Evaluate efficacy and safety in Japanese subjects with Type 2 diabetes mellitus

Study identifier:D1692C00006

ClinicalTrials.gov identifier:N/A

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A 24-week randomised, double-blind, parallel-group, multi-centre, placebo-controlled phase III trial to evaluate the efficacy and safety of dapagliflozin as monotherapy in Japanese subjects with Type 2 diabetes who have inadequate glycemic control with diet and exercise

Medical condition

Type 2 Diabetes

Phase

Phase 3

Healthy volunteers

Study drug

Dapagliflozin, Placebo

Sex

All

Actual Enrollment

261

Study type

Interventional

Age

20 Years +

Date

Study Start Date: 01 Feb 2011

Primary Completion Date: 01 Mar 2012

Study Completion Date: 01 Mar 2012

Study design

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

Verification:

Verified 01 Jul 2014 by AstraZeneca

Collaborators

Bristol-Myers Squibb

Inclusion and exclusion criteria

Location

Research Site

CHITOSE-SHI, Hokkaido, Japan

Location

Research Site

CHUO, Tokyo, Japan

Location

Research Site

CHUO-KU, Tokyo, Japan

Location

Research Site

EBINA-SHI, Kanagawa, Japan

Location

Research Site

FUKUOKA, Fukuoka, Japan

Location

Research Site

HAKUSAN-SHI, Ishikawa, Japan

Location

Research Site

KAMAKURA-SHI, Kanagawa, Japan

Location

Research Site

MATSUMOTO-SHI, Nagano, Japan

Arms	Assigned Interventions
Experimental: 1 Dapagliflozin 5 mg	Drug: Dapagliflozin Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Experimental: 2 Dapagliflozin 10 mg	Drug: Dapagliflozin Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo Comparator: 3	Drug: Placebo Matching placebo for Dapagliflozin 5mg/10mg oral dose

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: 25 Feb 2011. Last participant completed 24 week period: 12 Mar 2012. 354 participant were enrolled in 30 Japanese centers. 261 participants were randomized. Japanese men or women aged >= 20 years with inadequate glycemic control (HbA1c 6.5% to 10.0%) with diet and exercise.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Wash-out period was applicable only for participants with ongoing anti-diabetic treatment at enrolment. Drug-naive participants skip the period and directly proceed to a placebo lead-in period.

Reporting Groups

	Description
Dapagliflozin 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Participant Flow: Overall Study

	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
STARTED	86	88	87
COMPLETED	81	79	79
NOT COMPLETED	5	9	8
Adverse Event	1	2	3
Withdrawal by Subject	1	2	2
subject no longer meets study criteria	2	5	2
poor/non-compliance	1	0	1

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 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Baseline Measures

	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo	Total
Number of Participants [units: Participants]	86	88	87	261
Age Continuous [units: years] Mean ± Standard Deviation	58.6 ± 10.41	57.5 ± 9.29	60.4 ± 9.65	58.9 ± 9.83
Age, Customized [units: participants]
< 65 years	59	67	55	181
65 - <75 years	23	20	29	72
>= 75 years	4	1	3	8
Gender, Male/Female [units: participants]
Female	36	35	35	106
Male	50	53	52	155
Region of Enrollment [units: participants] Japan	86	88	87	261
Body Weight [units: kg] Mean ± Standard Deviation	65.81 ± 14.371	69.70 ± 13.821	65.96 ± 12.908	67.17 ± 13.777
Body Mass Index [units: kg/m^2] Mean ± Standard Deviation	24.88 ± 3.907	26.06 ± 4.519	25.22 ± 4.394	25.39 ± 4.296
Seated Systolic Blood Pressure [units: mmHg] Mean ± Standard Deviation	122.0 ± 13.01	126.2 ± 12.46	126.5 ± 14.36	124.9 ± 13.41
HbA1c [units: Percent] Mean ± Standard Deviation	7.50 ± 0.718	7.46 ± 0.608	7.50 ± 0.625	7.49 ± 0.649
FPG [units: mg/dL] Mean ± Standard Deviation	137.5 ± 24.41	138.8 ± 22.14	139.6 ± 21.63	138.6 ± 22.68

Outcome Measures

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

Measure Type	Primary
Measure Name	Adjusted mean change in HbA1c levels
Measure Description	To compare change from baseline in HbA1c achieved with each dose of dapagliflozin versus placebo after 24 weeks double-blind treatment.
Time Frame	From Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Measured Values

	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Number of Participants Analyzed [units:participants]	86	87	86
Adjusted mean change in HbA1c levels [units: Percent] Least Squares Mean (95% Confidence Interval)	-0.41 (-0.53 to -0.29)	-0.45 (-0.57 to -0.33)	-0.06 (-0.18 to 0.06)

Statistical Analysis 1 for Adjusted mean change in HbA1c levels

Groups^[1]	Dapagliflozin 5 mg, Placebo
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	± 0.0853
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 = 0.027 applying Dunnett's adjustment, 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 gender 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=0.027 (2-sided) applying Dunnett's adjustment. A hierarchical closed testing procedure was used to control the Type I error rate across the primary and key secondary endpoints.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted mean change in HbA1c levels

Groups^[1]	Dapagliflozin 10 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-0.39
Standard Error of the mean	± 0.0851
95% Confidence Interval	( -0.56 to -0.23 )

[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 = 0.027 applying Dunnett's adjustment, 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 gender 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=0.027 (2-sided) applying Dunnett's adjustment. A hierarchical closed testing procedure was used to control the Type I error rate across the primary and key secondary endpoints.
[5]	Other relevant estimation information:
	No text entered.

2. Secondary Outcome Measure: Adjusted mean change in Fasting Plasma Glucose (FPG) [ Time Frame: From Baseline to Week 24 ]

Measure Type	Secondary
Measure Name	Adjusted mean change in Fasting Plasma Glucose (FPG)
Measure Description	To compare the change from baseline in fasting plasma glucose (FPG) achieved with each dose of dapagliflozin versus placebo after 24 weeks double-blind treatment.
Time Frame	From Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Measured Values

	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Number of Participants Analyzed [units:participants]	86	87	86
Adjusted mean change in Fasting Plasma Glucose (FPG) [units: mg/dL] Least Squares Mean (95% Confidence Interval)	-8.6 (-12.9 to -4.3)	-13.7 (-18.0 to -9.5)	5.8 (1.6 to 10.1)

Statistical Analysis 1 for Adjusted mean change in Fasting Plasma Glucose (FPG)

Groups^[1]	Dapagliflozin 5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-14.4
Standard Error of the mean	± 2.902
95% Confidence Interval	( -20.1 to -8.7 )

[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
[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 at randomization by gender) 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). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted mean change in Fasting Plasma Glucose (FPG)

Groups^[1]	Dapagliflozin 10 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	<0.0001
Mean Difference (Final Values)^[5]	-19.5
Standard Error of the mean	± 2.892
95% Confidence Interval	( -25.2 to -13.8 )

[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
[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 at randomization by gender) 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). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
[5]	Other relevant estimation information:
	No text entered.

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

Measure Type	Secondary
Measure Name	Adjusted mean change in body weight
Measure Description	To compare the change from baseline in total body weight achieved with each dose of dapagliflozin versus placebo after 24 weeks double-blind treatment.
Time Frame	From Baseline to Week 24
Safety Issue?	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set, participants with non-missing baseline and Week 24 (LOCF) values

Reporting Groups

	Description
Dapagliflozin 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Measured Values

	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Number of Participants Analyzed [units:participants]	86	88	87
Adjusted mean change in body weight [units: kg] Least Squares Mean (95% Confidence Interval)	-2.13 (-2.65 to -1.60)	-2.22 (-2.73 to -1.71)	-0.84 (-1.36 to -0.32)

Statistical Analysis 1 for Adjusted mean change in body weight

Groups^[1]	Dapagliflozin 5 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0003
Mean Difference (Final Values)^[5]	-1.29
Standard Error of the mean	± 0.3533
95% Confidence Interval	( -1.98 to -0.59 )

[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
[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 at randomization by gender) 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). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
[5]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Adjusted mean change in body weight

Groups^[1]	Dapagliflozin 10 mg, Placebo
Non-Inferiority/Equivalence Test^[2]	No
Method^[3]	ANCOVA
P-Value^[4]	0.0001
Mean Difference (Final Values)^[5]	-1.38
Standard Error of the mean	± 0.3540
95% Confidence Interval	( -2.08 to -0.69 )

[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
[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 at randomization by gender) 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). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
[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 period plus 4/30 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 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Serious Adverse Events

Dapagliflozin 5 mg

Dapagliflozin 10 mg

Placebo

Total, serious adverse events

# participants affected / at risk

0/86 (0.00%)

1/88 (1.14%)

1/87 (1.15%)

Injury, poisoning and procedural complications

RIB FRACTURE¹,^†

# participants affected / at risk

0/86 (0.00%)

1/88 (1.14%)

0/87 (0.00%)

Nervous system disorders

PUTAMEN HAEMORRHAGE¹,^†

# participants affected / at risk

0/86 (0.00%)

0/88 (0.00%)

1/87 (1.15%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 14.1

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 period plus 4/30 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 5 mg	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose
Dapagliflozin 10 mg	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose
Placebo	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose

Other Adverse Events

Dapagliflozin 5 mg

Dapagliflozin 10 mg

Placebo

Total, other (not including serious) adverse events

# participants affected / at risk

11/86 (12.79%)

15/88 (17.05%)

14/87 (16.09%)

Infections and infestations

NASOPHARYNGITIS¹,^†

# participants affected / at risk

9/86 (10.47%)

15/88 (17.05%)

9/87 (10.34%)

Vascular disorders

HYPERTENSION¹,^†

# participants affected / at risk

2/86 (2.33%)

1/88 (1.14%)

5/87 (5.75%)

†	Events were collected by systematic assessment
1	Term from vocabulary, MedDRA 14.1

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 24 weeks LOCF (last observation carried forward) was used. Only values prior to rescue medication were used for outcome measures except for total body weight which was evaluated regardless of rescue.

Results Point of Contact

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

Documents available

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_6111&studyid=298&filename=CSR-D1692C00006.pdf
Download
CSR-D1692C00006.pdf
Download
D1692C00006_Clinical_Study_Protocol_and_Amendment
Download
Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information

800-236-9933

information.center@astrazeneca.com

Investigators

Principal Investigator

Jisin Yang

AstraZeneca KK

Sponsors

Collaborators

Inclusion Criteria

Exclusion Criteria

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

Research Site

https://filehosting.pharmacm.com/DownloadService.ashx?client=CTR_MED_6111&studyid=298&filename=CSR-D1692C00006.pdf

CSR-D1692C00006.pdf

D1692C00006_Clinical_Study_Protocol_and_Amendment

Trial Results Summaries