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Phase IV Study With a 36-week Extension Period to Evaluate the Efficacy and Safety of Dapagliflozin Therapy When Added to the Therapy of Japanese Patients With Type 2 Diabetes With Inadequate Glycemic Control on Insulin.

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ClinicalTrials.gov Identifier: NCT02157298
Recruitment Status : Completed
First Posted : June 6, 2014
Results First Posted : March 17, 2016
Last Update Posted : May 11, 2016
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Type 2 Diabetes Mellitus
Interventions Drug: Dapagliflozin 5 mg
Drug: Placebo tablet
Enrollment 266

Recruitment Details First participant enrolled: 06-Jun-2014; Last participant last visit of ST period: 02-Feb-2015; 266 participants were enrolled in 20 Japanese centers. 183 Japanese men or women aged >=20 years with inadequate glycemic control (HbA1c levels of >=7.2% to <11.0%) with diet, exercise and on stable dose of insulin +/- DPP-4 inhibitor were treated.
Pre-assignment Details A 8-week wash-out period was applicable only for participants on ongoing anti-diabetic treatment at enrollment. A 2-week lead-in period was applicable for all participants.
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor Placebo plus insulin alone or in combination with DPP-4 inhibitor
Period Title: Overall Study
Started 123 60
Completed 119 58
Not Completed 4 2
Reason Not Completed
Adverse Event             1             0
Subject no longer meets study criteria             1             2
Poor/Non-compliance             1             0
Withdrawal by Subject             1             0
Arm/Group Title Dapagliflozin Placebo Total
Hide Arm/Group Description Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor Placebo plus insulin alone or in combination with DPP-4 inhibitor Total of all reporting groups
Overall Number of Baseline Participants 122 60 182
Hide Baseline Analysis Population Description
The 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 the short-term double-blind treatment period.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 122 participants 60 participants 182 participants
58.3  (9.83) 57.6  (9.86) 58.0  (9.82)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 122 participants 60 participants 182 participants
<=65 years 84 43 127
Between 65 and 75 years 37 16 53
>=75 years 1 1 2
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 122 participants 60 participants 182 participants
Female
33
  27.0%
20
  33.3%
53
  29.1%
Male
89
  73.0%
40
  66.7%
129
  70.9%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Japan Number Analyzed 122 participants 60 participants 182 participants
122 60 182
Body Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 122 participants 60 participants 182 participants
73.90  (15.663) 71.89  (13.430) 73.24  (14.956)
Body Mass Index  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 122 participants 60 participants 182 participants
26.89  (4.930) 26.12  (3.485) 26.64  (4.510)
Waist Circumference  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 122 participants 60 participants 182 participants
93.2  (11.83) 92.3  (9.00) 92.9  (10.96)
HbA1c  
Mean (Standard Deviation)
Unit of measure:  Percent of hemoglobin glycosylated
Number Analyzed 122 participants 60 participants 182 participants
8.26  (0.792) 8.52  (0.937) 8.34  (0.849)
Fasting Plasma Glucose  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 122 participants 60 participants 182 participants
160.70  (44.948) 159.68  (38.001) 160.36  (42.679)
Calculated Mean Daily Insulin Dose  
Mean (Standard Deviation)
Unit of measure:  IU/Day
Number Analyzed 122 participants 60 participants 182 participants
37.87  (18.033) 40.58  (16.764) 38.76  (17.625)
DPP-4 Inhibitor Usage  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 122 participants 60 participants 182 participants
Yes 54 27 81
No 68 33 101
1.Primary Outcome
Title Adjusted Mean Change in HbA1c Levels
Hide Description Mean change in HbA1c levels from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time Frame Baseline to Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description:
Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor
Placebo plus insulin alone or in combination with DPP-4 inhibitor
Overall Number of Participants Analyzed 122 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percentage of hemoglobin glycosylated
-0.55
(-0.67 to -0.42)
0.05
(-0.13 to 0.23)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapagliflozin, Placebo
Comments H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Significant at alpha=0.05 (two-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
Method Mixed Models Analysis
Comments with fixed categorical effects of treatment, week, DPP-4, baseline eGFR, treatment-by-week interaction, continuous fixed covariate of baseline value.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.60
Confidence Interval (2-Sided) 95%
-0.81 to -0.39
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.1053
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Fasting Plasma Glucose
Hide Description Mean change in fasting plasma glucose from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time Frame Baseline to Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description:
Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor
Placebo plus insulin alone or in combination with DPP-4 inhibitor
Overall Number of Participants Analyzed 121 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-21.7
(-28.3 to -15.1)
1.0
(-8.4 to 10.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapagliflozin, Placebo
Comments H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Significant at alpha=0.05 (two-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
Method Mixed Models Analysis
Comments with fixed categorical effects of treatment, week, DPP-4, baseline eGFR, treatment-by-week interaction, continuous fixed covariate of baseline value.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -22.7
Confidence Interval (2-Sided) 95%
-33.2 to -12.2
Parameter Dispersion
Type: Standard Error of the mean
Value: 5.301
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Total Body Weight
Hide Description Mean change in total body weight from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time Frame Baseline to Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description:
Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor
Placebo plus insulin alone or in combination with DPP-4 inhibitor
Overall Number of Participants Analyzed 122 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: kg
-0.6
(-0.9 to -0.2)
0.7
(0.2 to 1.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapagliflozin, Placebo
Comments H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Significant at alpha=0.05 (two-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
Method Mixed Models Analysis
Comments with fixed categorical effects of treatment, week, DPP-4, baseline eGFR, treatment-by-week interaction, continuous fixed covariate of baseline value.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.2
Confidence Interval (2-Sided) 95%
-1.7 to -0.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.255
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Total Mean Daily Insulin Dose
Hide Description Mean change in calculated mean daily insulin dose from baseline to Week 16 between dapagliflozin 5 mg versus placebo
Time Frame Baseline to Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set, participants with non-missing baseline and at least one post-baseline value up to week 16
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description:
Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor
Placebo plus insulin alone or in combination with DPP-4 inhibitor
Overall Number of Participants Analyzed 121 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: IU/Day
-0.74
(-1.21 to -0.27)
-0.02
(-0.68 to 0.64)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapagliflozin, Placebo
Comments H0: mean(dapa) minus mean(placebo) = 0 versus alternative HA: mean(dapa) minus mean(placebo) =/= 0
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0743
Comments Significant at alpha=0.05 (two-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
Method Mixed Models Analysis
Comments with fixed categorical effects of treatment, week, DPP-4, baseline eGFR, treatment-by-week interaction, continuous fixed covariate of baseline value.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.72
Confidence Interval (2-Sided) 95%
-1.51 to 0.07
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.4017
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Proportion of Participants With Mean Daily Insulin Dose Reduction of Greater Than or Equal 10%
Hide Description Proportion of participants with mean daily insulin dose reduction greater than or equal 10% from baseline to week 16 (LOCF) between dapagliflozin 5 mg versus placebo
Time Frame Baseline to Week 16
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set, participants with non-missing baseline and Week 16 (LOCF) value
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description:
Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor
Placebo plus insulin alone or in combination with DPP-4 inhibitor
Overall Number of Participants Analyzed 121 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percentage of participants
8.2
(3.3 to 13.1)
4.9
(-0.7 to 10.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dapagliflozin, Placebo
Comments H0: proportion(dapa) minus proportion(placebo) = 0 versus alternative HA: proportion(dapa) minus proportion(placebo) =/= 0
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3727
Comments Significant at alpha=0.05 (two-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
Method Regression, Logistic
Comments Based on methodology of Zhang, Tsiatis & Davidian and Tsitatis, Davidian, Zhang & Lu, with adjustment with adjustment for baseline value and DPP-4
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 3.4
Confidence Interval (2-Sided) 95%
-4.0 to 10.7
Parameter Dispersion
Type: Standard Error of the mean
Value: 3.769
Estimation Comments [Not Specified]
Time Frame Non-serious/serious adverse events on or after the first date of double-blind treatment and on or prior to the last day plus 4/30 days or up to follow-up visit if earlier, or up to and excluding the start date of open-label extension period if earlier.
Adverse Event Reporting Description Participants were questioned at each study 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.
 
Arm/Group Title Dapagliflozin Placebo
Hide Arm/Group Description Dapagliflozin 5 mg plus insulin alone or in combination with DPP-4 inhibitor Placebo plus insulin alone or in combination with DPP-4 inhibitor
All-Cause Mortality
Dapagliflozin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Dapagliflozin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/123 (2.44%)      0/60 (0.00%)    
Hepatobiliary disorders     
Cholelithiasis  1  1/123 (0.81%)  1 0/60 (0.00%)  0
Injury, poisoning and procedural complications     
Hand fracture  1  1/123 (0.81%)  1 0/60 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Osteochondrosis  1  1/123 (0.81%)  1 0/60 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Dapagliflozin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   24/123 (19.51%)      10/60 (16.67%)    
Gastrointestinal disorders     
Constipation  1  3/123 (2.44%)  3/60 (5.00%) 
Infections and infestations     
Nasopharyngitis  1  13/123 (10.57%)  7/60 (11.67%) 
Renal and urinary disorders     
Pollakiuria  1  11/123 (8.94%)  3/60 (5.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
For HbA1c, FPG and TBW: excluding data after insulin up-titration and for Mean Daily Insulin Dose: including data after insulin up-titration were used. For participants who did not complete week 16 last observation carried forward (LOCF) was used.
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.
If an Investigator requests permission to publish data from this study any such publication is to be agreed with AstraZeneca (AZ) in advance. The investigator agrees to provide AZ as soon as possible with drafts of proposed publications. Unless otherwise agreed, AZ shall have a period of 60 days from receipt of the proposed final manuscript to review it and may within such time require that submission for publication of the manuscript be delayed in order for AZ to file patent applications.
Results Point of Contact
Name/Title: Yuji Ageishi
Organization: AstraZeneca K.K.
Phone: +81-3-6268-2740
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02157298     History of Changes
Other Study ID Numbers: D1692C00013
First Submitted: June 2, 2014
First Posted: June 6, 2014
Results First Submitted: February 18, 2016
Results First Posted: March 17, 2016
Last Update Posted: May 11, 2016