Study of Dapagliflozin in Combination With Metformin XR to Initiate the Treatment of Type 2 Diabetes
- Conditions
- Type 2 Diabetes Mellitus
- Interventions
- Registration Number
- NCT00859898
- Lead Sponsor
- AstraZeneca
- Brief Summary
The primary purpose of this study is to compare the change from baseline in hemoglobin A1C achieved with dapagliflozin 10 mg in combination with metformin XR as compared with metformin XR monotherapy and compared with Dapagliflozin monotherapy, after 24 weeks of oral administration of double-blind treatment. The safety of treatment with dapagliflozin will also be assessed in this study
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1093
- Treatment naive males and females, >= 18 years old and
<= 77 years old, with type 2 diabetes mellitus
- Subjects must have central laboratory pre-randomization hemoglobin A1C >= 7.5 and <= 12.0%
- C-peptide >= 1.0 ng/mL (0.34 nmol/L)
- Body Mass Index <= 45 kg/m2
- Must be able to perform self monitoring of blood glucose
- aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3X*upper limit of normal (ULN)
- Serum Total bilirubin >2 mg/dL (34.2 µmol/L)
- Creatinine kinase >3*ULN
- Serum creatinine >= 1.50 mg/dL (133 µmol/L) for male subjects, >= 1.40 mg/dL (124 µmol/L) for female subjects
- Calcium value outside of the central laboratory normal reference range
- Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases
- Urine albumin:creatinine ratio (UACR) >1800 mg/g (203.4 mg/mmol Cr)
- Severe uncontrolled hypertension defined as systolic blood pressure (SBP) >=180 mmHg and/or diastolic blood pressure (DBP) >=110 mmHg
- Hemoglobin >=11.0 g/dL (110 g/L) for men; hemoglobin >=10.0 g/dL (100 g/L) for women
- Positive for hepatitis B surface antigen
- Positive for anti-hepatitis C virus antibody
- History of diabetes insipidus
- History of diabetic ketoacidosis or hyperosmolar nonketotic coma
- Symptoms of poorly controlled diabetes that would preclude participation in this trial
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Metformin XR + Placebo Metformin XR Metformin XR: Tablets, Oral, 500 mg up to 2000 mg, once daily 24 weeks Placebo: Dapagliflozin matching placebo tablets once daily, 24 weeks Dapagliflozin + Placebo metformin HCl Modified Release matching Placebo Dapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks. Placebo: Metformin HCl Modified Release matching placebo tablets, once daily, 24 weeks. Dapagliflozin + Metformin XR Metformin XR Dapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks Metformin XR: Tablets, Oral, up to 2000 mg, once daily, 24 weeks Metformin XR + Placebo dapagliflozin matching Placebo Metformin XR: Tablets, Oral, 500 mg up to 2000 mg, once daily 24 weeks Placebo: Dapagliflozin matching placebo tablets once daily, 24 weeks Dapagliflozin + Metformin XR Dapagliflozin Dapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks Metformin XR: Tablets, Oral, up to 2000 mg, once daily, 24 weeks Dapagliflozin + Placebo Dapagliflozin Dapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks. Placebo: Metformin HCl Modified Release matching placebo tablets, once daily, 24 weeks.
- Primary Outcome Measures
Name Time Method Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 (Last Observation Carried Forward) - Randomized Treated Participants Week 24 Adjusted mean change in HbA1c from baseline at Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, ie, last observation carried forward (LOCF) was determined. 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.
- Secondary Outcome Measures
Name Time Method Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (LOCF) - Randomized, Treated Participants Week 24 Data after rescue medication was excluded from this analysis. FPG 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, 3, 4, 6, 8, 12, 16, 20, and 24 of the Double-Blind Period.
Percent Adjusted for Baseline HbA1c of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized, Treated Participants Week 24 Therapeutic glycemic response was defined as HbA1c less than 7.0%. n=Number of participants with HBA1c less than (\<) 7 % at Week 24, last observation carried forward (LOCF) while N=number of randomized participants with non-missing baseline and Week 24 (LOCF) values. Percent=n/N and was adjusted for Baseline HbA1c. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Adjusted Mean Change From Baseline in HbA1C at Week 24 (LOCF) in Participants Whose Baseline HbA1C Category ≥9.0% Week 24 HbA1c was measured as percent of hemoglobin by a central laboratory. The population included those randomized, treated participants whose Baseline HbA1c was greater than, equal to (\>=) 9.0%. 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.
The Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized, Treated Participants Week 24 Adjusted mean change from baseline in total body weight at Week 24 (or the last post-baseline 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 was measured in kilograms (kg). 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.
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuation Due to AEs, During the 12 Week Double Blind Period, Including Data After Rescue - All Treated Participants Day 1 of Double Blind Period to end of Week 24 Plus 30 days Medical Dictionary for Regulatory Activities (MedDRA), version 12.1 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. Treatment-related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Events captured from baseline to last dose plus 4 days for AEs, plus 30 days for SAEs during the Double Blind 12 Week Period. Data after rescue included.
Number of Participants With Adverse Events of Special Interest During the 12 Week Double Blind Period - All Treated Participants Baseline to last dose plus 4 days in 12 Week Double Blind Period Participants with AEs of hypoglycemia, cardiac/vascular disorders, renal impairment or failure, volume depletion (hypotension/dehydration/hypovolemia), fractures, urinary stones, and other reports suggestive of genital infection or urinary tract infection (UTI) were summarized using MedDRA version 13.0. Data after rescue included for all special AEs except hypoglycemia (excluded data after rescue). Major hypoglycemic episode: symptomatic requiring 3rd party assistance due to severe impairment in consciousness or behavior with a glucose value \< 54 mg/dL and prompt recovery after glucose/glucagon; Minor: either symptomatic with glucose measurement \< 63 mg/dL, regardless of need for 3rd party assistance, or asymptomatic with glucose \< 63 mg/dL that does not qualify as major; Other: suggestive but not meeting criteria for major or minor.
Mean Change From Baseline in Seated Systolic and Diastolic Blood Pressure at Week 24 - Treated Participants Week 24 Measurements were taken during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the Double Blind Period. 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. Systolic and Diastolic pressures were measured in millimeters of mercury (mmHg). 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.
Mean Change From Baseline in Seated Heart Rate at Week 24 - Randomized, Treated Participants Week 24 Measurements were taken during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the Double Blind Period. Heart rate 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 throughout the study. Heart rate was measured in beats per minute (bpm). 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.
Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Randomized, Treated Participants Week 24 12-Lead electrocardiograms (ECGs) were performed at entry into Lead-In Period Day -7 visit and Week 24/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator. Baseline (BL) was Day -7 for this parameter. Data after rescue included.
Number of Participants With Marked Laboratory Abnormalities (Not Including Liver Function) in 24 Week Double Blind Treatment Period, Including Data After Rescue - Randomized, Treated Participants Baseline to Week 24/end of treatment plus 4 days Laboratory samples: Qualification and Lead-In Periods, Day 1, Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of Double-Blind Period. Baseline (BL)=last assessment prior to start of first dose of double-blind study medication. Data after rescue included. Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); Units per liter (U/L), blood urea nitrogen (BUN). Marked abnormality Low (High) defined: hemoglobin \<6 (\>18 females or \>20 males) g/dL; hematocrit \<20% ( \>55% females or \>60% males); creatinine (\>=1.5\*preRX, \>=2.5 mg/dL); glucose \<54 (\>350) mg/dL; creatine kinase (\>5\*ULN);calcium \<7.5 (\>=1 mg/dL from ULN and \>= 0.5mg/dL from PreRX); sodium \<130 or \< 120 male/female (\>150 mEq/L; potassium \<=2.5 (\>=6.0) mEq/L; bicarbonate \<= 13 mEq/L; inorganic phosphorus: \<=1.8 if age 17-65 or \<=2.1 if age \>=66, (\>=5.6 if age 17-65 or \>=5.1) mg/dL if age \>=66; albumin \<=2 (\>6) g/dL; urine albumin(alb) / creatinine (creat) ratio (\>1800 mg/g)
Number of Participants With Marked Laboratory Abnormalities in Liver Function in 24 Week Double Blind Treatment Period, Including Data After Rescue - Randomized, Treated Participants Baseline to Week 24/end of treatment plus 30 days Safety laboratory measurements were obtained during the Qualification and Lead-In Periods and on Day 1 of the Double-Blind Period and at Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. BL was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from BL up to and including the last day of treatment plus 30 days. Liver function abnormality criteria: FDA Guidance for Industry: Premarketing Clinical Evaluation (July 2009). Data after rescue was also included. Abbreviations: Pretreatment (PreRX), upper limit of normal (ULN); greater than (\>) less than (\<); Units per liter (U/L), alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). Marked abnormality Low (High) defined: ALP, AST and ALT (\>3\*ULN); bilirubin (\>2\*ULN if PreRX \<= ULN; \>3\*ULN if PreRX \> ULN); AST or ALT plus (+) bilirubin elevation: AST or ALT \>3\*ULN and bilirubin \>1.5\*ULN within 14 days on or after ALT elevation.
Trial Locations
- Locations (64)
Clinical Research Advantage, Inc.
🇺🇸Tempe, Arizona, United States
Southland Clinical Research Center, Inc.
🇺🇸Fountain Valley, California, United States
Nextphase Clinical Trials, Inc.
🇺🇸Miami, Florida, United States
Baptist Diabetes Associates
🇺🇸Miami, Florida, United States
Cedar Crosse Research Center
🇺🇸Chicago, Illinois, United States
Physicians Research Group
🇺🇸Indianapolis, Indiana, United States
Holston Medical Group
🇺🇸Kingsport, Tennessee, United States
Newark Physician Associates
🇺🇸Newark, Ohio, United States
Pacific Sleep Medicine Services (Avastra Clinical Trials)
🇺🇸Redlands, California, United States
Metrolina Medical Research
🇺🇸Charlotte, North Carolina, United States
Pharmquest
🇺🇸Greensboro, North Carolina, United States
Physician Research, Inc.
🇺🇸Zanesville, Ohio, United States
Daniel G. Williams, Md
🇺🇸Perrysburg, Ohio, United States
Integrated Medical Group Pc/Fleetwood Clinical Research
🇺🇸Fleetwood, Pennsylvania, United States
Wellmon Family Practice
🇺🇸Shippensburg, Pennsylvania, United States
Valley Research
🇺🇸Fresno, California, United States
Irvine Center For Clinical Research, Inc.
🇺🇸Irvine, California, United States
Orange County Research Center
🇺🇸Tustin, California, United States
Lynn Institute Of The Rockies
🇺🇸Colorado Springs, Colorado, United States
Clinical Therapeutics Corporation
🇺🇸Coral Gables, Florida, United States
Metabolic Research Institute, Inc.
🇺🇸W Palm Beach, Florida, United States
Lake Hartwell Family Medicine
🇺🇸Hartwell, Georgia, United States
Middle Georgia Drug Study Center, Llc
🇺🇸Perry, Georgia, United States
Provident Clinical Research
🇺🇸Addison, Illinois, United States
Deerbrook Medical Associates
🇺🇸Vernon Hills, Illinois, United States
Olive Branch Family Medical Center
🇺🇸Olive Branch, Mississippi, United States
Clinilabs, Inc.
🇺🇸New York, New York, United States
Crescent Medical Research
🇺🇸Salisbury, North Carolina, United States
Community Health Care, Inc.
🇺🇸Canal Fulton, Ohio, United States
Holzer Clinic, Inc
🇺🇸Gallipolis, Ohio, United States
Wells Institute For Health Awareness
🇺🇸Kettering, Ohio, United States
Gilbert Medical Research, Llc
🇺🇸Bethany, Oklahoma, United States
Integris Family Care Yukon
🇺🇸Yukon, Oklahoma, United States
Tulsa Clinical Research, Llc
🇺🇸Tulsa, Oklahoma, United States
Safe Harbor Clinical Research
🇺🇸E. Providence, Rhode Island, United States
Dingmans Medical
🇺🇸Dingmans Ferry, Pennsylvania, United States
Southeastern Research Associates, Inc.
🇺🇸Greenville, South Carolina, United States
Dallas Diabetes & Endocrine Center
🇺🇸Dallas, Texas, United States
Endocrine Associates
🇺🇸Houston, Texas, United States
Village Family Practice
🇺🇸Houston, Texas, United States
Juno Research, Llc.
🇺🇸Houston, Texas, United States
Excel Clinical Research
🇺🇸Houston, Texas, United States
Non-Invasive Cardiovascular, Pa
🇺🇸Houston, Texas, United States
Texas Center For Drug Development
🇺🇸Houston, Texas, United States
Midland Clinical Research Center
🇺🇸Midland, Texas, United States
Hill Country Medical Associates
🇺🇸New Braunfels, Texas, United States
Williamette Valley Clinical Studies
🇺🇸Eugene, Oregon, United States
Southwind Medical Specialists
🇺🇸Memphis, Tennessee, United States
Parkway Medical Group
🇺🇸Fayetteville, Tennessee, United States
Northwest Clinical Trials
🇺🇸Boise, Idaho, United States
Borgess Research Institute
🇺🇸Kalamazoo, Michigan, United States
Radiant Research, Inc.
🇺🇸Denver, Colorado, United States
Encompass Clinical Research-North Coast
🇺🇸Encinitas, California, United States
International Institute Of Clinical Research
🇺🇸Ozark, Alabama, United States
John Muir Physician Network Clinical Research Center
🇺🇸Concord, California, United States
Del Rosario Medical Clinic, Inc.
🇺🇸Huntington Park, California, United States
Clinical Research Advantage, Inc./Mesa Family Med Ctr, Pc
🇺🇸Tempe, Arizona, United States
Northwest Clinical Research Center
🇺🇸Bellevue, Washington, United States
Tidewater Integrated Medical Research
🇺🇸Virginia Beach, Virginia, United States
Avastra Clinical Trials
🇺🇸Midvale, Utah, United States
Covenant Clinical Research, Pa
🇺🇸San Antonio, Texas, United States
Local Institution
🇷🇺Yaroslavl, Russian Federation
Seven Corners Medical Center
🇺🇸Falls Church, Virginia, United States
S.A.M. Clinical Research Center
🇺🇸San Antonio, Texas, United States