Evaluation of dapagliflozin taken twice-daily

Study identifier:D1691C00003

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A 16-week, Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Safety and Efficacy of Dapagliflozin 2.5 mg BID, 5 mg BID and 10 mg QD Versus Placebo in Patients with Type 2 Diabetes Who Are Inadequately Controlled on Metformin-IR Monotherapy

Medical condition

Type 2 Diabetes

Phase

Phase 3

Healthy volunteers

Study drug

dapagliflozin, metformin, placebo

Sex

All

Actual Enrollment

400

Study type

Interventional

Age

18 Years - 77 Years

Date

Study Start Date: 01 Nov 2010

Primary Completion Date: 01 Aug 2011

Study Completion Date: 01 Aug 2011

Study design

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

Verification:

Verified 01 Oct 2014 by AstraZeneca

Collaborators

Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Research Site

ASSLAR, Germany

Location

Research Site

BERLIN, Germany

Location

Research Site

BIBERACH A.D. RISS, Germany

Location

Research Site

BOSENHEIM, Germany

Location

Research Site

DIPPOLDISWALDE, Germany

Location

Research Site

FALKENSEE, Germany

Location

Research Site

MEISSEN, Germany

Location

Research Site

MUNCHEN, Germany

Arms	Assigned Interventions
Experimental: 1 Dapagliflozin 2.5 mg twice-daily plus open-label metformin	Drug: dapagliflozin 2.5 mg tablet, taken orally, twice daily Drug: metformin >/= 1500 mg total daily dose, tablets taken orally, twice daily
Experimental: 2 Dapagliflozin 5.0 mg twice-daily plus open-label metformin	Drug: dapagliflozin 5 mg tablet taken orally, twice daily Drug: metformin >/= 1500 mg total daily dose, tablets taken orally, twice daily
Experimental: 3 Dapagliflozin 10 mg once-daily plus open-label metformin	Drug: dapagliflozin 10 mg tablet taken orally, once daily Drug: metformin >/= 1500 mg total daily dose, tablets taken orally, twice daily
Placebo Comparator: 4 Placebo plus open-label metformin	Drug: metformin >/= 1500 mg total daily dose, tablets taken orally, twice daily Drug: placebo placebo

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: 5 November 2010. Last participant last visit for the 16-week period: 25 August 2011. 520 participants were enrolled, and 400 were randomized in 53 study centers in Europe and South Africa. Subjects with T2DM who showed inadequate glycemic control on metformin therapy alone.

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. Subjects eligible for the study were stratified according to their baseline HbA1c.

Reporting Groups

	Description
Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Participant Flow: Overall Study

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin
STARTED	100	100	99	101
COMPLETED	93	94	90	93
NOT COMPLETED	7	6	9	8
Adverse Event	1	1	1	0
Withdrawal by Subject	0	2	1	0
Lab value	1	0	1	0
Subject no longer meets study criteria	5	2	4	8
Incorrect enrollment	0	1	1	0
Poor/Non-Compliance	0	0	1	0

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 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Baseline Measures

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin	Total
Number of Participants [units: Participants]	100	99	99	101	399
Age Continuous [units: Years] Mean ± Standard Deviation	58.3 ± 9.01	55.3 ± 9.34	58.5 ± 9.78	58.5 ± 9.40	57.7 ± 9.45
Gender, Male/Female [units: Participants]
Female	63	53	50	54	220
Male	37	46	49	47	179
HbA1c [units: Percent [%]] Mean ± Standard Deviation	7.77 ± 0.747	7.78 ± 0.762	7.71 ± 0.709	7.94 ± 0.848	7.80 ± 0.770
Fasting Plasma Glucose (FPG) [units: mg/dL] Mean ± Standard Deviation	153.3 ± 33.27	155.3 ± 31.92	155.3 ± 36.26	157.8 ± 35.93	155.4 ± 34.30
Body weight [units: kg] Mean ± Standard Deviation	92.49 ± 18.632	93.62 ± 16.641	90.58 ± 15.929	88.82 ± 15.327	91.37 ± 16.716

Outcome Measures

1. Primary Outcome Measure: Adjusted mean change in HbA1c levels [ Time Frame: Baseline to Week 16 ]

Measure Type	Primary
Measure Name	Adjusted mean change in HbA1c levels
Measure Description	To compare the change from baseline in HbA1c achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment.
Time Frame	Baseline to Week 16
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 16 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Measured Values

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin
Number of Participants Analyzed [units:participants]	99	97	98	100
Adjusted mean change in HbA1c levels [units: Percent] Least Squares Mean (Standard Error)	-0.52 (0.0594)	-0.65 (0.0600)	-0.59 (0.0598)	-0.30 (0.0593)

Statistical Analysis 1 for Adjusted mean change in HbA1c levels

Groups^[1]	Dapagliflozin 2.5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0106
Mean Difference (Final Values)^[5]	-0.22
Standard Error of the mean	± 0.0840
95% Confidence Interval	( -0.38 to -0.05 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05 using Hochberg's method to control the overall Type I error across hypotheses in the two Dapagliflozin BID groups, two-sided)
[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 (all treatment groups included) 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) applying Hochberg's method across the two Dapagliflozin BID groups.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted mean change in HbA1c levels

Groups^[1]	Dapagliflozin 5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.35
Standard Error of the mean	± 0.0843
95% Confidence Interval	( -0.52 to -0.18 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05 using Hochberg's method to control the overall Type I error across hypotheses in the two Dapagliflozin BID groups, two-sided)
[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 (all treatment groups included) 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) applying Hochberg's method across the two Dapagliflozin BID groups.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Adjusted percent change in body weight [ Time Frame: Baseline to Week 16 ]

Measure Type	Secondary
Measure Name	Adjusted percent change in body weight
Measure Description	To compare the percent change from baseline in body weight achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID, and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment.
Time Frame	Baseline to Week 16
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 16 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Measured Values

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin
Number of Participants Analyzed [units:participants]	100	99	99	101
Adjusted percent change in body weight [units: Percent] Least Squares Mean (Standard Error)	-2.84 (0.3099)	-3.20 (0.3125)	-2.76 (0.3086)	-1.04 (0.3105)

Statistical Analysis 1 for Adjusted percent change in body weight

Groups^[1]	Dapagliflozin 2.5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-1.82
Standard Error of the mean	± 0.3630
95% Confidence Interval	( -2.53 to -1.10 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)
[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 (all treatment groups included) and stratum (HbA1c <7.0% vs >=7.0% at randomization) 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted percent change in body weight

Groups^[1]	Dapagliflozin 5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-2.18
Standard Error of the mean	± 0.3636
95% Confidence Interval	( -2.89 to -1.46 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)
[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 (all treatment groups included) and stratum (HbA1c <7.0% vs >=7.0% at randomization) 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

3. Secondary Outcome Measure: Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 1 [ Time Frame: Baseline to Week 1 ]

Measure Type	Secondary
Measure Name	Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 1
Measure Description	To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 1 week of double-blind treatment.
Time Frame	Baseline to Week 1
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 1 values

Reporting Groups

	Description
Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Measured Values

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin
Number of Participants Analyzed [units:participants]	99	99	98	101
Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 1 [units: mg/dL] Least Squares Mean (Standard Error)	-13.7 (2.657)	-14.7 (2.672)	-15.5 (2.634)	2.0 (2.584)

Statistical Analysis 1 for Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 1

Groups^[1]	Dapagliflozin 2.5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-15.7
Standard Error of the mean	± 3.040
95% Confidence Interval	( -21.7 to -9.7 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)
[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 (all treatment groups included) and stratum (HbA1c <7.0% vs >=7.0% at randomization) 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 1

Groups^[1]	Dapagliflozin 5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-16.7
Standard Error of the mean	± 3.039
95% Confidence Interval	( -22.7 to -10.7 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)
[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 (all treatment groups included) and stratum (HbA1c <7.0% vs >=7.0% at randomization) 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

4. Secondary Outcome Measure: Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 16 [ Time Frame: Baseline to Week 16 ]

Measure Type	Secondary
Measure Name	Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 16
Measure Description	To compare the change from baseline in fasting plasma glucose (FPG) achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment.
Time Frame	Baseline to Week 16
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 16 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Measured Values

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin
Number of Participants Analyzed [units:participants]	100	99	98	101
Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 16 [units: mg/dL] Least Squares Mean (Standard Error)	-20.8 (2.738)	-25.6 (2.759)	-20.4 (2.720)	-10.4 (2.669)

Statistical Analysis 1 for Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 16

Groups^[1]	Dapagliflozin 2.5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0010
Mean Difference (Final Values)^[5]	-10.4
Standard Error of the mean	± 3.132
95% Confidence Interval	( -16.5 to -4.2 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)
[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 (all treatment groups included) and stratum (HbA1c <7.0% vs >=7.0% at randomization) 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted mean change in Fasting Plasma Glucose (FPG) from baseline to Week 16

Groups^[1]	Dapagliflozin 5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-15.3
Standard Error of the mean	± 3.139
95% Confidence Interval	( -21.4 to -9.1 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0 (with alpha = 0.05, two-sided)
[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 (all treatment groups included) and stratum (HbA1c <7.0% vs >=7.0% at randomization) 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

5. Secondary Outcome Measure: Proportion of participants with HbA1c<7.0% at week 16, in participants who had HbA1c ≥7.0% at baseline. [ Time Frame: Baseline to Week 16 ]

Measure Type	Secondary
Measure Name	Proportion of participants with HbA1c<7.0% at week 16, in participants who had HbA1c ≥7.0% at baseline.
Measure Description	To compare the adjusted proportions controlling for baseline HbA1c [acc. to Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu] of participants with HbA1c <7.0% achieved with each of the 2 BID doses of dapagliflozin (2.5 mg BID and 5 mg BID) co-administered with metformin versus placebo co-administered with metformin after 16 weeks of double-blind treatment, in patients who had HbA1c ≥7.0% at baseline.
Time Frame	Baseline to Week 16
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 16 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Measured Values

	Dapagliflozin 2.5mg BID plus Metformin	Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 10mg OD plus Metformin	Placebo plus Metformin
Number of Participants Analyzed [units:participants]	89	90	81	87
Proportion of participants with HbA1c<7.0% at week 16, in participants who had HbA1c ≥7.0% at baseline. [units: Percentage of participants] Least Squares Mean (95% Confidence Interval)	33.6 (24.6 to 42.5)	38.2 (29.1 to 47.3)	28.1 (19.0 to 37.1)	21.4 (13.2 to 29.6)

Statistical Analysis 1 for Proportion of participants with HbA1c<7.0% at week 16, in participants who had HbA1c ≥7.0% at baseline.

Groups^[1]	Dapagliflozin 2.5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Regression, Logistic
P-Value^[4]	0.0455
Risk Difference (RD)^[5]	12.2
Standard Error of the mean	± 6.097
95% Confidence Interval	( 0.2 to 24.1 )

[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:
	Methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Proportion of participants with HbA1c<7.0% at week 16, in participants who had HbA1c ≥7.0% at baseline.

Groups^[1]	Dapagliflozin 5mg BID plus Metformin, Placebo plus Metformin
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	Regression, Logistic
P-Value^[4]	0.0062
Risk Difference (RD)^[5]	16.8
Standard Error of the mean	± 6.153
95% Confidence Interval	( 4.8 to 28.9 )

[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:
	Methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, 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). Key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group for treatment groups tested significantly different from placebo for the primary endpoint.
[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 16 weeks double-blind treatment period plus 4 days / 30 days or up to follow-up visit 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 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Serious Adverse Events

Dapagliflozin 2.5mg BID plus Metformin

Dapagliflozin 5mg BID plus Metformin

Dapagliflozin 10mg OD plus Metformin

Placebo plus Metformin

Total, serious adverse events

# participants affected / at risk

4/100 (4.00%)

1/100 (1.00%)

2/99 (2.02%)

0/101 (0.00%)

Cardiac disorders

SICK SINUS SYNDROME¹,^†

# participants affected / at risk

0/100 (0.00%)

1/99 (1.01%)

0/101 (0.00%)

Cardiac disorders

CARDIAC FAILURE¹,^†

# participants affected / at risk

0/100 (0.00%)

1/100 (1.00%)

0/99 (0.00%)

0/101 (0.00%)

Vascular disorders

HYPERTENSIVE CRISIS¹,^†

# participants affected / at risk

0/100 (0.00%)

1/99 (1.01%)

0/101 (0.00%)

Vascular disorders

FEMORAL ARTERY OCCLUSION¹,^†

# participants affected / at risk

1/100 (1.00%)

0/100 (0.00%)

0/99 (0.00%)

0/101 (0.00%)

Infections and infestations

ENDOMETRITIS¹,^†

# participants affected / at risk

1/100 (1.00%)

0/100 (0.00%)

0/99 (0.00%)

0/101 (0.00%)

Respiratory, thoracic and mediastinal disorders

EPISTAXIS¹,^†

# participants affected / at risk

1/100 (1.00%)

0/100 (0.00%)

0/99 (0.00%)

0/101 (0.00%)

Respiratory, thoracic and mediastinal disorders

HAEMOPTYSIS¹,^†

# participants affected / at risk

1/100 (1.00%)

0/100 (0.00%)

0/99 (0.00%)

0/101 (0.00%)

†	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 16 weeks double-blind treatment period plus 4 days / 30 days or up to follow-up visit 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 2.5mg BID plus Metformin	Dapagliflozin 2.5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 5mg BID plus Metformin	Dapagliflozin 5mg, oral, twice daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Dapagliflozin 10mg OD plus Metformin	Dapagliflozin 10mg, oral, once daily plus Metformin, oral, twice daily, >=1500mg total daily dose
Placebo plus Metformin	Placebo plus Metformin, oral, twice daily, >=1500mg total daily dose

Other Adverse Events

Dapagliflozin 2.5mg BID plus Metformin

Dapagliflozin 5mg BID plus Metformin

Dapagliflozin 10mg OD plus Metformin

Placebo plus Metformin

Total, other (not including serious) adverse events

# participants affected / at risk

8/100 (8.00%)

0/100 (0.00%)

6/99 (6.06%)

9/101 (8.91%)

Infections and infestations

INFLUENZA¹,^†

# participants affected / at risk

5/100 (5.00%)

0/100 (0.00%)

2/99 (2.02%)

3/101 (2.97%)

Vascular disorders

HYPERTENSION¹,^†

# participants affected / at risk

3/100 (3.00%)

0/100 (0.00%)

4/99 (4.04%)

6/101 (5.94%)

†	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 16 weeks LOCF (last observation carried forward) was used.

Results Point of Contact

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

Documents available

CSR-D1691C00003.pdf
Download
D1691C00003_Clinical_Study_Protocol_Redacted
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

information.center@astrazeneca.com

Investigators

Principal Investigator

Shamik Parikh

AstraZeneca

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

CSR-D1691C00003.pdf

D1691C00003_Clinical_Study_Protocol_Redacted

Trial Results Summaries