Evaluation of Safety and Efficacy of Dapagliflozin in subjects with Type 2 Diabetes who have Inadequate Glycaemic Control on background combination of Metformin and Sulfonylurea

Study identifier:D1693C00005

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A 24-week, Multicentre, Randomised, Double-Blind, Placebo-Controlled, International Phase III Study with a 28-week Extension Period to Evaluate the Safety and Efficacy of Dapagliflozin 10mg once daily in Patients with Type 2 Diabetes who have Inadequate Glycaemic Control on a background combination of Metformin and Sulfonylurea

Medical condition

Type 2 Diabetes Mellitus

Phase

Phase 3

Healthy volunteers

Study drug

dapagliflozin, placebo

Sex

All

Actual Enrollment

311

Study type

Interventional

Age

18 Years - 150 Years

Date

Study Start Date: 01 Oct 2011

Primary Completion Date: 01 Aug 2013

Study Completion Date: 01 Aug 2013

Study design

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

Verification:

Verified 01 Jan 2015 by AstraZeneca

Collaborators

Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Research Site

Brampton, ON, Canada

Location

Research Site

Edmonton, AB, Canada

Location

Research Site

Quebec, QC, Canada

Location

Research Site

Laval, QC, Canada

Location

Research Site

Halifax, NS, Canada

Location

Research Site

St. John's, NL, Canada

Location

Research Site

Winnipeg, MB, Canada

Location

Research Site

Kensington, PE, Canada

Arms	Assigned Interventions
Experimental: Dapagliflozin 10 mg tablet	Drug: dapagliflozin 10 mg tablet, oral, once daily, 24- week treatment and 28- week extension period
Placebo Comparator: matching placebo tablet	Drug: placebo matching placebo tablet, oral, once daily, 24- week treatment and 28- 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: 24 Oct 2011. Last participant completed 24 week period: 07 Jan 2013. 311 participants were enrolled, 219 were randomized in 45 centers in 5 European countries and in North America. Men and women aged >= 18 years with inadequate glycemic control (HbA1c 7.0% to 10.5% prior to randomization).

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
During enrollment, diet and life-style advice was given to participants and was reinforced during a placebo lead-in period. Dose of anti-hyperglycemic combination therapy of metformin >= 1500 mg/day and maximum tolerated dose which must be at least half the maximum dose of sulfonylurea for at least 8 weeks prior to enrollment were to remain stable.

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Participant Flow: Overall Study

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea
STARTED	109	109
COMPLETED	101	101
NOT COMPLETED	8	8
Adverse Event	3	1
Withdrawal by Subject	0	2
Incorrect enrollment	2	3
Other reason	3	2

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 study medication during the 24-week short-term double blind treatment period who have a non-missing baseline value and at least one post-baseline value for at least one efficacy variable to be analyzed at week 24.

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Baseline Measures

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea	Total
Number of Participants [units: Participants]	108	108	216
Age Continuous [units: Years] Mean ± Standard Deviation	60.9 ± 9.24	61.1 ± 9.65	61.0 ± 9.42
Gender, Male/Female [units: Participants]
Female	48	62	110
Male	60	46	106
Race/Ethnicity, Customized [units: Participants]
White	102	104	206
Black/African American	1	0	1
Asian	4	3	7
Other	1	1	2
Body Weight [units: kg] Mean ± Standard Deviation	90.07 ± 16.175	88.57 ± 17.584	89.32 ± 16.872
Body Mass Index [units: kg/m^2] Mean ± Standard Deviation	32.02 ± 4.581	31.93 ± 4.840	31.97 ± 4.702
Glycosylated hemoglobin A1c (HbA1c) [units: Percent] Mean ± Standard Deviation	8.24 ± 0.865	8.08 ± 0.912	8.16 ± 0.890
Fasting Plasma Glucose [units: mg/dL] Mean ± Standard Deviation	180.2 ± 43.13	167.4 ± 43.32	173.8 ± 43.61
Fasting C-Peptide [units: ng/mL] Mean ± Standard Deviation	2.5 ± 0.98	2.5 ± 1.06	2.5 ± 1.02

Outcome Measures

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

Measure Type	Primary
Measure Name	Adjusted mean change from baseline in HbA1c levels
Measure Description	To compare the change from baseline in HbA1c to week 24 between dapagliflozin 10 mg in combination with metformin and sulfonylurea and placebo in combination with metformin and sulfonylurea.
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 values

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Measured Values

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea
Number of Participants Analyzed [units:participants]	108	108
Adjusted mean change from baseline in HbA1c levels [units: Percent] Least Squares Mean (95% Confidence Interval)	-0.17 (-0.31 to -0.02)	-0.86 (-1.00 to -0.72)

Statistical Analysis 1 for Adjusted mean change from baseline in HbA1c levels

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Mixed Models Analysis
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.69
Standard Error of the mean	± 0.1022
95% Confidence Interval	( -0.89 to -0.49 )

[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:
	Longitudinal repeated measures model using mixed model with treatment group, baseline value, week and weektreatment and weekbaseline
[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). 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.

2. Secondary Outcome Measure: Adjusted mean change from baseline in FPG [ Time Frame: Baseline to week 24 ]

Measure Type	Secondary
Measure Name	Adjusted mean change from baseline in FPG
Measure Description	To compare the change from baseline in fasting plasma glucose (FPG) to week 24 (LOCF) between dapagliflozin and 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, participants with non-missing baseline and week 24 (LOCF) values

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Measured Values

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea
Number of Participants Analyzed [units:participants]	107	108
Adjusted mean change from baseline in FPG [units: mg/dL] Least Squares Mean (95% Confidence Interval)	-0.78 (-7.56 to 6.01)	-34.23 (-40.98 to -27.48)

Statistical Analysis 1 for Adjusted mean change from baseline in FPG

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-33.45
Standard Error of the mean	± 4.8846
95% Confidence Interval	( -43.08 to -23.82 )

[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 as effect 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). 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 change from baseline in total body weight [ Time Frame: Baseline to week 24 ]

Measure Type	Secondary
Measure Name	Adjusted mean change from baseline in total body weight
Measure Description	To compare the change from baseline in total body weight to week 24 (LOCF) between dapagliflozin and 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, participants with non-missing baseline and week 24 (LOCF) values

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Measured Values

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea
Number of Participants Analyzed [units:participants]	108	108
Adjusted mean change from baseline in total body weight [units: kg] Least Squares Mean (95% Confidence Interval)	-0.58 (-1.09 to -0.07)	-2.65 (-3.16 to -2.14)

Statistical Analysis 1 for Adjusted mean change from baseline in total 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]	-2.07
Standard Error of the mean	± 0.3651
95% Confidence Interval	( -2.79 to -1.35 )

[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 as effect 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). 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.

4. Secondary Outcome Measure: Proportion of participants with HbA1c value < 7.0% at week 24 (LOCF) [ Time Frame: Baseline to week 24 ]

Measure Type	Secondary
Measure Name	Proportion of participants with HbA1c value < 7.0% at week 24 (LOCF)
Measure Description	To compare the proportion of subjects achieving a therapeutic glycemic response, defined as HbA1c <7.0%, at week 24 (LOCF) between dapagliflozin and 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, participants with non-missing baseline and week 24 (LOCF) values

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Measured Values

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea
Number of Participants Analyzed [units:participants]	108	108
Proportion of participants with HbA1c value < 7.0% at week 24 (LOCF) [units: Percentage of participants] Least Squares Mean (95% Confidence Interval)	11.1 (5.4 to 16.8)	31.8 (23.3 to 40.2)

Statistical Analysis 1 for Proportion of participants with HbA1c value < 7.0% at week 24 (LOCF)

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Regression, Logistic
P-Value^[4]	<0.0001
Risk Difference (RD)^[5]	20.7
Standard Error of the mean	± 5.056
95% Confidence Interval	( 10.7 to 30.6 )

[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 Tsiatis, Davidian, Zhang & Lu, with adjustment for baseline value
[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). 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.

5. Secondary Outcome Measure: Adjusted mean change from baseline in seated systolic blood pressure [ Time Frame: Baseline to week 8 ]

Measure Type	Secondary
Measure Name	Adjusted mean change from baseline in seated systolic blood pressure
Measure Description	To compare the change from baseline in seated systolic blood pressure (SBP) to week 8 (LOCF) between dapagliflozin and 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, participants with non-missing baseline and week 8 (LOCF) values

Reporting Groups

	Description
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Measured Values

	Placebo plus metformin plus sulfonylurea	Dapagliflozin 10mg plus metformin plus sulfonylurea
Number of Participants Analyzed [units:participants]	105	105
Adjusted mean change from baseline in seated systolic blood pressure [units: mmHg] Least Squares Mean (95% Confidence Interval)	-0.27 (-2.60 to 2.05)	-4.04 (-6.36 to -1.72)

Statistical Analysis 1 for Adjusted mean change from baseline in seated systolic blood pressure

Groups^[1]	All groups
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.025
Mean Difference (Final Values)^[5]	-3.76
Standard Error of the mean	± 1.6677
95% Confidence Interval	( -7.05 to -0.48 )

[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 as effect 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). 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.

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
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Serious Adverse Events

Placebo plus metformin plus sulfonylurea

Dapagliflozin 10mg plus metformin plus sulfonylurea

Total, serious adverse events

# participants affected / at risk

6/109 (5.50%)

1/109 (0.92%)

Cardiac disorders

aortic valve stenosis¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

Cardiac disorders

arrhythmia¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

Infections and infestations

diabetic gangrene¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

Musculoskeletal and connective tissue disorders

sympathetic posterior cervical syndrome¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

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

renal cell carcinoma¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

Renal and urinary disorders

calculus ureteric¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

Respiratory, thoracic and mediastinal disorders

chronic obstructive pulmonary disease¹,^†

# participants affected / at risk

0/109 (0.00%)

1/109 (0.92%)

Vascular disorders

peripheral arterial occlusive disease¹,^†

# participants affected / at risk

1/109 (0.92%)

0/109 (0.00%)

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

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
Placebo plus metformin plus sulfonylurea	Placebo once daily plus background combination of metformin and sulfonylurea
Dapagliflozin 10mg plus metformin plus sulfonylurea	Dapagliflozin 10mg once daily plus background combination of metformin and sulfonylurea

Other Adverse Events

Placebo plus metformin plus sulfonylurea

Dapagliflozin 10mg plus metformin plus sulfonylurea

Total, other (not including serious) adverse events

# participants affected / at risk

7/109 (6.42%)

5/109 (4.59%)

Infections and infestations

urinary tract infection¹,^†

# participants affected / at risk

7/109 (6.42%)

5/109 (4.59%)

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

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, last observation carried forward (LOCF) was used for analyses of secondary endpoints. All endpoints were evaluated by excluding data after rescue.

Results Point of Contact

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

Documents available

D1693C00005.pdf
Download
D1693C00005_CSP
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

ClinicalTrialTransparency@astrazeneca.com

Investigators

Principal Investigator

Eva Johnsson

AstraZeneca R&D, Global Medicines Development CVGI, SE-431 83 Mölndal, Sweden

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

D1693C00005.pdf

D1693C00005_CSP

Trial Results Summaries