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
  Hide Participant Flow

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
  Hide Baseline Characteristics

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
  Hide All Outcome Measures

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

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  
Number of 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 ]

Measure Type Secondary
Measure Title Adjusted Mean Change in Body Weight
Measure Description To assess the effect of dapagliflozin plus metformin compared to glipizide plus metformin on body weight after 52 weeks double-blind treatment.
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  
Number of Participants Analyzed  
[units: participants]
  400     401  
Adjusted Mean Change in Body Weight  
[units: kg]
Least Squares Mean ( 95% Confidence Interval )
  -3.22  
  ( -3.56 to -2.87 )  
  1.44  
  ( 1.09 to 1.78 )  


Statistical Analysis 1 for Adjusted Mean Change in Body Weight
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Final Values) [4] -4.65
Standard Error of the mean ± 0.2483
95% Confidence Interval ( -5.14 to -4.17 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  H0: mean(treat) minus mean(reference) = 0 versus the alternative HA: mean(treat) minus mean(reference) =/= 0
[2] Other relevant method information, such as adjustments or degrees of freedom:
  with treatment group as effect and baseline value as covariate
[3] 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=0.05 (2-sided). Key secondary endpoints are tested following a hierarchical closed testing procedure
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title Proportion of Participants With at Least One Episode of Hypoglycemia
Measure Description To assess the effect of dapagliflozin plus metformin treatment compared to glipizide plus metformin on the occurrence of hypoglycemic events. Least Squares Mean represents the percent of participants adjusted for HbA1c baseline value.
Time Frame Baseline to Week 52  
Safety Issue Yes  

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

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  
Number of Participants Analyzed  
[units: participants]
  400     401  
Proportion of Participants With at Least One Episode of Hypoglycemia  
[units: Percentage of participants]
Least Squares Mean ( 95% Confidence Interval )
  3.5  
  ( 1.7 to 5.3 )  
  40.8  
  ( 36.1 to 45.5 )  


Statistical Analysis 1 for Proportion of Participants With at Least One Episode of Hypoglycemia
Groups [1] All groups
Method [2] Regression, Logistic
P Value [3] <0.0001
Risk Difference (RD) [4] -37.2
Standard Error of the mean ± 2.578
95% Confidence Interval ( -42.3 to -32.2 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  H0: proportion(treat) minus proportion(reference) = 0 versus the alternative HA: proportion(treat) minus proportion(reference) =/= 0
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Based on methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu, with adjustment for baseline value.
[3] 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=0.05 (2-sided). Key secondary endpoints are tested following a hierarchical closed testing procedure
[4] Other relevant estimation information:
  No text entered.



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

Measure Type Secondary
Measure Title Proportion of Participants With Body Weight Reduction of at Least 5%
Measure Description To evaluate the effect of dapagliflozin plus metformin compared to glipizide plus metformin on body weight assessed by a reduction after 52 weeks of at least 5% compared to baseline. Least Squares Mean represents the percent of participants adjusted for baseline value.
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  
Number of Participants Analyzed  
[units: participants]
  400     401  
Proportion of Participants With Body Weight Reduction of at Least 5%  
[units: Percentage of participants]
Least Squares Mean ( 95% Confidence Interval )
  33.3  
  ( 28.7 to 37.9 )  
  2.5  
  ( 1.0 to 4.0 )  


Statistical Analysis 1 for Proportion of Participants With Body Weight Reduction of at Least 5%
Groups [1] All groups
Method [2] Regression, Logistic
P Value [3] <0.0001
Risk Difference (RD) [4] 30.8
Standard Error of the mean ± 2.480
95% Confidence Interval ( 26.0 to 35.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  H0: proportion(treat) minus proportion(reference) = 0 versus the alternative HA: proportion(treat) minus proportion(reference) =/= 0
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Based on methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu, with adjustment for baseline value.
[3] 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=0.05 (2-sided). Key secondary endpoints are tested following a hierarchical closed testing procedure
[4] Other relevant estimation information:
  No text entered.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

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
  Hide More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Eva Johnsson
Organization: AstraZeneca
e-mail: ClinicalTrialTransparency@astrazeneca.com


No publications provided by AstraZeneca

Publications automatically indexed to this study:

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT00660907     History of Changes
Other Study ID Numbers: D1690C00004
Study First Received: April 15, 2008
Results First Received: January 21, 2013
Last Updated: September 24, 2013
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Brazil: National Health Surveillance Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Mexico: Federal Commission for Protection Against Health Risks
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency