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Clinical Trial Results:
A 28-week, Multicenter, Randomized, Double-Blind, Active-Controlled, Phase 3 Study with a 24-week Extension Phase Followed by a 52-week Extension Phase to Evaluate the Efficacy and Safety of Simultaneous Administration of Exenatide Once Weekly 2 mg and Dapagliflozin Once Daily 10 mg Compared to Exenatide Once Weekly 2 mg Alone and Dapagliflozin Once Daily 10 mg Alone in Patients with Type 2 Diabetes who have Inadequate Glycemic Control on Metformin

Summary
EudraCT number	2014-003503-29
Trial protocol	SK HU
Global end of trial date	28 Dec 2017

Results information
Results version number	v1(current)
This version publication date	22 Dec 2018
First version publication date	22 Dec 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

D5553C00003

ISRCTN number

US NCT number

NCT02229396

WHO universal trial number (UTN)

Sponsor organisation name

AstraZeneca

Sponsor organisation address

One MedImmune Way, Gaithersburg, United States, MD 20878

Public contact

Global Clinical Leader, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com

Scientific contact

Global Clinical Leader, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Dec 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

28 Dec 2017

Was the trial ended prematurely?

Main objective of the trial

To compare the change from baseline in hemoglobin A1c (HbA1c) at 28 weeks between exenatide once weekly (EQW) 2 milligrams (mg) and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Dapagliflozin was administered orally and EQW as subcutaneous (SC) injection.

Protection of trial subjects

This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.

Background therapy

Patients continued to administer the same type and dose of metformin therapy they were using at study entry (at least 1500 mg/day).

Evidence for comparator

Actual start date of recruitment

04 Sep 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Slovakia: 71

Country: Number of subjects enrolled

South Africa: 58

Country: Number of subjects enrolled

United States: 394

Country: Number of subjects enrolled

Hungary: 78

Country: Number of subjects enrolled

Poland: 24

Country: Number of subjects enrolled

Romania: 70

Worldwide total number of subjects

695

EEA total number of subjects

243

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

608

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Study conducted between 04 September 2014 and 28 December 2017. 118 centers in 6 countries randomized patients in the study. A Primary Analysis was performed following completion of the 28-week Treatment Period with a data cut-off date of 26 April 2016. All Primary and Secondary End Points were reported at the time of the Primary Analysis.

Screening details

The study had a Screening Visit, a 1-week placebo Lead-in Period, a Randomization Visit, and 9 further visits at 1- to 4-week intervals during a 28-week Treatment Period. Patients then entered a 24-week Extension Period 1 and subsequent 52-week Extension Period 2. A follow-up visit occurred 10 weeks after last dose of study medication.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Carer, Data analyst, Subject, Assessor

Blinding implementation details

Patients received single-blind dapagliflozin and exenatide placebo during the Lead-in Period. From the Randomization Visit and throughout the 28-week Treatment Period, the study was double-blind. The Sponsor and its applicable representatives were unblinded in the Extension Periods (ie, from Week 28 onwards). Sites and patients remained blinded during the Extension Periods.

Are arms mutually exclusive

Yes

Dapagliflozin + Placebo

Arm description

Dapagliflozin 10 mg tablet administered orally once daily + matching placebo for exenatide administered as SC injection once weekly. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

Arm type

Active comparator

Investigational medicinal product name

Dapagliflozin

Investigational medicinal product code

Other name

Farxiga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg tablets administered once daily.

Investigational medicinal product name

Placebo-matched exenatide once weekly

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for suspension for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo powder for injection administered once weekly.

Exenatide + Dapagliflozin

Arm description

Exenatide once weekly (EQW) 2 mg administered as SC injection + dapagliflozin 10 mg tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

Arm type

Experimental

Investigational medicinal product name

Exenatide once weekly

Investigational medicinal product code

Other name

EQW, Bydureon

Pharmaceutical forms

Powder for suspension for injection

Routes of administration

Subcutaneous use

Dosage and administration details

2.0 mg powder for injection administered once weekly.

Investigational medicinal product name

Dapagliflozin

Investigational medicinal product code

Other name

Farxiga

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

10 mg tablets administered once daily.

Exenatide + Placebo

Arm description

Exenatide once weekly (EQW) 2 mg administered as SC injection + matching placebo for dapagliflozin tablet administered orally once daily. Patients continued to administer the same type and dose of metformin therapy they were using at study entry.

Arm type

Active comparator

Investigational medicinal product name

Placebo-matched dapagliflozin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablets administered once daily.

Investigational medicinal product name

Exenatide once weekly

Investigational medicinal product code

Other name

EQW, Bydureon

Pharmaceutical forms

Powder for suspension for injection

Routes of administration

Subcutaneous use

Dosage and administration details

2.0 mg powder for injection administered once weekly.

Number of subjects in period 1	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Started	233	231	231
Randomization Code Allocated	233	231	231
Safety Analysis Set	233	231	230
Intent-to-Treat (ITT) Analysis Set	230	228	227
Completed 28-Week Study Period	208	202	193
Completed 52-Week Study Period	194	193	177
Completed	155	154	136
Not completed	78	77	95
Adverse event, serious fatal	2	3	1
Consent withdrawn by subject	42	28	41
Adverse event, non-fatal	6	12	12
Withdrew; No Record on Termination Page	2	-	1
Unspecified	10	18	15
Lost to follow-up	14	14	21
Patient Incorrectly Randomized	-	-	1
Protocol deviation	2	1	-
Study-Specific Withdrawal Criteria	-	1	3

Baseline characteristics

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Reporting group title

Dapagliflozin + Placebo

Reporting group description

Reporting group title

Exenatide + Dapagliflozin

Reporting group description

Reporting group title

Exenatide + Placebo

Reporting group description

Reporting group values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo	Total
Number of subjects	233	231	231	695
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	206	200	202	608
From 65-84 years	27	31	29	87
85 years and over	0	0	0	0
Gender, Male/Female
Units: Subjects
Female	121	128	114	363
Male	112	103	117	332
Race, Customized
Units: Subjects
American Indian Or Alaska Native\|	0	0	2	2
Asian\|	1	3	1	5
Black Or African American\|	33	36	27	96
Other\|	7	1	3	11
White\|	192	191	198	581

End points

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Reporting group title

Dapagliflozin + Placebo

Reporting group description

Reporting group title

Exenatide + Dapagliflozin

Reporting group description

Reporting group title

Exenatide + Placebo

Reporting group description

Primary: Change in HbA1c from baseline to Week 28

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End point title

Change in HbA1c from baseline to Week 28

End point description

To compare the change from baseline to Week 28 in HbA1c between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Primary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: % HbA1c
least squares mean (confidence interval 95%)	-1.39 (-1.57 to -1.21)	-1.98 (-2.16 to -1.79)	-1.60 (-1.79 to -1.41)

Change in HbA1c - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.63

upper limit

-0.13

Variability estimate

Standard error of the mean

Dispersion value

0.129

Change in HbA1c - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-0.84

upper limit

-0.34

Variability estimate

Standard error of the mean

Dispersion value

0.127

Secondary: Change in body weight from baseline to Week 28

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End point title

Change in body weight from baseline to Week 28

End point description

To compare the change from baseline to Week 28 in body weight between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: kilogram
least squares mean (confidence interval 95%)	-2.22 (-2.78 to -1.66)	-3.55 (-4.12 to -2.99)	-1.56 (-2.13 to -0.98)

Change in body weight - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.79

upper limit

-1.2

Variability estimate

Standard error of the mean

Dispersion value

0.406

Change in body weight - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.33

Confidence interval

level

95%

sides

2-sided

lower limit

-2.12

upper limit

-0.55

Variability estimate

Standard error of the mean

Dispersion value

0.4

Secondary: Change in fasting plasma glucose from baseline to Week 28

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End point title

Change in fasting plasma glucose from baseline to Week 28

End point description

To compare the change from baseline to Week 28 in fasting plasma glucose (FPG) between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: milligrams/deciliter (mg/dL)
least squares mean (confidence interval 95%)	-49.19 (-54.91 to -43.47)	-65.83 (-71.60 to -60.06)	-45.75 (-51.67 to -39.83)

Change in FPG - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-20.08

Confidence interval

level

95%

sides

2-sided

lower limit

-27.95

upper limit

-12.2

Variability estimate

Standard error of the mean

Dispersion value

4.007

Change in FPG - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-16.64

Confidence interval

level

95%

sides

2-sided

lower limit

-24.39

upper limit

-8.89

Variability estimate

Standard error of the mean

Dispersion value

3.947

Secondary: Change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test

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End point title

Change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test

End point description

To compare the change from baseline to Week 28 in 2-hour postprandial glucose (PPG) after a standard Meal Tolerance Test (MTT) between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: mg/dL
least squares mean (confidence interval 95%)	-61.05 (-69.10 to -53.00)	-87.83 (-95.83 to -79.84)	-60.09 (-68.48 to -51.71)

Change in 2 hr PPG - baseline to Week 28

Statistical analysis description

Treatment, region, and baseline HbA1c stratum (<9.0% or ≥9.0%), as fixed factors; baseline value as covariate.

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-27.74

Confidence interval

level

95%

sides

2-sided

lower limit

-37.89

upper limit

-17.59

Variability estimate

Standard error of the mean

Dispersion value

5.168

Change in 2 hr PPG - baseline to Week 28

Statistical analysis description

Treatment, region, and baseline HbA1c stratum (<9.0% or ≥9.0%), as fixed factors; baseline value as covariate.

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

-26.78

Confidence interval

level

95%

sides

2-sided

lower limit

-36.78

upper limit

-16.78

Variability estimate

Standard error of the mean

Dispersion value

5.09

Secondary: Percentage of patients achieving weight loss ≥5.0% at Week 28

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End point title

Percentage of patients achieving weight loss ≥5.0% at Week 28

End point description

To compare the percentage of patients achieving weight loss ≥5.0% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: % of patients
number (confidence interval 95%)	20.0 (14.8 to 25.2)	33.3 (27.2 to 39.5)	13.7 (9.2 to 18.1)

Percentage of patients achieving weight loss >=5%

Statistical analysis description

Treatment comparison at Week 28 is based on a Cochran-Mantel-Haenszel test, stratified by baseline HbA1c (<9.0% or ≥9.0%).

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[1]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[1] - Difference in percentages = 19.7

Percentage of patients achieving weight loss >=5%

Statistical analysis description

A Cochran-Mantel-Haenszel analysis was performed at Week 28, stratified by baseline HbA1c (<9.0% or ≥9.0%).

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[2]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[2] - Difference in percentages = 13.3

Secondary: Change in fasting plasma glucose from baseline to Week 2

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End point title

Change in fasting plasma glucose from baseline to Week 2

End point description

To compare the change from baseline to Week 2 in FPG between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 2

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: mg/dL
least squares mean (confidence interval 95%)	-26.31 (-31.42 to -21.20)	-41.34 (-46.48 to -36.20)	-21.08 (-26.29 to -15.86)

Change in FPG - baseline to Week 2

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-20.26

Confidence interval

level

95%

sides

2-sided

lower limit

-27.12

upper limit

-13.4

Variability estimate

Standard error of the mean

Dispersion value

3.494

Change in FPG - baseline to Week 2

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[3]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-15.03

Confidence interval

level

95%

sides

2-sided

lower limit

-21.85

upper limit

-8.2

Variability estimate

Standard error of the mean

Dispersion value

3.477

Notes
[3] - This is a nominal p-value.

Secondary: Percentage of patients achieving HbA1c <7% at Week 28

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End point title

Percentage of patients achieving HbA1c <7% at Week 28

End point description

To compare the percentage of patients achieving HbA1c <7% at 28 weeks between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: % of patients
number (confidence interval 95%)	19.1 (14.1 to 24.2)	44.7 (38.3 to 51.2)	26.9 (21.1 to 32.6)

Percentage of patients achieving HbA1c <7%

Statistical analysis description

A Cochran-Mantel-Haenszel analysis was performed at Week 28, stratified by baseline HbA1c (<9.0% or ≥9.0%).

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[4]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[4] - Difference in percentages = 17.9

Percentage of patients achieving HbA1c <7%

Statistical analysis description

A Cochran-Mantel-Haenszel analysis was performed at Week 28, stratified by baseline HbA1c (<9.0% or ≥9.0%).

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001 ^[5]

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[5] - Difference in percentages = 25.6

Secondary: Change in systolic blood pressure from baseline to Week 28

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End point title

Change in systolic blood pressure from baseline to Week 28

End point description

To compare the change from baseline to Week 28 in systolic blood pressure between exenatide once weekly (EQW) 2 mg and dapagliflozin 10 mg administered simultaneously compared to EQW 2 mg alone and dapagliflozin 10 mg alone. Analysis performed on the ITT analysis set which included all randomized patients who received at least 1 dose of study medication and had at least 1 post-baseline HbA1c assessment.

End point type

Secondary

End point timeframe

Baseline to Week 28

End point values	Dapagliflozin + Placebo	Exenatide + Dapagliflozin	Exenatide + Placebo
Number of subjects analysed	230	228	227
Units: millimeters of mercury (mmHg)
least squares mean (confidence interval 95%)	-1.8 (-3.4 to -0.3)	-4.3 (-5.8 to -2.7)	-1.2 (-2.8 to 0.4)

Change in SBP - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Exenatide + Dapagliflozin v Exenatide + Placebo

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.005

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-3

Confidence interval

level

95%

sides

2-sided

lower limit

-5.2

upper limit

-0.9

Variability estimate

Standard error of the mean

Dispersion value

1.08

Change in SBP - baseline to Week 28

Statistical analysis description

Treatment, region, baseline HbA1c stratum (<9.0% or ≥9.0%), week, and treatment by week interaction as fixed factors; baseline value as covariate.

Comparison groups

Dapagliflozin + Placebo v Exenatide + Dapagliflozin

Number of subjects included in analysis

458

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.022

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

-0.4

Variability estimate

Standard error of the mean

Dispersion value

1.06

Adverse events

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Timeframe for reporting adverse events

From baseline (Day 1) up to Week 104 (28-week Treatment Period + 24-week Extension Period 1 + 52-week Extension Period 2).

Adverse event reporting additional description

Treatment-emergent adverse event (AE) data is reported for the Safety Analysis set defined as all randomized patients receiving at least 1 dose of study medication. One patient who was randomized did not receive study medication (the patient was randomized in error); this patient was not counted as completing or discontinuing treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Dapagliflozin + Placebo

Reporting group description

Reporting group title

Exenatide + Placebo

Reporting group description

Reporting group title

Exenatide + Dapagliflozin

Reporting group description

Serious adverse events	Dapagliflozin + Placebo	Exenatide + Placebo	Exenatide + Dapagliflozin
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 233 (7.73%)	18 / 230 (7.83%)	17 / 231 (7.36%)
number of deaths (all causes)	2	1	3
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lipoma
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal neoplasm
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 233 (0.43%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 233 (0.43%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 233 (0.00%)	2 / 230 (0.87%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Rib fracture
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Spinal compression fracture
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	2 / 233 (0.86%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Atrial fibrillation
subjects affected / exposed	1 / 233 (0.43%)	2 / 230 (0.87%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 233 (0.00%)	2 / 230 (0.87%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Palpitations
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Diabetic neuropathy
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	1 / 233 (0.43%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Optic neuritis
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic necrosis
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary dyskinesia
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	2 / 231 (0.87%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Pituitary-dependent Cushing's syndrome
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Exostosis
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 233 (0.00%)	0 / 230 (0.00%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periarthritis
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis viral
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 233 (0.00%)	1 / 230 (0.43%)	1 / 231 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 233 (0.43%)	0 / 230 (0.00%)	0 / 231 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Dapagliflozin + Placebo	Exenatide + Placebo	Exenatide + Dapagliflozin
Total subjects affected by non serious adverse events
subjects affected / exposed	73 / 233 (31.33%)	78 / 230 (33.91%)	87 / 231 (37.66%)
Nervous system disorders
Headache
subjects affected / exposed	12 / 233 (5.15%)	12 / 230 (5.22%)	16 / 231 (6.93%)
occurrences all number	12	12	18
General disorders and administration site conditions
Injection site nodule
subjects affected / exposed	13 / 233 (5.58%)	14 / 230 (6.09%)	20 / 231 (8.66%)
occurrences all number	22	24	40
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	11 / 233 (4.72%)	17 / 230 (7.39%)	13 / 231 (5.63%)
occurrences all number	14	25	17
Nausea
subjects affected / exposed	10 / 233 (4.29%)	26 / 230 (11.30%)	13 / 231 (5.63%)
occurrences all number	12	29	14
Vomiting
subjects affected / exposed	7 / 233 (3.00%)	12 / 230 (5.22%)	8 / 231 (3.46%)
occurrences all number	7	15	10
Infections and infestations
Nasopharyngitis
subjects affected / exposed	12 / 233 (5.15%)	8 / 230 (3.48%)	15 / 231 (6.49%)
occurrences all number	15	10	17
Upper respiratory tract infection
subjects affected / exposed	22 / 233 (9.44%)	17 / 230 (7.39%)	15 / 231 (6.49%)
occurrences all number	25	29	22
Urinary tract infection
subjects affected / exposed	16 / 233 (6.87%)	15 / 230 (6.52%)	19 / 231 (8.23%)
occurrences all number	23	24	31

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Were there any global substantial amendments to the protocol? Yes

03 Oct 2014

-Exclusion/inclusion criteria amended for clarification of patients that could be included in the study (those on antihypertensive agents, thyroid replacement therapy and antidepressant agents were eligible if on a stable treatment regimen for 2 months prior to Visit 1). -Exclusion criterion amended to reduce threshold for exclusion based on calcitonin levels to align with new project-wide criteria. -Exclusion criterion amended to correct errors in exclusionary laboratory values for serum creatinine. -Methods for ensuring blinding amended to clarify blinding during the Extension Periods and blinding procedures for central laboratory results updated to help prevent indirect unblinding of study treatment. -Restrictions updated to clarify substances and activities from which patients were to abstain for 24 hours prior to visits. -Procedures for discontinuation amended to allow patients that temporarily stop drug treatment due to an AE or other significant event to continue participating in the trial. -Study Plan and Timing of Procedures updated. -Treatment period and study assessment text amended to clarify procedures for performing the 6-point self-monitored blood glucose profile for patients receiving rescue therapy. -Removed requirement that patients take doses of study medication during clinic visits. -Study assessment text regarding the MTT updated to include additional instruction on timing and to clarify the sequence of steps of the MTT. -Urinalysis text updated to specify that urine glucose results were blinded to reduce the possibility of study treatment unblinding. -Text added to clarify procedures for monitoring and assessing potential liver injuries. -Text updated to clarify Hy’s Law information to conform with updated Sponsor standards. -Updated description of hypoglycaemia assessment and reporting to clarify that classification would be done programmatically rather than by Investigators.

20 Feb 2015

-Exclusion criterion modified to be less restrictive with respect to prior study participation. -Study Plan and Timing of Procedures were updated. -Review of potential cardiovascular (CV) event triggers was added to all visits where AEs and concomitant medication were reviewed. -Text was added to indicate that metformin should be taken with the next meal, and does not need to be taken at the study site, and that urine should be collected right before time 0 of the MTT. -Extension Period Visit text was amended so that instead of plasma fasting glucose, HbA1c levels were used to determine the need for rescue during the extension period. -New section regarding paternal exposure was added to align with current AstraZeneca protocol template language. -New section regarding CV adjudication was added to enable assessment of CV risk across the exenatide clinical program.

02 Sep 2015

-A 52-week extension (Extension Period 2) was added to the study. -Sample collection during the End of Treatment Period Visit or Early Termination or Rescue during Treatment Period was amended to state that blood samples were to be collected after administration of dapagliflozin and that a between visit telephone contact was to take place between Visit 12 to 13 for safety information. -Sample collection and storage of biological samples for future research was amended for clarification.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in HbA1c from baseline to Week 28

Primary: Change in HbA1c from baseline to Week 28

Secondary: Change in body weight from baseline to Week 28

Secondary: Change in body weight from baseline to Week 28

Secondary: Change in fasting plasma glucose from baseline to Week 28

Secondary: Change in fasting plasma glucose from baseline to Week 28

Secondary: Change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test

Secondary: Change from baseline to Week 28 in 2-hour postprandial glucose after a standard Meal Tolerance Test

Secondary: Percentage of patients achieving weight loss ≥5.0% at Week 28

Secondary: Percentage of patients achieving weight loss ≥5.0% at Week 28

Secondary: Change in fasting plasma glucose from baseline to Week 2

Secondary: Change in fasting plasma glucose from baseline to Week 2

Secondary: Percentage of patients achieving HbA1c <7% at Week 28

Secondary: Percentage of patients achieving HbA1c <7% at Week 28

Secondary: Change in systolic blood pressure from baseline to Week 28

Secondary: Change in systolic blood pressure from baseline to Week 28

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

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