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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: March 10, 2015
Last verified: March 2015
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 1st patient was enrolled on 31 Mar 2008. The last patient last visit was on 15 Dec 2009. 1901 patients (pts) were screened and 1217 pts were enrolled with the aim to randomize 816. 2 randomized pts were excluded since they received no medication. Eventually, 814 pts received medication. This study was conducted at 95 centers world-wide.

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 
Overall Participants Analyzed 
[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 ]
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Measure Type Primary
Measure Title Adjusted Mean Change in HbA1c Levels
Measure Description To assess the effect of dapagliflozin plus metformin compared to glipizide plus metformin on the absolute change from baseline in HbA1c level after 52 weeks double-blind treatment in patients with type 2 diabetes who have inadequate glycaemic control on 1500 mg/day or higher doses of metformin therapy alone.
Time Frame Baseline to Week 52  
Safety Issue No  

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, participants with non-missing baseline and Week 52 (LOCF) values

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

Measured Values
   Dapagliflozin Plus Metformin   Glipizide Plus Metformin 
Participants Analyzed 
[Units: Participants]
 400   401 
Adjusted Mean Change in HbA1c Levels 
[Units: Percent]
Least Squares Mean (95% Confidence Interval)
 -0.52 
 (-0.60 to -0.44) 
 -0.52 
 (-0.60 to -0.44) 


Statistical Analysis 1 for Adjusted Mean Change in HbA1c Levels
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Method [3] ANCOVA
P Value [4] <0.0001
Mean Difference (Final Values) [5] 0.00
Standard Error of the mean (0.0569)
95% Confidence Interval -0.11 to 0.11
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The null hypothesis is given as H0: mean(treat) minus mean(reference) >= delta versus the alternative HA: mean(treat) minus mean(reference) < delta (with alpha = 0.025, one-sided)
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  non-inferior margin delta = 0.35
[3] Other relevant method information, such as adjustments or degrees of freedom:
  with treatment group as effect and baseline value as covariate
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Significant at alpha=0.025 (1-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
[5] Other relevant estimation information:
  No text entered.



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


  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.


  More Information