Trial Outcomes & Findings for Efficacy and Safety in Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease (NCT NCT01042977)

Last Updated: 2014-02-17

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

964 participants

Primary outcome timeframe

Baseline to Week 24

Results posted on

2014-02-17

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	Dapagliflozin Dapagliflozin 10 mg plus usual care	Placebo Placebo plus usual care
Overall Study STARTED	482	483
Overall Study COMPLETED	441	428
Overall Study NOT COMPLETED	41	55

Reasons for withdrawal

Reasons for withdrawal
Measure	Dapagliflozin Dapagliflozin 10 mg plus usual care	Placebo Placebo plus usual care
Overall Study Adverse Event	4	12
Overall Study Death	2	1
Overall Study Withdrawal by Subject	8	16
Overall Study Lost to Follow-up	0	2
Overall Study Poor/non-compliance	3	4
Overall Study Subject no longer meets study criteria	15	13
Overall Study Incorrect enrollment	6	4
Overall Study Safety	0	2
Overall Study Administrative reason by sponsor	0	1
Overall Study Various	3	0

Baseline Characteristics

Efficacy and Safety in Patients With Type 2 Diabetes Mellitus and Cardiovascular Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dapagliflozin n=480 Participants Dapagliflozin 10 mg plus usual care	Placebo n=482 Participants Placebo plus usual care	Total n=962 Participants Total of all reporting groups
Sex: Female, Male Male	321 Participants n=5 Participants	323 Participants n=7 Participants	644 Participants n=5 Participants
Race/Ethnicity, Customized White	454 Participants n=5 Participants	449 Participants n=7 Participants	903 Participants n=5 Participants
Race/Ethnicity, Customized Black/African American	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Age, Continuous	63.9 Years STANDARD_DEVIATION 7.60 • n=5 Participants	63.6 Years STANDARD_DEVIATION 7.02 • n=7 Participants	63.8 Years STANDARD_DEVIATION 7.31 • n=5 Participants
Sex: Female, Male Female	159 Participants n=5 Participants	159 Participants n=7 Participants	318 Participants n=5 Participants
Race/Ethnicity, Customized Asian	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Race/Ethnicity, Customized Other	11 Participants n=5 Participants	16 Participants n=7 Participants	27 Participants n=5 Participants
HbA1c	8.04 Percent STANDARD_DEVIATION 0.759 • n=5 Participants	8.08 Percent STANDARD_DEVIATION 0.795 • n=7 Participants	8.06 Percent STANDARD_DEVIATION 0.777 • n=5 Participants
Body weight	94.53 kg STANDARD_DEVIATION 17.804 • n=5 Participants	93.23 kg STANDARD_DEVIATION 16.842 • n=7 Participants	93.88 kg STANDARD_DEVIATION 17.332 • n=5 Participants
Systolic Blood Pressure	134.9 mmHg STANDARD_DEVIATION 14.53 • n=5 Participants	134.6 mmHg STANDARD_DEVIATION 13.96 • n=7 Participants	134.7 mmHg STANDARD_DEVIATION 14.24 • n=5 Participants
Number of participants with BMI >= 27 kg/m2 at baseline < 25 kg/m²	15 Participants n=5 Participants	31 Participants n=7 Participants	46 Participants n=5 Participants
Number of participants with BMI >= 27 kg/m2 at baseline >= 25 kg/m²	465 Participants n=5 Participants	451 Participants n=7 Participants	916 Participants n=5 Participants
Number of participants with BMI >= 27 kg/m2 at baseline >= 27 kg/m²	428 Participants n=5 Participants	416 Participants n=7 Participants	844 Participants n=5 Participants
Number of participants with BMI >= 27 kg/m2 at baseline >= 30 kg/m²	339 Participants n=5 Participants	325 Participants n=7 Participants	664 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 24

Population: Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Outcome measures

Outcome measures
Measure	Dapagliflozin n=474 Participants Dapagliflozin 10 mg plus usual care	Placebo n=471 Participants Placebo plus usual care
Adjusted Mean Change in HbA1c Levels	-0.33 Percent 95% Confidence Interval 0.0434 • Interval -0.42 to -0.25	0.07 Percent Interval -0.02 to 0.15

PRIMARY outcome

Timeframe: Baseline to Week 24

Population: Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values

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.

Outcome measures

Outcome measures
Measure	Dapagliflozin n=468 Participants Dapagliflozin 10 mg plus usual care	Placebo n=469 Participants Placebo plus usual care
Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit	10.0 Percentage of participants 95% Confidence Interval 0.7 • Interval 7.3 to 12.8	1.9 Percentage of participants 95% Confidence Interval 7.3 • Interval 0.7 to 3.2

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Full Analysis Set, subjects with non-missing baseline and Week 24 (LOCF) values

To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.

Outcome measures

Outcome measures
Measure	Dapagliflozin n=480 Participants Dapagliflozin 10 mg plus usual care	Placebo n=481 Participants Placebo plus usual care
Adjusted Mean Percent Change in Body Weight	-2.53 Percentage of Body Weight 95% Confidence Interval 0.1770 • Interval -2.87 to -2.18	-0.61 Percentage of Body Weight 95% Confidence Interval 0.1736 • Interval -0.96 to -0.26

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Full Analysis Set, subjects with baseline BMI ≥27 kg/m2 and Week 24 (LOCF) values

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.

Outcome measures

Outcome measures
Measure	Dapagliflozin n=428 Participants Dapagliflozin 10 mg plus usual care	Placebo n=415 Participants Placebo plus usual care
Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m²	18.4 Percentage of participants 95% Confidence Interval 1.051 • Interval 14.8 to 22.1	4.8 Percentage of participants 95% Confidence Interval 1.876 • Interval 2.8 to 6.9

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: Full Analysis Set, subjects with non-missing baseline and Week 8 (LOCF) values

To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.

Outcome measures

Outcome measures
Measure	Dapagliflozin n=473 Participants Dapagliflozin 10 mg plus usual care	Placebo n=479 Participants Placebo plus usual care
Adjusted Mean Change in Systolic Blood Pressure at Week 8 (LOCF)	-1.85 mmHg 95% Confidence Interval 0.7105 • Interval -3.25 to -0.45	0.86 mmHg 95% Confidence Interval 0.7135 • Interval -0.53 to 2.26

SECONDARY outcome

Timeframe: Baseline to Week 24

Population: Full Analysis set, subjects with non-missing baseline and Week 24 (LOCF) values

To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.

Outcome measures

Outcome measures
Measure	Dapagliflozin n=473 Participants Dapagliflozin 10 mg plus usual care	Placebo n=479 Participants Placebo plus usual care
Adjusted Mean Change in Seated Systolic Blood Pressure at Week 24 (LOCF)	-2.70 mmHg 95% Confidence Interval 0.7109 • Interval -4.1 to -1.3	0.32 mmHg 95% Confidence Interval 0.7140 • Interval -1.07 to 1.72

SECONDARY outcome

Timeframe: Baseline to Week 8

Population: Full Analysis set, participants with baseline seated SBP ≥130 mmHg and Week 8 (LOCF) value

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.

Outcome measures

Outcome measures
Measure	Dapagliflozin n=300 Participants Dapagliflozin 10 mg plus usual care	Placebo n=309 Participants Placebo plus usual care
Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 8 (LOCF) in Participants With Baseline SBP>=130 mmHg	-5.33 mmHg 95% Confidence Interval 0.8612 • Interval -7.02 to -3.64	-1.89 mmHg 95% Confidence Interval 0.8612 • Interval -3.58 to -0.2

Adverse Events

Dapagliflozin

Serious events: 41 serious events

Other events: 147 other events

Deaths: 0 deaths

Placebo

Serious events: 46 serious events

Other events: 134 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Dapagliflozin n=482 participants at risk Dapagliflozin 10 mg plus usual care	Placebo n=483 participants at risk Placebo plus usual care
Infections and infestations Urinary tract infection	5.6% 27/482 • 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. 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.	3.7% 18/483 • 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. 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.
Infections and infestations Nasopharyngitis	5.4% 26/482 • 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. 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.	5.4% 26/483 • 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. 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.
Infections and infestations Upper respiratory tract infection	3.1% 15/482 • 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. 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.	5.0% 24/483 • 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. 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.
Endocrine disorders Hypoglycemia	21.0% 101/482 • 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. 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.	17.4% 84/483 • 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. 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.

Additional Information

Eva Johnsson

AstraZeneca

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER