Add-on to Thiazolidinedione (TZD) Failures

Study identifier:MB102-030

ClinicalTrials.gov identifier:NCT00683878

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Combination with Thiazolidinedione Therapy in Subjects with Type 2 Diabetes who have Inadequate Glycemic Control on Thiazolidinedione Therapy Alone

Medical condition

Type 2 Diabetes

Phase

Phase 3

Healthy volunteers

Study drug

Dapagliflozin, Placebo matching Dapagliflozin, Thiazolidinedione (Pioglitazone)

Sex

All

Actual Enrollment

972

Study type

Interventional

Age

18 Years +

Date

Study Start Date: 01 Jul 2008

Primary Completion Date: 01 Jan 2010

Study Completion Date: 01 Jun 2010

Study design

Allocation: Randomized
Endpoint Classification: Safety/Efficacy
Intervention Model: Parallel Assignment
Masking: Double Blind
Primary Purpose: Treatment

Verification:

Verified 01 Jan 2017 by AstraZeneca Pharmaceuticals

Collaborators

Astra-Zeneca, Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Local Institution

Cebu City, Philippines, 6000

Location

Local Institution

Pasig City, Philippines, 1600

Location

Local Institution

Manila, Philippines, 1000

Location

Local Institution

Lima, Lima, Peru, 17

Location

Local Institution

Lima, Lima, Peru, 31

Location

The Center For Nutrition & Preventive Medicine, Pllc

Charlotte, NC, United States, 28277

Location

Diabetes Medical Center Of California

Northridge, CA, United States, 91325

Location

Banksville Medical, Pc

Pittsburgh, PA, United States, 15216

Arms	Assigned Interventions
Experimental: Arm 1	Drug: Dapagliflozin Tablets, Oral, 5.0 mg, once daily, up to 48 weeks Other Name: BMS-512148 Drug: Thiazolidinedione (Pioglitazone) Tablets, ≥ 30 mg, Once daily, up to 48 weeks
Experimental: Arm 2	Drug: Dapagliflozin Tablets, Oral, 10.0 mg, once daily, up to 48 weeks Other Name: BMS-512148 Drug: Thiazolidinedione (Pioglitazone) Tablets, ≥ 30 mg, Once daily, up to 48 weeks
Placebo Comparator: Arm 3	Drug: Placebo matching Dapagliflozin Tablets, Oral, 0 mg, once daily, up to 48 weeks Drug: Thiazolidinedione (Pioglitazone) Tablets, ≥ 30 mg, Once daily, up to 48 weeks

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Of 972 participants enrolled, 558 completed a qualification period. Before entering lead-in period, 344 participants entered dose optimization period and 263 completed. A total of 480 participants entered the lead-in period, 420 randomized and received treatment, 367 completed double-blind treatment period.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Participant Flow: Overall Study

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
STARTED	139	141	140
COMPLETED	116	125	126
NOT COMPLETED	23	16	14
Lack of Efficacy	3	0	1
Adverse Event	4	3	3
Withdrawal by Subject	9	8	6
Death	0	1	0
Lost to Follow-up	4	2	4
Non-compliance, not met criteria etc.	3	2	0

Baseline Characteristics

Analysis Population Description -- Explanation of how the number of participants for analysis was determined.

All randomized patients who received at least one dose of study medication.

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Baseline Measures

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone	Total
Number of Participants [units: Participants]	139	141	140	420
Age Continuous [units: Years] Mean ± Standard Deviation	53.5 ± 11.38	53.2 ± 10.90	53.8 ± 10.35	53.5 ± 10.86
Age, Customized [units: Participants]
Yonger than 65 years	115	120	118	353
65 to younger than 75 years	21	16	20	57
75 years and older	3	5	2	10
Gender, Male/Female [units: Participants]
Female	68	63	81	212
Male	71	78	59	208
Race/Ethnicity, Customized [units: Participants]
Asian	24	26	21	71
Black/African American	6	9	7	22
White	102	102	101	305
Other	7	4	11	22

Outcome Measures

1. Primary Outcome Measure: Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Primary
Measure Name	Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 24 (LOCF)

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	138	140	140
Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) [units: % of hemoglobin] Mean (Standard Error)	-0.42 (0.0834)	-0.82 (0.0828)	-0.97 (0.0828)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0007
Mean Difference (Final Values)^[5]	-0.40
Standard Error of the mean	± 0.1175
95% Confidence Interval	( -0.63 to -0.17 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Primary endpoints were tested at alpha=0.027 applying Dunnett’s adjustment
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.55
Standard Error of the mean	± 0.1175
95% Confidence Interval	( -0.78 to -0.31 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Primary endpoints were tested at alpha=0.027 applying Dunnett’s adjustment
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. In post oral glucose tolerance test (OGTT), glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained on Day 1 and week 24 in the double-blind period.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 24 (LOCF)

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	112	116	115
Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF]) [units: mg/dL] Mean (Standard Error)	-14.1 (6.421)	-65.1 (6.325)	-67.5 (6.359)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-51.0
Standard Error of the mean	± 9.007
95% Confidence Interval	( -68.7 to -33.2 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in 120-minute Post-challenge Plasma Glucose (PPG) (mg/dL) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-53.3
Standard Error of the mean	± 9.039
95% Confidence Interval	( -71.1 to -35.6 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the double-blind period.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing body weight values at baseline and Week 24 (LOCF)

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	139	140	140
Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) [units: kg] Mean (Standard Error)	1.64 (0.2760)	0.09 (0.2752)	-0.14 (0.2753)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-1.55
Standard Error of the mean	± 0.3896
95% Confidence Interval	( -2.32 to -0.79 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-1.78
Standard Error of the mean	± 0.3896
95% Confidence Interval	( -2.55 to -1.02 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing FPG values at baseline and Week 24 (LOCF)

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	139	140	140
Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) [units: mg/dL] Mean (Standard Error)	-5.5 (2.893)	-24.9 (2.884)	-29.6 (2.880)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-19.5
Standard Error of the mean	± 4.088
95% Confidence Interval	( -27.5 to -11.4 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-24.1
Standard Error of the mean	± 4.082
95% Confidence Interval	( -32.2 to -16.1 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. Mean and standard error for percentage of participants were estimated by modified logistic regression model.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF)

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	138	140	140
Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) [units: Percentage of participants] Mean (Standard Error)	22.4 (3.276)	32.5 (3.669)	38.8 (3.835)

Statistical Analysis 1 for Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Modified logistic regression]
P-Value^[4]	0.0496
Mean Difference (Final Values)^[5]	10.1
Standard Error of the mean	± 5.119
95% Confidence Interval	( 0.0 to 20.1 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Modified logistic regression]
P-Value^[4]	0.0018
Mean Difference (Final Values)^[5]	16.4
Standard Error of the mean	± 5.253
95% Confidence Interval	( 6.1 to 26.7 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

6. Secondary Outcome Measure: Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in waist circumference at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Waist circumference measurements were obtained during the qualification and lead-in periods and on Day 1 and Week 24 of the double-blind period.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing waist circumference values at baseline and Week 24 (LOCF)

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	126	132	133
Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF]) [units: cm] Mean (Standard Error)	1.38 (0.4301)	0.52 (0.4198)	-0.17 (0.4182)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.1566
Mean Difference (Final Values)^[5]	-0.85
Standard Error of the mean	± 0.6006
95% Confidence Interval	( -2.03 to 0.33 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Waist Circumference (cm) at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0101
Mean Difference (Final Values)^[5]	-1.55
Standard Error of the mean	± 0.5995
95% Confidence Interval	( -2.73 to -0.37 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

7. Secondary Outcome Measure: Adjusted Mean Change From Baseline in Total Body Weight (kg) among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted Mean Change From Baseline in Total Body Weight (kg) among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF])
Measure Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 4, 8, 12, 16, 20, and 24 of the double-blind period.
Time Frame	From Baseline to Week 24
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.
All randomized participants who received study medication and had nonmissing body weight values at baseline and Week 24 (LOCF) among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Measured Values

	PLACEBO + Pioglitazone	Dapagliflozin 5MG + Pioglitazone	Dapagliflozin 10MG + Pioglitazone
Number of Participants Analyzed [units:participants]	113	101	113
Adjusted Mean Change From Baseline in Total Body Weight (kg) among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) [units: kg] Mean (Standard Error)	1.83 (0.3313)	0.26 (0.3523)	-0.07 (0.3332)

Statistical Analysis 1 for Adjusted Mean Change From Baseline in Total Body Weight (kg) among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 5MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Mean Difference (Final Values)^[5]	-1.58
Standard Error of the mean	± 0.4838
95% Confidence Interval	( -2.53 to -0.62 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted Mean Change From Baseline in Total Body Weight (kg) among subjects with baseline body mass index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF])

Groups^[1]	PLACEBO + Pioglitazone, Dapagliflozin 10MG + Pioglitazone
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-1.90
Standard Error of the mean	± 0.4688
95% Confidence Interval	( -2.83 to -0.98 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	Onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment 24 weeks plus 4 days for non-serious adverse event; plus 30 days for serious adverse event.
Additional Description	No text entered.

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Serious Adverse Events

PLACEBO + Pioglitazone

Dapagliflozin 5MG + Pioglitazone

Dapagliflozin 10MG + Pioglitazone

Total, serious adverse events

# participants affected / at risk

1/139 (0.72%)

4/141 (2.84%)

2/140 (1.43%)

Gastrointestinal disorders

ABDOMINAL PAIN UPPER ¹,^†

# participants affected / at risk

0/139 (0.00%)

0/141 (0.00%)

1/140 (0.71%)

# events

Investigations

HEPATIC ENZYME INCREASED¹,^†

# participants affected / at risk

0/139 (0.00%)

0/141 (0.00%)

1/140 (0.71%)

# events

Musculoskeletal and connective tissue disorders

PAIN IN EXTREMITY¹,^†

# participants affected / at risk

0/139 (0.00%)

0/141 (0.00%)

1/140 (0.71%)

# events

Cardiac disorders

ACUTE MYOCARDIAL INFARCTION¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

Cardiac disorders

CORONARY ARTERY DISEASE¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

General disorders

NON-CARDIAC CHEST PAIN¹,^†

# participants affected / at risk

1/139 (0.72%)

0/141 (0.00%)

0/140 (0.00%)

# events

Hepatobiliary disorders

CHOLECYSTITIS ACUTE¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

Hepatobiliary disorders

CHOLELITHIASIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

Infections and infestations

SEPTIC SHOCK¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

TRANSITIONAL CELL CARCINOMA¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

Renal and urinary disorders

NEPHROLITHIASIS¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

Renal and urinary disorders

RENAL COLIC¹,^†

# participants affected / at risk

0/139 (0.00%)

1/141 (0.71%)

0/140 (0.00%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA Version: 12.1

Other Adverse Events

Time Frame	Onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment 24 weeks plus 4 days for non-serious adverse event; plus 30 days for serious adverse event.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
PLACEBO + Pioglitazone	Placebo tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 5MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks
Dapagliflozin 10MG + Pioglitazone	Dapagliflozin tablets, oral, once daily, up to 48 weeks plus pioglitazone tablets, ≥ 30 mg, once daily up to 48 weeks

Other Adverse Events

PLACEBO + Pioglitazone

Dapagliflozin 5MG + Pioglitazone

Dapagliflozin 10MG + Pioglitazone

Total, other (not including serious) adverse events

# participants affected / at risk

37/139 (26.62%)

34/141 (24.11%)

45/140 (32.14%)

Metabolism and nutrition disorders

DYSLIPIDAEMIA¹,^†

# participants affected / at risk

6/139 (4.32%)

8/141 (5.67%)

13/140 (9.29%)

# events

Infections and infestations

NASOPHARYNGITIS¹,^†

# participants affected / at risk

5/139 (3.60%)

7/141 (4.96%)

11/140 (7.86%)

# events

Gastrointestinal disorders

DIARRHOEA¹,^†

# participants affected / at risk

6/139 (4.32%)

4/141 (2.84%)

9/140 (6.43%)

# events

Musculoskeletal and connective tissue disorders

BACK PAIN¹,^†

# participants affected / at risk

2/139 (1.44%)

5/141 (3.55%)

7/140 (5.00%)

# events

Infections and infestations

UPPER RESPIRATORY TRACT INFECTION¹,^†

# participants affected / at risk

8/139 (5.76%)

9/141 (6.38%)

7/140 (5.00%)

# events

Nervous system disorders

HEADACHE¹,^†

# participants affected / at risk

9/139 (6.47%)

3/141 (2.13%)

4/140 (2.86%)

# events

General disorders

OEDEMA PERIPHERAL¹,^†

# participants affected / at risk

7/139 (5.04%)

4/141 (2.84%)

3/140 (2.14%)

# events

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA Version: 12.1

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT 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.

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
No text entered.

Results Point of Contact

Name/Title:	Anna Maria Langkilde
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm
Download
Publication
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Bristol-Myers Squibb

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Local Institution

Local Institution

Local Institution

Local Institution

Local Institution

The Center For Nutrition & Preventive Medicine, Pllc

Diabetes Medical Center Of California

Banksville Medical, Pc

For FDA Safety Alerts and Recalls refer to the following link: http://www.fda.gov/MEDWATCH/safety.htm

Publication

Trial Results Summaries