A Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes and Inadequately Controlled Hypertension on an Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker

This study has been completed.
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT01137474
First received: June 3, 2010
Last updated: April 1, 2014
Last verified: April 2014
Results First Received: February 7, 2014  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Condition: Type 2 Diabetes
Interventions: Drug: Dapagliflozin
Drug: Placebo-matching dapagliflozin
Drug: Oral antidiabetic agent
Drug: Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB)
Drug: With or without insulin

  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
This study was originally designed with 2 additional double-blind treatment arms, dapagliflozin 2.5 and 5 mg, but randomization of new patients into these arms stopped with implementation of Protocol Amendment 8 on 1-11-11. Patients randomized to dapagliflozin 2.5 or 5 mg remained on their blinded medication until study completion.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Of 2996 participants enrolled, 944 were randomized and received double-blind treatment.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 2.5 mg, daily with a morning meal.
Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 5 mg, daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.

Participant Flow for 2 periods

Period 1:   Day 1 to Week 12 (Double-blind Period)
    Placebo     Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 10 mg  
STARTED     311     166     165     302  
Received Treatment     311     166     165     302  
COMPLETED     287     154     158     281  
NOT COMPLETED     24     12     7     21  
Adverse Event                 3                 5                 1                 3  
Withdrawal by Subject                 7                 2                 6                 9  
No longer met study criteria                 6                 1                 0                 5  
Lost to Follow-up                 5                 1                 0                 2  
Lack of Efficacy                 0                 0                 0                 2  
Not specified                 3                 1                 0                 0  
Pregnancy                 0                 1                 0                 0  
Administrative reason by sponsor                 0                 1                 0                 0  

Period 2:   Follow-up (1 Week Post Last Dose)
    Placebo     Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 10 mg  
STARTED     288 [1]   155 [1]   158     284 [2]
COMPLETED     265     153     157     266  
NOT COMPLETED     23     2     1     18  
Withdrawal by Subject                 9                 0                 0                 10  
Lost to Follow-up                 5                 0                 0                 2  
Administrative reason by sponsor                 1                 0                 0                 2  
Not specified                 8                 2                 1                 4  
[1] Includes 1 participant who discontinued prematurely in Period 1 and returned for follow-up
[2] Includes 3 participants who discontinued prematurely in Period 1 and returned for follow-up



  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.
All randomized participants who received a least 1 dose of double-blind study medication

Reporting Groups
  Description
Placebo Participants with type 2 diabetes and inadequate glycemic control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 2.5 mg, daily with a morning meal.
Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 5 mg, daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Total Total of all reporting groups

Baseline Measures
    Placebo     Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 10 mg     Total  
Number of Participants  
[units: participants]
  311     166     165     302     944  
Age, Customized  
[units: Participants]
         
Younger than 65 years     259     141     142     260     802  
65 years and older to younger than 75 years     46     25     21     42     134  
75 years and older     6     0     2     0     8  
Gender  
[units: Participants]
         
Female     140     76     76     123     415  
Male     171     90     89     179     529  
Ethnicity (NIH/OMB) [1]
[units: Participants]
         
Hispanic or Latino     81     28     23     87     219  
Not Hispanic or Latino     43     16     20     31     110  
Unknown or Not Reported     187     122     122     184     615  
Race/Ethnicity, Customized  
[units: Participants]
         
White     241     105     108     239     693  
Black or African American     14     11     8     12     45  
Asian     54     49     49     49     201  
Other     2     1     0     2     5  
Body Mass Index  
[units: Participants]
         
Less than 25 kg/m^2     28     20     18     34     100  
25 kg/m^2 and greater     283     146     147     268     844  
27 kg/m^2 and greater     240     123     129     238     730  
30 kg/m^2 and greater     152     79     84     173     488  
[1] Reported only for US participants



  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Primary
Measure Title Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12
Measure Description Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Dapagliflozin, 10 mg Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Placebo Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.

Measured Values
    Dapagliflozin, 10 mg     Placebo  
Number of Participants Analyzed  
[units: participants]
  280     279  
Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12  
[units: mm Hg]
Mean ± Standard Error
  -10.40  ± 0.8822     -7.34  ± 0.8812  


Statistical Analysis 1 for Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12
Groups [1] All groups
Method [2] Longitudinal repeated measures analysis
P Value [3] 0.0010
Mean Difference (Final Values) [4] -03.05
Standard Error of the mean ± 0.9251
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change from baseline to week 12 calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction. Data after rescue were not included in the analysis. With 253 patients per group, there is >80% power to detect a difference of 3.5 mm Hg at alpha=0.05, assuming a common SD of 14 mm Hg.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Endpoint tested following a sequential testing procedure at two-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
[4] Other relevant estimation information:
  No text entered.



2.  Primary:   Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Primary
Measure Title Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12
Measure Description HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an angiotensin-converting enzyme ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  279     278  
Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12  
[units: Percent]
Mean ± Standard Error
  -0.10  ± 0.0631     -0.56  ± 0.0633  


Statistical Analysis 1 for Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12
Groups [1] All groups
Method [2] Longitudinal repeated measures analysis
P Value [3] <0.0001
Mean Difference (Final Values) [4] -0.46
Standard Error of the mean ± 0.0673
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change from baseline to week 12 was calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction. With 253 subjects per group, there is >98% power to detect a difference of 0.4% at a=0.05, assuming a common SD of 1.1%.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Only Week 12 data are presented; data from all weeks in the double-blind treatment period were included in the longitudinal repeated measures model
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Endpoint tested following a sequential testing procedure at two-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward)   [ Time Frame: From Baseline to Week 12 ]

Measure Type Secondary
Measure Title Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward)
Measure Description Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24-hrs each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hr ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  263     267  
Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward)  
[units: mm Hg]
Mean ± Standard Error
  -6.73  ± 1.2427     -9.62  ± 1.2277  


Statistical Analysis 1 for Adjusted Mean Change From Baseline in 24-Hour Ambulatory Systolic Blood Pressure at Week 12 (Last Observation Carried Forward)
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.0043
Mean Difference (Final Values) [4] -2.89
Standard Error of the mean ± 1.0091
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change from baseline to week 12 LOCF was calculated using an ANCOVA model with treatment group as an effect and baseline value and randomization strata as covariate. Data after rescue are excluded from blood pressure analyses.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Endpoint tested following a sequential testing procedure at 2-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Secondary
Measure Title Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12
Measure Description All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  279     280  
Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12  
[units: mm Hg]
Mean ± Standard Error
  -4.79  ± 0.5418     -5.79  ± 0.5425  


Statistical Analysis 1 for Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12
Groups [1] All groups
Method [2] Longitudinal repeated measures analysis
P Value [3] 0.0843
Mean Difference (Final Values) [4] -1.00
Standard Error of the mean ± 0.5811
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change from baseline to week 12 was calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction. Data after rescue were not included in the analysis.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Endpoint tested following a sequential testing procedure at two-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF])   [ Time Frame: From Baseline to Week 12 ]

Measure Type Secondary
Measure Title Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF])
Measure Description Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24 hours each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hour ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  263     267  
Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF])  
[units: mm Hg]
Mean ± Standard Error
  -5.53  ± 0.8458     -6.15  ± 0.8353  


Statistical Analysis 1 for Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF])
Groups [1] All groups
Method [2] ANCOVA
Mean Difference (Final Values) [3] -0.62
Standard Error of the mean ± 0.6866
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change from baseline to week 12 LOCF was calculated using an ANCOVA model with treatment group as an effect and baseline value and randomization strata as covariate. Data after rescue are excluded from blood pressure analyses.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Other relevant estimation information:
  No text entered.



6.  Secondary:   Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Secondary
Measure Title Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12
Measure Description Central laboratory serum uric acid levels will be determined at the Enrollment, Day -28, Day 1, and at Week 4, 8, 12, and 13 visits. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  279     278  
Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12  
[units: mg/dL]
Mean ± Standard Error
  0.05  ± 0.0747     -0.27  ± 0.0754  


Statistical Analysis 1 for Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12
Groups [1] All groups
Method [2] Longitudinal repeated measures analysis
Mean Difference (Final Values) [3] -0.32
Standard Error of the mean ± 0.0717
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Change from baseline to week 12 was calculated using a longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata and continuous fixed covariates of baseline value and baseline value by week interaction.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
[3] Other relevant estimation information:
  No text entered.



7.  Other Pre-specified:   Number of Participants With Adverse Events (AEs), Hypoglycemic Events, Related AEs, Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Discontinuations Due to AEs, and Discontinuations Due to Hypoglycemic Events   [ Time Frame: Day 1 of treatment to last dose plus 4 days for AEs and hypoglycemic events and plus 30 days for SAEs ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Adverse Events (AEs), Hypoglycemic Events, Related AEs, Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Discontinuations Due to AEs, and Discontinuations Due to Hypoglycemic Events
Measure Description 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 unknown relationship to study drug. Includes nonserious AEs with onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment plus 4 days and SAEs with onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment plus 30 days. Includes data after rescue. Only hypoglycemia reported as an SAE is included in AE/SAE categories. All reported hypoglycemia events within 4 days of last day of treatment are included as hypoglycemic events.
Time Frame Day 1 of treatment to last dose plus 4 days for AEs and hypoglycemic events and plus 30 days for SAEs  
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.
All randomized participants who received at least 1 dose of study medication

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 2.5 mg, daily with a morning meal.
Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8) Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 5 mg, daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin,10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  311     166     165     302  
Number of Participants With Adverse Events (AEs), Hypoglycemic Events, Related AEs, Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Discontinuations Due to AEs, and Discontinuations Due to Hypoglycemic Events  
[units: Participants]
       
AEs     109     65     73     111  
Hypoglycemic events     4     4     4     10  
Related AEs     13     10     9     22  
Deaths     0     0     0     0  
SAEs     4     3     2     2  
Related SAEs     0     0     0     0  
Discontinuations due to SAEs     1     1     0     0  
Discontinuations due to AEs     4     5     1     3  
Discontinuations due to hypoglycemic events     0     0     0     0  

No statistical analysis provided for Number of Participants With Adverse Events (AEs), Hypoglycemic Events, Related AEs, Death as Outcome, Serious Adverse Events (SAEs), Related SAEs, Discontinuations Due to SAEs, Discontinuations Due to AEs, and Discontinuations Due to Hypoglycemic Events



8.  Other Pre-specified:   Number of Participants With Clinical Laboratory Results Meeting Criteria for Marked Abnormality   [ Time Frame: Day 1 of treatment to last dose, plus 4 days ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Clinical Laboratory Results Meeting Criteria for Marked Abnormality
Measure Description Laboratory abnormalities were evaluated based on laboratory values meeting predefined marked abnormality (MA) criteria. Includes data after the start date of double-blind treatment up to and including the last day of double-blind treatment plus 4 days. BUN=blood urea nitrogen; preRX=pretreatment; unspecif=unspecified; ULN=upper limit of normal. High total calcium= ≥1 mg/dL from ULN and ≥0.5 mg/dL from preRX value; high inorganic phosphorus= ≥5.6 mg/dL if age 17-65 years or ≥5.1 mg/dL if age ≥66 years.
Time Frame Day 1 of treatment to last dose, plus 4 days  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused on 10-mg and placebo data, only patients in these arms who received study drug were included. n=number of participants with nonmissing laboratory test values.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic agent (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotension-receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  311     302  
Number of Participants With Clinical Laboratory Results Meeting Criteria for Marked Abnormality  
[units: Participants]
   
Hematocrit >55% (n=304, 296)     0     1  
Hemoglobin >18 g/dL (n=304, 296)     0     1  
BUN ≥60 mg/dL or Urea >21.4 mmol/L (n=305, 297)     2     0  
Creatinine ≥1.5 preRX (n=305, 297)     4     3  
Glucose, plasma unspecif >350 mg/dL (n=307, 297)     3     3  
Glucose, plasma unspecif <54 mg/dL (n=307, 297)     0     1  
Creatine kinase >5*ULN (n=305, 297)     2     1  
Creatine kinase >10*ULN (n=305, 297)     1     0  
Calcium, total <7.5 mg/dL (n=305, 297)     2     2  
Calcium, total high (n=305, 297)     0     2  
Bicarbonate ≤13 mEq/L (n=304, 297)     1     1  
Potassium, serum≥6 mEq/L (n=305, 297)     8     3  
Sodium, serum <130 mEq/L (n=305, 297)     1     3  
Sodium, serum >150 mEq/L (n=305, 297)     1     2  
Phosphorus, inorganic high (n=305, 297)     1     1  
Albumin/creatinine ratio >1800 mg/g (n=304, 297)     4     3  

No statistical analysis provided for Number of Participants With Clinical Laboratory Results Meeting Criteria for Marked Abnormality



9.  Other Pre-specified:   Changes From Baseline in Electrocardiogram (ECG) Findings at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Other Pre-specified
Measure Title Changes From Baseline in Electrocardiogram (ECG) Findings at Week 12
Measure Description The normality or abnormality of the ECG tracing, determined by the investigator, was summarized by normal or abnormal ECG tracing at Week 12 overall and at baseline. When the data at Week 12 were not available, the last observation before discontinuation of that patient was used for summary.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic agent (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an or OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  311     302  
Changes From Baseline in Electrocardiogram (ECG) Findings at Week 12  
[units: Participants]
   
Baseline normal/Week 12 normal     200     195  
Baseline normal/Week 12 abnormal     15     14  
Baseline normal/ Week 12 not reported     0     0  
Baseline abnormal/Week 12 normal     17     15  
Baselline abnormal/Week 12 abnormal     51     62  
Baseline abnormal/Week 12 not reported     0     0  
Baseline not reported/Week 12 normal     0     0  
Baseline not reported/Week 12 abnormal     0     0  
Baseline not reported/Week 12 not reported     28     16  

No statistical analysis provided for Changes From Baseline in Electrocardiogram (ECG) Findings at Week 12



10.  Other Pre-specified:   Changes From Baseline in Supine and Standing Systolic and Diastolic Blood Pressure (BP) at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Other Pre-specified
Measure Title Changes From Baseline in Supine and Standing Systolic and Diastolic Blood Pressure (BP) at Week 12
Measure Description Supine BP was measured prior to standing BP. The patient was to rest in the supine position for at least 5 minutes prior to measurement of BP. Supine BP was determined from 3 replicate measurements obtained at least 1 minute apart. The average BP was determined from these 3 replicate measurements. The patient then stood for 2 to 3 minutes. After this time, BP was measured with the arm supported at the antecubital fossa at heart level.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug were included. n=number of patients with nonmissing Week 12 values

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic agent (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotension-receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  311     302  
Changes From Baseline in Supine and Standing Systolic and Diastolic Blood Pressure (BP) at Week 12  
[units: mm Hg]
Mean ± Standard Deviation
   
Supine systolic BP (n=276, 275)     -5.52  ± 11.042     -9.26  ± 12.049  
Standing systolic BP (n=277, 276)     -6.35  ± 12.354     -9.64  ± 12.601  
Supine diastolic BP (n=276, 275)     -3.70  ± 6.787     -5.11  ± 8.026  
Standing diastolic BP (n=277, 276)     -3.64  ± 7.124     -5.25  ± 7.376  

No statistical analysis provided for Changes From Baseline in Supine and Standing Systolic and Diastolic Blood Pressure (BP) at Week 12



11.  Other Pre-specified:   Changes From Baseline in Supine and Standing Heart Rate (HR) at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Other Pre-specified
Measure Title Changes From Baseline in Supine and Standing Heart Rate (HR) at Week 12
Measure Description Supine HR was measured prior to the standing HR. The patient was to rest in the supine position for at least 5 minutes prior to measurement of HR. Supine HR will be determined from 3 replicate measurements obtained at least 1 minute apart. The average HR was determined from these 3 replicate measurements and reported in the case report form. The patient then stood for 2 to 3 minutes. All measurements were to occur at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused on 10-mg and placebo data, only patients in these arms who received study drug were included. n=number of participants with nonmissing Week 12 values

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic agent (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotension-receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  311     302  
Changes From Baseline in Supine and Standing Heart Rate (HR) at Week 12  
[units: bpm]
Mean ± Standard Deviation
   
Supine heart rate (n=276, 275)     -1.05  ± 8.491     -0.89  ± 8.363  
Standing heart rate (n=277, 276)     -0.95  ± 8.325     -0.74  ± 8.362  

No statistical analysis provided for Changes From Baseline in Supine and Standing Heart Rate (HR) at Week 12



12.  Other Pre-specified:   Changes From Baseline in 24-Hour Ambulatory Heart Rate at Week 12   [ Time Frame: From Baseline to Week 12 ]

Measure Type Other Pre-specified
Measure Title Changes From Baseline in 24-Hour Ambulatory Heart Rate at Week 12
Measure Description Changes from baseline in 24-hour mean ambulatory heart rate were summarized at each visit using descriptive statistics.
Time Frame From Baseline to Week 12  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic agent (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotension-receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  260     259  
Changes From Baseline in 24-Hour Ambulatory Heart Rate at Week 12  
[units: bpm]
Mean ± Standard Deviation
  -1.69  ± 10.307     -1.99  ± 9.543  

No statistical analysis provided for Changes From Baseline in 24-Hour Ambulatory Heart Rate at Week 12



13.  Other Pre-specified:   Number of Participants With Elevated Results of Liver Laboratory Tests   [ Time Frame: Day 1 of double-blind treatment to last double-blind dose, plus 30 days ]

Measure Type Other Pre-specified
Measure Title Number of Participants With Elevated Results of Liver Laboratory Tests
Measure Description ALT=alanine aminotransferase; ALP=alkaline phosphatase
Time Frame Day 1 of double-blind treatment to last double-blind dose, plus 30 days  
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.
This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug were included. n=participants with nonmissing laboratory test results

Reporting Groups
  Description
Placebo Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an oral antidiabetic agent (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotension-receptor blocker (ARB) received dapagliflozin-matching placebo daily with a morning meal.
Dapagliflozin, 10 mg Participants with type 2 diabetes mellitus and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB received dapagliflozin, 10 mg, daily with a morning meal.

Measured Values
    Placebo     Dapagliflozin, 10 mg  
Number of Participants Analyzed  
[units: participants]
  311     302  
Number of Participants With Elevated Results of Liver Laboratory Tests  
[units: Participants]
   
ALT elevation 3*ULN (n=305, 300)     2     2  
Total bilirubin elevation 1.5*ULN (n=305, 300)     1     0  
Total bilirubin elevation 2*ULN (n=305, 300)     1     0  
ALP elevation 1.5*ULN (n=305, 300)     4     7  

No statistical analysis provided for Number of Participants With Elevated Results of Liver Laboratory Tests




  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
Study originally had 2 additional arms, dapagliflozin 2.5 and 5 mg, but enrolment stopped after Protocol Amendment 8 (1-11-11) implemented. Because endpoints focused on comparison of dapagliflozin 10 mg with placebo, only these arms were summarized.


  More Information
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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: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT01137474     History of Changes
Other Study ID Numbers: MB102-073 ST, 2010-019797-32
Study First Received: June 3, 2010
Results First Received: February 7, 2014
Last Updated: April 1, 2014
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration
Canada: Health Canada
Mexico: Secretaria de Salud
Germany: Federal Institute for Drugs and Medical Devices
Australia: Department of Health and Ageing Therapeutic Goods Administration
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Hungary: National Institute of Pharmacy
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation