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

Study identifier:MB102-073 ST

ClinicalTrials.gov identifier:NCT01137474

EudraCT identifier:2010-019797-32

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 Subjects with Type 2 Diabetes with Inadequately Controlled Hypertension on an Angiotensin-Converting Enzyme Inhibitor (ACEI) or Angiotensin Receptor Blocker (ARB)

Medical condition

Type 2 Diabetes

Phase

Phase 3

Healthy volunteers

Study drug

Dapagliflozin, Placebo-matching dapagliflozin

Sex

All

Actual Enrollment

2996

Study type

Interventional

Age

18 Years - 89 Years

Date

Study Start Date: 01 Jul 2010

Primary Completion Date: 01 Feb 2013

Study Completion Date: 01 Feb 2013

Study design

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

Verification:

Verified 01 Nov 2016 by AstraZeneca

Collaborators

Bristol-Myers Squibb

Inclusion and exclusion criteria

Inclusion Criteria

- Participants willing and able to give signed and written informed consent
- Males and females, aged 18 to 89 years, who have type 2 diabetes with inadequate glycemic control (hemoglobin A1c between 7% and 10.5%) and uncontrolled hypertension (seated systolic blood pressure of 140 to 165 mm Hg and seated diastolic blood pressure 85 to 105 mm Hg)
- Mean 24-hour BP>=130/80 mmHg determined by ABPM
- Stable dose of oral antidiabetic agent (OAD) for at least 6 weeks (12 weeks for thiazolidinedione) or a stable daily dose of insulin as monotherapy or in combination with another OAD, for 8 weeks, and a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for at least 4 weeks
- C-peptide level ≥0.8 ng/mL
- Body mass index ≤ 45.0 kg/m^2
Key

Exclusion Criteria

- Aspartate aminotransferase or alanine aminotransferase level >3*upper limit of normal (ULN)
- Serum total bilirubin level >1.5*ULN
- Serum creatinine ≥2.0 mg/dL unless subject was on metformin, where exclusionary limits were serum creatinine ≥1.50 mg/dL for men and ≥1.40 mg/dL for women
-Estimated creatinine clearance of <60 mL/min
-Hemoglobin ≤10.0 g/dL for men and ≤9.0 g/dL for women
-Creatine kinase >3*ULN
-Positive for hepatitis B surface antigen
-Positive for antihepatitis C virus antibody
-Abnormal free T4 value
-History of diabetes insipidus
-Symptoms of poorly controlled diabetes that would preclude participation in this trial, including but not limited to, marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to enrollment.
-History of diabetic ketoacidosis or hyperosmolar nonketotic coma
-History of malignant and accelerated hypertension
-Known or suspected secondary hypertension
-Any of the following within 6 months of enrollment visit:
--Myocardial infarction
--Cardiac surgery or revascularization (coronary artery bypass surgery /percutaneous transluminal coronary angioplasty)
-- Unstable angina
--Unstable congestive heart disease or New York Heart Association Class III or IV
--Transient ischemic attack or significant cerebrovascular disease
--Unstable or previously undiagnosed arrhythmia

Location

Local Institution

Hyderabad, India, 500063

Location

Local Institution

Jaipur, RAJASTHAN, India, 202023

Location

Arlington Family Research Center, Inc.

Arlington, TX, United States, 76012

Location

Sooner Clinical Research

Oklahoma City, OK, United States, 73112

Location

Innovative Research Of West Florida, Inc

Clearwater, FL, United States, 33756

Location

Hope Research Institute

Phoenix, AZ, United States, 85050

Location

Local Institution

Barcelona, Spain, 08036

Location

Local Institution

Cidra, Puerto Rico, 00739

Arms	Assigned Interventions
Experimental: Dapagliflozin, 10 mg Oral tablets administered as 10 mg once daily for up to 12 weeks	Drug: Dapagliflozin Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks Other Name: BMS-512148
Placebo Comparator: Placebo-matching dapagliflozin Oral tablets administered once daily in the morning	Drug: Placebo-matching dapagliflozin Oral tablets administered as 0 mg once daily for up to 12 weeks
Experimental: Dapagliflozin, 2. 5 mg Oral tablets administered as 2.5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)	Drug: Dapagliflozin Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks Other Name: BMS-512148
Experimental: Dapagliflozin, 5 mg Oral tablets administered as 5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)	Drug: Dapagliflozin Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks Other Name: BMS-512148

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: Overall Study

	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

Baseline Characteristics

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

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 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 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 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.

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, Male/Female [units: Participants]
Female	140	76	76	123	415
Male	171	90	89	179	529
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 to 30 kg/m^2	131	67	63	95	356
30 kg/m^2 and greater	152	79	84	173	488

Outcome Measures

1. Primary Outcome Measure: 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 Name	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
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measures analysis]
P-Value^[4]	0.0010
Mean Difference (Final Values)^[5]	-3.05
Standard Error of the mean	± 0.9251
95% Confidence Interval	( -4.87 to -1.24 )

[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]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant 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.
[4]	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.
[5]	Other relevant estimation information:
	No text entered.

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

Measure Type	Primary
Measure Name	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 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 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 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
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measures analysis]
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.46
Standard Error of the mean	± 0.0673
95% Confidence Interval	( -0.59 to -0.33 )

[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]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant 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
[4]	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.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: 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 Name	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 (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 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 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
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0043
Mean Difference (Final Values)^[5]	-2.89
Standard Error of the mean	± 1.0091
95% Confidence Interval	( -4.88 to -0.91 )

[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]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant 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.
[4]	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.
[5]	Other relevant estimation information:
	No text entered.

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

Measure Type	Secondary
Measure Name	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 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 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
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measures analysis]
P-Value^[4]	0.0843
Mean Difference (Final Values)^[5]	-1.00
Standard Error of the mean	± 0.5811
95% Confidence Interval	( -2.15 to 0.14 )

[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]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant 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.
[4]	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.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: 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 Name	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 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 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
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
Mean Difference (Final Values)^[5]	-0.62
Standard Error of the mean	± 0.6866
95% Confidence Interval	( -1.96 to 0.73 )

[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]	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.

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

Measure Type	Secondary
Measure Name	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 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 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
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Other [Longitudinal repeated measures analysis]
Mean Difference (Final Values)^[5]	-0.32
Standard Error of the mean	± 0.0717
95% Confidence Interval	( -0.46 to -0.18 )

[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]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant 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.
[5]	Other relevant estimation information:
	No text entered.

Serious Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

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 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 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.

Serious Adverse Events

Placebo

Dapagliflozin, 2.5 mg (Randomized before Protocol Amendment 8)

Dapagliflozin, 5 mg (Randomized before Protocol Amendment 8)

Dapagliflozin 10 mg

Total, serious adverse events

# participants affected / at risk

4/311 (1.29%)

3/166 (1.81%)

2/165 (1.21%)

2/302 (0.66%)

Infections and infestations

Mastoiditis¹,^†

# participants affected / at risk

0/311 (0.00%)

0/166 (0.00%)

0/165 (0.00%)

1/302 (0.33%)

Injury, poisoning and procedural complications

Craniocerebral injury¹,^†

# participants affected / at risk

0/311 (0.00%)

0/166 (0.00%)

1/165 (0.61%)

0/302 (0.00%)

Injury, poisoning and procedural complications

Fall¹,^†

# participants affected / at risk

0/311 (0.00%)

0/166 (0.00%)

1/165 (0.61%)

0/302 (0.00%)

Hepatobiliary disorders

Cholecystitis acute¹,^†

# participants affected / at risk

0/311 (0.00%)

0/166 (0.00%)

1/165 (0.61%)

0/302 (0.00%)

Musculoskeletal and connective tissue disorders

Intervertebral disc disorder¹,^†

# participants affected / at risk

0/311 (0.00%)

1/166 (0.60%)

0/165 (0.00%)

0/302 (0.00%)

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

1/311 (0.32%)

1/166 (0.60%)

0/165 (0.00%)

0/302 (0.00%)

Injury, poisoning and procedural complications

Lumbar vertebral fracture¹,^†

# participants affected / at risk

0/311 (0.00%)

1/166 (0.60%)

0/165 (0.00%)

0/302 (0.00%)

Skin and subcutaneous tissue disorders

Subcutaneous emphysema¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

Infections and infestations

Abscess intestinal¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

Infections and infestations

Appendiceal abscess¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

General disorders and administration site conditions

Chest pain¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

Injury, poisoning and procedural complications

Rib fracture¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

Injury, poisoning and procedural complications

Road traffic accident¹,^†

# participants affected / at risk

1/311 (0.32%)

1/166 (0.60%)

0/165 (0.00%)

0/302 (0.00%)

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

Infections and infestations

Appendicitis¹,^†

# participants affected / at risk

1/311 (0.32%)

0/166 (0.00%)

0/165 (0.00%)

0/302 (0.00%)

Injury, poisoning and procedural complications

Cervical vertebral fracture¹,^†

# participants affected / at risk

0/311 (0.00%)

1/166 (0.60%)

0/165 (0.00%)

0/302 (0.00%)

Infections and infestations

Otitis media¹,^†

# participants affected / at risk

0/311 (0.00%)

0/166 (0.00%)

0/165 (0.00%)

1/302 (0.33%)

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

Rectal adenoma¹,^†

# participants affected / at risk

0/311 (0.00%)

0/166 (0.00%)

0/165 (0.00%)

1/302 (0.33%)

Musculoskeletal and connective tissue disorders

Intervertebral disc protrusion¹,^†

# participants affected / at risk

0/311 (0.00%)

1/166 (0.60%)

0/165 (0.00%)

0/302 (0.00%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 15.1

Other Adverse Events

Time Frame	No text entered.
Additional Description	No text entered.

Frequency Threshold

Threshold above which other adverse events are reported	5%

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 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 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.

Other Adverse Events

	Placebo	Dapagliflozin, 2.5 mg (Randomized before Protocol Amendment 8)	Dapagliflozin, 5 mg (Randomized before Protocol Amendment 8)	Dapagliflozin 10 mg
Total, other (not including serious) adverse events
# participants affected / at risk	0/311 (0.00%)	0/166 (0.00%)	0/165 (0.00%)	0/302 (0.00%)

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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.

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.

Results Point of Contact

Name/Title:	AstraZeneca
Organization:	Clinical Trial Transparency
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
Redacted_Protocol
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center AstraZeneca

1-877-240 9479

information.center@astrazeneca.com

Investigators

Principal Investigator

Bristol-Myers Squibb

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Local Institution

Local Institution

Arlington Family Research Center, Inc.

Sooner Clinical Research

Innovative Research Of West Florida, Inc

Hope Research Institute

Local Institution

Local Institution

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

Redacted_Protocol

Trial Results Summaries