Efficacy and Safety of Dapagliflozin in Combination With Metformin in Type 2 Diabetes Patients

This study has been completed.
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT00660907
First received: April 15, 2008
Last updated: September 24, 2013
Last verified: September 2013
Results First Received: January 21, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Type 2 Diabetes
Interventions: Drug: dapagliflozin
Drug: glipizide
Drug: metformin hydrochloride

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The first participant enrolled on 31 March 2008. The last participant last visit was on 15 December 2009. 1901 participants were screened and 1217 participants were enrolled to randomize 816 participants. This study was conducted at 95 centers world-wide. Two randomized patients were excluded because they didn’t receive any dose of study medication

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
For participants with a metformin dose of less than 1500 mg/day, a change in metformin dose in the past 8 weeks or on an Oral Anti-Diabetic (OAD), an 8-week metformin-only dose stabilisation period occurred. A 2-week placebo lead in period occurred after the dose stabilisation period or after enrolment if dose stabilisation period was skipped.

Reporting Groups
  Description
Dapagliflozin Plus Metformin Experimental dapagliflozin plus metformin
Glipizide Plus Metformin Active Comparator glipizide plus metformin

Participant Flow:   Overall Study
    Dapagliflozin Plus Metformin     Glipizide Plus Metformin  
STARTED     406 [1]   408 [2]
COMPLETED     322     314  
NOT COMPLETED     84     94  
Incorrect Enrollment                 1                 1  
Adverse Event                 33                 19  
Subject No Longer Meets Study Criteria                 6                 27  
Withdrawal by Subject                 23                 32  
Lost to Follow-up                 3                 3  
Poor/Non-Compliance                 5                 1  
Safety                 1                 0  
Death                 1                 3  
Various                 11                 8  
[1] Of the 406 randomized participants only 400 were included in the full analysis set.
[2] Of the 408 randomized participants only 401 were included in the full analysis set.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set defined as all randomized participants (as randomized) who received at least one dose of double-blind study medication, who have a non-missing baseline value and at least one post-baseline efficacy value for at least one efficacy variable during double-blind treatment period.

Reporting Groups
  Description
Dapagliflozin Plus Metformin Experimental dapagliflozin plus metformin
Glipizide Plus Metformin Active Comparator glipizide plus metformin
Total Total of all reporting groups

Baseline Measures
    Dapagliflozin Plus Metformin     Glipizide Plus Metformin     Total  
Number of Participants  
[units: participants]
  400     401     801  
Age  
[units: years]
Mean ± Standard Deviation
  58.1  ± 9.37     58.6  ± 9.80     58.4  ± 9.58  
Gender  
[units: Participants]
     
Female     179     181     360  
Male     221     220     441  
Race/Ethnicity, Customized  
[units: Participants]
     
American Indian or Alaska Native     0     0     0  
Asian     27     34     61  
Native Hawaiian or Other Pacific Islander     0     0     0  
Black or African American     26     24     50  
White     327     323     650  
More than one race     0     0     0  
Unknown or Not Reported     20     20     40  
BMI  
[units: kg/m2]
Mean ± Standard Deviation
  31.71  ± 5.104     31.23  ± 5.053     31.47  ± 5.081  
HbA1c  
[units: percent]
Mean ± Standard Deviation
  7.69  ± 0.855     7.74  ± 0.886     7.72  ± 0.870  
FPG  
[units: ng/mL]
Mean ± Standard Deviation
  162.24  ± 37.796     163.91  ± 41.559     163.07  ± 39.708  



  Outcome Measures
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1.  Primary:   Adjusted Mean Change in HbA1c Levels   [ Time Frame: Baseline to Week 52 ]

2.  Secondary:   Adjusted Mean Change in Body Weight   [ Time Frame: Baseline to Week 52 ]

3.  Secondary:   Proportion of Participants With at Least One Episode of Hypoglycemia   [ Time Frame: Baseline to Week 52 ]

4.  Secondary:   Proportion of Participants With Body Weight Reduction of at Least 5%   [ Time Frame: Baseline to Week 52 ]


  Serious Adverse Events
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Time Frame Non-serious / serious adverse events on or after the first day and on or prior to the last day of the 52-week double-blind treatment plus 4/30 days or up to follow-up visit if earlier, or up to and including the start date of extension period if earlier.
Additional Description Participants were questioned at each study visit about the occurrence of any health problems and any examination conducted at a study visit was assessed in comparison to the status at study entry.

Reporting Groups
  Description
Dapagliflozin Plus Metformin Experimental dapagliflozin plus metformin
Glipizide Plus Metformin Active Comparator glipizide plus metformin

Serious Adverse Events
    Dapagliflozin Plus Metformin     Glipizide Plus Metformin  
Total, serious adverse events      
# participants affected / at risk     35/406 (8.62%)     46/408 (11.27%)  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     0/406 (0.00%)     2/408 (0.49%)  
Cardiac disorders      
Myocardial Infarction † 1    
# participants affected / at risk     1/406 (0.25%)     3/408 (0.74%)  
Acute Coronary Syndrome † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Acute Myocardial Infarction † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Angina Pectoris † 1    
# participants affected / at risk     1/406 (0.25%)     1/408 (0.25%)  
Atrial Fibrillation † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Atrioventricular Block Complete † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Bradycardia † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Cardiac Arrest † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Cardiac Failure † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Cardiac Failure Congestive † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Coronary Artery Disease † 1    
# participants affected / at risk     1/406 (0.25%)     1/408 (0.25%)  
Left Ventricular Failure † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Ventricular Arrhythmia † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Eye disorders      
Cataract † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Retinal Detachment † 1    
# participants affected / at risk     1/406 (0.25%)     1/408 (0.25%)  
Gastrointestinal disorders      
Abdominal Pain † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Abdominal Pain Upper † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Anal Fissure † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Constipation † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Dyspepsia † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Gastritis † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Haemorrhoids † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Upper Gastrointestinal Haemorrhage † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
General disorders      
Chest Pain † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Non-Cardiac Chest Pain † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Sudden Death † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Hepatobiliary disorders      
Cholecystitis † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Cholecystitis Acute † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Cholelithiasis † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Hepatic Cirrhosis † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Infections and infestations      
Diverticulitis † 1    
# participants affected / at risk     0/406 (0.00%)     2/408 (0.49%)  
Bronchitis † 1    
# participants affected / at risk     1/406 (0.25%)     1/408 (0.25%)  
Erysipelas † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Gastroenteritis † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Gastroenteritis Viral † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Liver Abscess † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Lower Respiratory Tract Infection † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Pneumonia † 1    
# participants affected / at risk     1/406 (0.25%)     1/408 (0.25%)  
Pyelonephritis † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Sepsis † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Septic Shock † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Injury, poisoning and procedural complications      
Overdose † 1    
# participants affected / at risk     0/406 (0.00%)     2/408 (0.49%)  
Ankle Fracture † 1    
# participants affected / at risk     1/406 (0.25%)     1/408 (0.25%)  
Clavicle Fracture † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Contusion † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Humerus Fracture † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Multiple Injuries † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Postoperative Renal Failure † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Road Traffic Accident † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Wrist Fracture † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Investigations      
Creatinine Renal Clearance Decreased † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Metabolism and nutrition disorders      
Hypoglycaemia † 1    
# participants affected / at risk     0/406 (0.00%)     3/408 (0.74%)  
Hyponatraemia † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Intervertebral Disc Protrusion † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Rotator Cuff Syndrome † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
Prostate Cancer † 1    
# participants affected / at risk     3/406 (0.74%)     1/408 (0.25%)  
Basal Cell Carcinoma † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Breast Cancer † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Bronchial Carcinoma † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Nervous system disorders      
Carotid Artery Stenosis † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Cerebral Thrombosis † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Cervicobrachial Syndrome † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Loss Of Consciousness † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Migraine † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Transient Ischaemic Attack † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Psychiatric disorders      
Depression Suicidal † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Obsessive-Compulsive Disorder † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Renal and urinary disorders      
Diabetic Nephropathy † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Nephrolithiasis † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Urinary Incontinence † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Reproductive system and breast disorders      
Uterine Prolapse † 1    
# participants affected / at risk     2/406 (0.49%)     0/408 (0.00%)  
Respiratory, thoracic and mediastinal disorders      
Alveolitis Allergic † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Asthma † 1    
# participants affected / at risk     0/406 (0.00%)     1/408 (0.25%)  
Pulmonary Embolism † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Skin and subcutaneous tissue disorders      
Angioedema † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Urticaria † 1    
# participants affected / at risk     1/406 (0.25%)     0/408 (0.00%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA 12.1




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
For participants who did not complete 52 weeks LOCF (last observation carried forward) was used.


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