Efficacy and Safety in Patients with type 2 Diabetes Mellitus and Cardiovascular Disease

Study identifier:D1690C00019

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A 24-week, multicentre, randomised, double-blind,age-stratified, placebo controlled phase III study with an 80-week extension period to evaluate the efficacy and safety of dapagliflozin 10 mg once daily in patients with T2DM and cardiovascular disease, who exhibit inadequate glycaemic control on usual care

Medical condition

Type 2 Diabetes Mellitus

Phase

Phase 3

Healthy volunteers

Study drug

Dapagliflozin, Placebo

Sex

All

Actual Enrollment

964

Study type

Interventional

Age

45 Years - 150 Years

Date

Study Start Date: 01 Mar 2010

Primary Completion Date: 01 May 2011

Study Completion Date: 01 Dec 2012

Study design

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

Verification:

Verified 01 Dec 2013 by AstraZeneca

Collaborators

Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Research Site

BUENOS AIRES, CABA, Argentina

Location

Research Site

CORDOBA, Cordoba, Argentina

Location

Research Site

ROSARIO, SANTA FE, Argentina

Location

Research Site

SALTA, Salta, Argentina

Location

Research Site

SANTA FE, SANTA FE, Argentina

Location

Research Site

ADELAIDE, SA, Australia

Location

Research Site

BEDFORD PARK, SA, Australia

Location

Research Site

BLACKTOWN, NSW, Australia

Arms	Assigned Interventions
Experimental: 1 dapagliflozin 10 mg tablet	Drug: Dapagliflozin 10 mg tablet, oral, once daily, 24- week treatment and 80-week extension period
Placebo Comparator: 2 matching placebo tablet	Drug: Placebo matching placebo tablet, oral, once daily, 24- week treatment and 80-week extension period

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
First participant enrolled 15 Mar 2010, last part. last visit for 24-week period: 30 May 2011. 1489 part. enrolled, 964 randomized in USA, Canada, Australia, Chile, Argentina and 5 European countries (value presented in ‘Enrolment’ field). One add. part. treated but not randomized. Part. with T2DM and CVD who showed inadequate glycemic control.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
During a placebo lead-in period, participants were counselled on dietary and life-style modifications. Anti-diabetic therapy should be kept constant 4 weeks prior to enrolment. Participants eligible for the study were stratified according to age (<65 years or ≥65 years), insulin use and time from most recent qualifying CV event (>1 or ≤1 year).

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Participant Flow: Overall Study

	Dapagliflozin	Placebo
STARTED	482^[1]	483^[2]
COMPLETED	441	428
NOT COMPLETED	41	55
Adverse Event	4	12
Death	2	1
Withdrawal by Subject	8	16
Lost to Follow-up	0	2
Poor/non-compliance	3	4
Subject no longer meets study criteria	15	13
Incorrect enrollment	6	4
Safety	0	2
Administrative reason by sponsor	0	1
Various	3	0

[1]	Of 482 part. 480 were included in full analysis set. Thereof, 1 part. treated but not randomized.
[2]	Of the 483 participants only 482 were included in the full analysis set.

Baseline Characteristics

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

Full Analysis Set defined as all randomized participants (as randomized) who received at least one dose of double-blind study medication, who have a non-missing baseline value and at least one post-baseline efficacy value for at least one efficacy variable during double-blind treatment period.

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Baseline Measures

	Dapagliflozin	Placebo	Total
Number of Participants [units: Participants]	480	482	962
Age Continuous [units: Years] Mean ± Standard Deviation	63.9 ± 7.60	63.6 ± 7.02	63.8 ± 7.31
Gender, Male/Female [units: Participants]
Female	159	159	318
Male	321	323	644
Race, Customized [units: Participants]
White	454	449	903
Black/African American	9	10	19
Asian	6	7	13
Other	11	16	27
HbA1c [units: Percent] Mean ± Standard Deviation	8.04 ± 0.759	8.08 ± 0.795	8.06 ± 0.777
Body weight [units: kg] Mean ± Standard Deviation	94.53 ± 17.804	93.23 ± 16.842	93.88 ± 17.332
Systolic Blood Pressure [units: mmHg] Mean ± Standard Deviation	134.9 ± 14.53	134.6 ± 13.96	134.7 ± 14.24
Number of participants with BMI >= 27 kg/m2 at baseline [units: Participants]
< 25 kg/m²	15	31	46
>= 25 kg/m²	465	451	916
>= 27 kg/m²	428	416	844
>= 30 kg/m²	339	325	664

Outcome Measures

1. Primary Outcome Measure: Adjusted mean change in HbA1c levels [ Time Frame: Baseline to Week 24 ]

Measure Type	Primary
Measure Name	Adjusted mean change in HbA1c levels
Measure Description	To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease, measured as the mean change in HbA1c from baseline to week 24.
Time Frame	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.
Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	474	471
Adjusted mean change in HbA1c levels [units: Percent] Least Squares Mean (95% Confidence Interval)	-0.33 (-0.42 to -0.25)	0.07 (-0.02 to 0.15)

Statistical Analysis 1 for Adjusted mean change in HbA1c levels

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.40
Standard Error of the mean	± 0.0489
95% Confidence Interval	( -0.50 to -0.30 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	with treatment group and stratum as effects and baseline value as covariate for each endpoint
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.025 (2-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
[5]	Other relevant estimation information:
	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

2. Primary Outcome Measure: Proportion of responders meeting all criteria of a 3-item endpoint of clinical benefit [ Time Frame: Baseline to Week 24 ]

Measure Type	Primary
Measure Name	Proportion of responders meeting all criteria of a 3-item endpoint of clinical benefit
Measure Description	To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.
Time Frame	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.
Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	468	469
Proportion of responders meeting all criteria of a 3-item endpoint of clinical benefit [units: Percentage of participants] Number (95% Confidence Interval)	10.0 (7.3 to 12.8)	1.9 (0.7 to 3.2)

Statistical Analysis 1 for Proportion of responders meeting all criteria of a 3-item endpoint of clinical benefit

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Cochran-Mantel-Haenszel
P-Value^[4]	<0.0001
Risk Difference (RD)^[5]	7.0
95% Confidence Interval	( 4.3 to 9.8 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	with age-by-insulin use-by-time from most recent qualifying CV event as stratum
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.025 (2-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Adjusted mean percent change in body weight [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted mean percent change in body weight
Measure Description	To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time Frame	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.
Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	480	481
Adjusted mean percent change in body weight [units: Percentage of Body Weight] Least Squares Mean (95% Confidence Interval)	-2.53 (-2.87 to -2.18)	-0.61 (-0.96 to -0.26)

Statistical Analysis 1 for Adjusted mean percent change in body weight

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-1.93
Standard Error of the mean	± 0.1957
95% Confidence Interval	( -2.31 to -1.54 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	with treatment group and stratum as effects and baseline value as covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
[5]	Other relevant estimation information:
	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

4. Secondary Outcome Measure: Proportion of participants with a reduction from baseline of 5% or more in body weight in participants with baseline BMI ≥27 kg/m² [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Proportion of participants with a reduction from baseline of 5% or more in body weight in participants with baseline BMI ≥27 kg/m²
Measure Description	To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum.
Time Frame	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.
Full Analysis Set, subjects with baseline BMI ≥27 kg/m2 and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	428	415
Proportion of participants with a reduction from baseline of 5% or more in body weight in participants with baseline BMI ≥27 kg/m² [units: Percentage of participants] Least Squares Mean (95% Confidence Interval)	18.4 (14.8 to 22.1)	4.8 (2.8 to 6.9)

Statistical Analysis 1 for Proportion of participants with a reduction from baseline of 5% or more in body weight in participants with baseline BMI ≥27 kg/m²

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Regression, Logistic
P-Value^[4]	<0.0001
Risk Difference (RD)^[5]	13.6
Standard Error of the mean	± 2.149
95% Confidence Interval	( 9.4 to 17.8 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	Based on methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu, with adjustment for baseline total body weight and age stratum
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Adjusted mean change in systolic blood pressure at Week 8 (LOCF) [ Time Frame: Baseline to Week 8 ]

Measure Type	Secondary
Measure Name	Adjusted mean change in systolic blood pressure at Week 8 (LOCF)
Measure Description	To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 8
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set, subjects with non-missing baseline and Week 8 (LOCF) values

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	473	479
Adjusted mean change in systolic blood pressure at Week 8 (LOCF) [units: mmHg] Least Squares Mean (95% Confidence Interval)	-1.85 (-3.25 to -0.45)	0.86 (-0.53 to 2.26)

Statistical Analysis 1 for Adjusted mean change in systolic blood pressure at Week 8 (LOCF)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0007
Mean Difference (Final Values)^[5]	-2.71
Standard Error of the mean	± 0.7977
95% Confidence Interval	( -4.28 to -1.15 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	with treatment group and stratum as effects and baseline value as covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
[5]	Other relevant estimation information:
	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

6. Secondary Outcome Measure: Adjusted mean change in seated systolic blood pressure at Week 24 (LOCF) [ Time Frame: Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted mean change in seated systolic blood pressure at Week 24 (LOCF)
Measure Description	To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time Frame	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.
Full Analysis set, subjects with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	473	479
Adjusted mean change in seated systolic blood pressure at Week 24 (LOCF) [units: mmHg] Least Squares Mean (95% Confidence Interval)	-2.70 (-4.10 to -1.30)	0.32 (-1.07 to 1.72)

Statistical Analysis 1 for Adjusted mean change in seated systolic blood pressure at Week 24 (LOCF)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0002
Mean Difference (Final Values)^[5]	-3.02
Standard Error of the mean	± 0.7983
95% Confidence Interval	( -4.59 to -1.46 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	with treatment group and stratum as effects and baseline value as covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
[5]	Other relevant estimation information:
	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

7. Secondary Outcome Measure: Adjusted mean change in seated systolic blood pressure (SBP) at Week 8 (LOCF) in participants with baseline SBP>=130 mmHg [ Time Frame: Baseline to Week 8 ]

Measure Type	Secondary
Measure Name	Adjusted mean change in seated systolic blood pressure (SBP) at Week 8 (LOCF) in participants with baseline SBP>=130 mmHg
Measure Description	To compare the mean change in seated systolic blood pressure (SBP) in participants with baseline seated SBP ≥130 mmHg achieved with dapagliflozin versus placebo from baseline to week 8.
Time Frame	Baseline to Week 8
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis set, participants with baseline seated SBP ≥130 mmHg and Week 8 (LOCF) value

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Measured Values

	Dapagliflozin	Placebo
Number of Participants Analyzed [units:participants]	300	309
Adjusted mean change in seated systolic blood pressure (SBP) at Week 8 (LOCF) in participants with baseline SBP>=130 mmHg [units: mmHg] Least Squares Mean (95% Confidence Interval)	-5.33 (-7.02 to -3.64)	-1.89 (-3.58 to -0.20)

Statistical Analysis 1 for Adjusted mean change in seated systolic blood pressure (SBP) at Week 8 (LOCF) in participants with baseline SBP>=130 mmHg

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0004
Mean Difference (Final Values)^[5]	-3.44
Standard Error of the mean	± 0.9746
95% Confidence Interval	( -5.35 to -1.53 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
[2]	Additional details about a non-inferiority or equivalence analysis:
	No text entered.
[3]	Other relevant information, such as adjustments or degrees of freedom:
	with treatment group and stratum as effects and baseline value as covariate
[4]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
[5]	Other relevant estimation information:
	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

Serious Adverse Events

Time Frame	Non-serious / serious adverse events on or after the first day and on or prior to the last day of the 24-week double-blind treatment plus 4/30 days or up to follow-up visit if earlier, or up to and including the start date of extension period if earlier.
Additional Description	Participants were questioned at each study visit 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.

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Serious Adverse Events

Dapagliflozin

Placebo

Total, serious adverse events

# participants affected / at risk

41/482 (8.51%)

46/483 (9.52%)

Cardiac disorders

Angina unstable¹,^†

# participants affected / at risk

3/482 (0.62%)

2/483 (0.41%)

Cardiac disorders

Myocardial infarction¹,^†

# participants affected / at risk

3/482 (0.62%)

1/483 (0.21%)

Cardiac disorders

Acute coronary syndrome¹,^†

# participants affected / at risk

2/482 (0.41%)

0/483 (0.00%)

Cardiac disorders

Atrial fibrillation¹,^†

# participants affected / at risk

2/482 (0.41%)

3/483 (0.62%)

Cardiac disorders

Angina pectoris¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Cardiac disorders

Cardiac failure¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Cardiac disorders

Coronary artery disease¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Cardiac disorders

Ventricular tachycardia¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Cardiac disorders

Acute myocardial infarction¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Cardiac disorders

Cardiac failure congestive¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Nervous system disorders

Carotid artery stenosis¹,^†

# participants affected / at risk

2/482 (0.41%)

0/483 (0.00%)

Nervous system disorders

Dizziness¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Nervous system disorders

Ischaemic stroke¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Nervous system disorders

Spinal cord compression¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Nervous system disorders

Syncope¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Nervous system disorders

Cerebrovascular accident¹,^†

# participants affected / at risk

0/482 (0.00%)

2/483 (0.41%)

Nervous system disorders

Transient ischaemic attack¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Infections and infestations

Respiratory tract infection¹,^†

# participants affected / at risk

2/482 (0.41%)

1/483 (0.21%)

Infections and infestations

Bronchitis¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Infections and infestations

Osteomyelitis¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Infections and infestations

Peritonsillar abscess¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Infections and infestations

Gastroenterits¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Infections and infestations

Herpes zoster¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Infections and infestations

Lung abscess¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Infections and infestations

Pneumonia¹,^†

# participants affected / at risk

0/482 (0.00%)

2/483 (0.41%)

Infections and infestations

Pyelonephritis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

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

Adrenal adenoma¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

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

Basal cell carcinoma¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

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

Benign salivary gland neoplasm¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

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

Meningioma¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

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

Renal neoplasm¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

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

Bladder cancer¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

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

Prostate cancer¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Gastrointestinal disorders

Abdominal pain¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Gastrointestinal disorders

Gastric haemorrhage¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Gastrointestinal disorders

Gastric polyps¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Gastrointestinal disorders

Gastritis¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Gastrointestinal disorders

Haemorrhoids¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Gastrointestinal disorders

Rectal haemorrhage¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Gastrointestinal disorders

Small intestine obstruction¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Musculoskeletal and connective tissue disorders

Intervertebral disc disorder¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Musculoskeletal and connective tissue disorders

Intervertebral disc protrusion¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Musculoskeletal and connective tissue disorders

Osteoarthritis¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Musculoskeletal and connective tissue disorders

Polyarthritis¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Musculoskeletal and connective tissue disorders

Back pain¹,^†

# participants affected / at risk

0/482 (0.00%)

2/483 (0.41%)

Renal and urinary disorders

Bladder diverticulum¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Renal and urinary disorders

Renal failure¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Renal and urinary disorders

Urinary retention¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Renal and urinary disorders

Nephrolithiasis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Renal and urinary disorders

Renal failure acute¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Vascular disorders

Peripheral arterial occlusive disease¹,^†

# participants affected / at risk

2/482 (0.41%)

2/483 (0.41%)

Vascular disorders

Diabetic vascular disorder¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Vascular disorders

Circulatory collapse¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Vascular disorders

Deep vein thrombosis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Vascular disorders

Extremity necrosis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Vascular disorders

Hypertensive crisis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Vascular disorders

Peripheral ischaemia¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Vascular disorders

Thrombosis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Skin and subcutaneous tissue disorders

Angioedema¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Skin and subcutaneous tissue disorders

Skin ulcer¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Immune system disorders

Drug hypersensitivity¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Injury, poisoning and procedural complications

Excoriation¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Injury, poisoning and procedural complications

Cervical vertebral fracture¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Injury, poisoning and procedural complications

Clavicle fracture¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Injury, poisoning and procedural complications

Contusion¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Injury, poisoning and procedural complications

Femoral neck fracture¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Injury, poisoning and procedural complications

Road traffic accident¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Injury, poisoning and procedural complications

Vascular graft thrombosis¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Investigations

Blood parathyroid hormone decreased¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Metabolism and nutrition disorders

Hypoglycaemia¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Metabolism and nutrition disorders

Hyperglycaemia¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism¹,^†

# participants affected / at risk

1/482 (0.21%)

1/483 (0.21%)

Surgical and medical procedures

Angioplasty¹,^†

# participants affected / at risk

1/482 (0.21%)

0/483 (0.00%)

Ear and labyrinth disorders

Acute vestibular syndrome¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

General disorders

Chest pain¹,^†

# participants affected / at risk

0/482 (0.00%)

3/483 (0.62%)

Psychiatric disorders

Schizophrenia, paranoid type¹,^†

# participants affected / at risk

0/482 (0.00%)

1/483 (0.21%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 14.0

Other Adverse Events

Time Frame	Non-serious / serious adverse events on or after the first day and on or prior to the last day of the 24-week double-blind treatment plus 4/30 days or up to follow-up visit if earlier, or up to and including the start date of extension period if earlier.
Additional Description	Participants were questioned at each study visit 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.

Frequency Threshold

Threshold above which other adverse events are reported	5%

Reporting Groups

	Description
Dapagliflozin	Dapagliflozin 10 mg plus usual care
Placebo	Placebo plus usual care

Other Adverse Events

Dapagliflozin

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

147/482 (30.50%)

134/483 (27.74%)

Infections and infestations

Urinary tract infection¹,^†

# participants affected / at risk

27/482 (5.60%)

18/483 (3.73%)

Infections and infestations

Nasopharyngitis¹,^†

# participants affected / at risk

26/482 (5.39%)

26/483 (5.38%)

Infections and infestations

Upper respiratory tract infection¹,^†

# participants affected / at risk

15/482 (3.11%)

24/483 (4.97%)

Endocrine disorders

Hypoglycemia¹,^†

# participants affected / at risk

101/482 (20.95%)

84/483 (17.39%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 14.0

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: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
For participants who did not complete 8 and/or 24 weeks, respectively, LOCF was used. For HbA1c: excluding data after glycemic rescue, Weight: including data after rescue, SBP: excluding data after anti-hypertensive rescue.

Results Point of Contact

Name/Title:	Eva Johnsson
Organization:	AstraZeneca
E-mail:	[email protected]

Documents available

CSR-D1690C00019.pdf
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

ClinicalTrialTransparency@astrazeneca.com

Investigators

Principal Investigator

Dr. Lawrence A Leiter, MD

Division of Endocrinology & Metabolism, St Michael’s Hospital

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSR-D1690C00019.pdf

Trial Results Summaries