 or ≤2.1 mg/dL if age ≥66. Calcium, total (high): ≥1 mg/dL from ULN and ≥0.5 mg/dL from preRx value.	Day 1 to Week 102
Number of Participants With Changes in Baseline in Electrocardiogram Findings at Week 102 (Last Observation Carried Forward [LOCF])	12-Lead electrocardiograms (ECGs) were performed at entry into lead-in period Day -7 visit and Week 24/dnd of treatment visit (LOCF) on participants who were supine. ECGs were assessed by the investigator. Baseline was Day -7 for this parameter. Data after rescue included.The Week 102 value is the last observation, regardless of rescue prior to Week 102 if no Week 102 measurement was available.	Baseline to Week 102
Mean Changes From Baseline in Seated Systolic Blood Pressure	Blood pressure values were obtained after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Data after rescue were also included. 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.	From Baseline to Week 102
Mean Changes From Baseline in Seated Diastolic Blood Pressure	Blood pressure values were obtained after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Data after rescue were also included. 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.	From Baseline to Week 102
Number of Participants With Orthostatic Hypotension	Orthostatic hypotension was defined as a decrease from supine to standing blood pressure of >20 mm Hg in systolic blood pressure or >10 mm Hg in diastolic blood pressure.	From Baseline to Week 102

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: 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.
• Bailey CJ, Del Prato S, Wei C, Reyner D, Saraiva G. Durability of glycaemic control with dapagliflozin, an SGLT2 inhibitor, compared with saxagliptin, a DPP4 inhibitor, in patients with inadequately controlled type 2 diabetes. Diabetes Obes Metab. 2019 Nov;21(11):2564-2569. doi: 10.1111/dom.13841. Epub 2019 Aug 26.
• Mellander A, Billger M, Johnsson E, Traff AK, Yoshida S, Johnsson K. Hypersensitivity Events, Including Potentially Hypersensitivity-Related Skin Events, with Dapagliflozin in Patients with Type 2 Diabetes Mellitus: A Pooled Analysis. Clin Drug Investig. 2016 Nov;36(11):925-933. doi: 10.1007/s40261-016-0438-3.
• 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.
• Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013 Feb 20;11:43. doi: 10.1186/1741-7015-11-43. Erratum In: BMC Med. 2013;11:193.
• Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Jun 26;375(9733):2223-33. doi: 10.1016/S0140-6736(10)60407-2.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): November 1, 2008
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: September 11, 2007
• First Submitted That Met QC Criteria: September 11, 2007
• First Posted (Estimate): September 12, 2007

Study Record Updates

• Last Update Posted (Estimate): October 20, 2015
• Last Update Submitted That Met QC Criteria: September 30, 2015
• Last Verified: September 1, 2015

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Metformin; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Pharmacologic Actions; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hypoglycemic Agents
• 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; Metformin
• Other Study ID Numbers: MB102-014 LT; MB102-014 (Other Identifier: Other Study ID Numbers:)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No