Evaluate Efficacy and Safety in Japanese Subjects With Type 2 Diabetes Mellitus

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01294423
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 261
• Locations: 27
• Arms: 3
• Duration (Months): 12.9
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This is a 24-week randomised, multi-centre phase III study to evaluate the efficacy and safety of dapagliflozin as monotherapy in Japanese subjects with Type 2 diabetes mellitus who have inadequate glycemic control with diet and exercise.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes; High Blood Sugar	Drug: Dapagliflozin; Drug: Dapagliflozin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 261 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change in HbA1c Levels [From Baseline to Week 24]

   To compare change from baseline in HbA1c achieved with each dose of dapagliflozin versus placebo after 24 weeks double-blind treatment.

Secondary Outcome Measures

1. Adjusted Mean Change in Fasting Plasma Glucose (FPG) [From Baseline to Week 24]

   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.

2. Adjusted Mean Change in Body Weight [From Baseline to Week 24]

   To compare the change from baseline in total body weight achieved with each dose of dapagliflozin versus placebo after 24 weeks double-blind treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provision of informed consent prior to any study specific procedures

• Men or women age ≥20 years old (Either gender needs to be 40% or higher of total number of treated subjects)diagnosed with type 2 DM ; ≥6.5% and ≤10% at 1 week before randomization

Exclusion Criteria:

• Type 1 diabetes mellitus

• FPG >240 mg/dL before randomization

• Subjects who have history of unstable or rapidly progressing renal disease

• Subjects who have severe hepatic insufficiency and/or significant abnormal liver function

• Significant cardiovascular history

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Noda	Chiba	Japan
2	Research Site	Yukuhashi	Fukuoka	Japan
3	Research Site	Hiroshima-shi	Hiroshima	Japan
4	Research Site	Chitose-shi	Hokkaido	Japan
5	Research Site	Sapporo	Hokkaido	Japan
6	Research Site	Takasago-shi	Hyogo	Japan
7	Research Site	Hakusan-shi	Ishikawa	Japan
8	Research Site	Sanuki-shi	Kagawa	Japan
9	Research Site	Takamatsu-shi	Kagawa	Japan
10	Research Site	Ebina-shi	Kanagawa	Japan
11	Research Site	Kamakura-shi	Kanagawa	Japan
12	Research Site	Sendai-shi	Miyagi	Japan
13	Research Site	Sendai	Miyagi	Japan
14	Research Site	Matsumoto-shi	Nagano	Japan
15	Research Site	Osaka-shi	Osaka	Japan
16	Research Site	Suita	Osaka	Japan
17	Research Site	Otsu-shi	Shiga	Japan
18	Research Site	Shizuoka-shi	Shizuoka	Japan
19	Research Site	Chuo-ku	Tokyo	Japan
20	Research Site	Chuo	Tokyo	Japan
21	Research Site	Meguro-ku,	Tokyo	Japan
22	Research Site	Ota-ku	Tokyo	Japan
23	Research Site	Takaoka-shi	Toyama	Japan
24	Research Site	Toyama-shi	Toyama	Japan
25	Research Site	Fukuoka		Japan
26	Research Site	Okayama		Japan
27	Research Site	Tokyo		Japan

Sponsors and Collaborators

• AstraZeneca
• Bristol-Myers Squibb

Investigators

• Study Director: Jisin Yang, MD, AstraZeneca KK

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• CSR-D1692C00006.pdf
• D1692C00006_Clinical_Study_Protocol_and_Amendment

Publications

• Kaku K, Kiyosue A, Inoue S, Ueda N, Tokudome T, Yang J, Langkilde AM. Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. Diabetes Obes Metab. 2014 Nov;16(11):1102-10. doi: 10.1111/dom.12325. Epub 2014 Jul 8.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01294423
• Other Study ID Numbers: D1692C00006
• First Posted: Feb 11, 2011
• Last Update Posted: Jul 24, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by AstraZeneca: Phase3; Clinical trial; Type2 Diabetes Mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Hyperglycemia; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	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 Detail	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.

Arm/Group Title	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Arm/Group Description	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose
Period Title: Overall Study
STARTED	86	88	87
COMPLETED	81	79	79
NOT COMPLETED	5	9	8

Baseline Characteristics

Arm/Group Title	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo	Total
Arm/Group Description	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose	Total of all reporting groups
Overall Participants	86	88	87	261
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.6 (10.41)	57.5 (9.29)	60.4 (9.65)	58.9 (9.83)
Age, Customized (participants) [Number]
< 65 years	59 68.6%	67 76.1%	55 63.2%	181 69.3%
65 - <75 years	23 26.7%	20 22.7%	29 33.3%	72 27.6%
>= 75 years	4 4.7%	1 1.1%	3 3.4%	8 3.1%
Sex: Female, Male (Count of Participants)
Female	36 41.9%	35 39.8%	35 40.2%	106 40.6%
Male	50 58.1%	53 60.2%	52 59.8%	155 59.4%
Region of Enrollment (participants) [Number]
Japan	86 100%	88 100%	87 100%	261 100%
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	65.81 (14.371)	69.70 (13.821)	65.96 (12.908)	67.17 (13.777)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.88 (3.907)	26.06 (4.519)	25.22 (4.394)	25.39 (4.296)
Seated Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	122.0 (13.01)	126.2 (12.46)	126.5 (14.36)	124.9 (13.41)
HbA1c (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	7.50 (0.718)	7.46 (0.608)	7.50 (0.625)	7.49 (0.649)
FPG (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	137.5 (24.41)	138.8 (22.14)	139.6 (21.63)	138.6 (22.68)

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change in HbA1c Levels
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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Arm/Group Description	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose
Measure Participants	86	87	86
Least Squares Mean (95% Confidence Interval) [Percent]	-0.41	-0.45	-0.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg, Placebo
	Comments	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)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	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.
	Method	ANCOVA
	Comments	with treatment group (all treatment groups included) and gender as effect and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.52 to -0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0853
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	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)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	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.
	Method	ANCOVA
	Comments	with treatment group (all treatment groups included) and gender as effect and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0851
	Estimation Comments

2. Secondary Outcome

Title	Adjusted Mean Change in Fasting Plasma Glucose (FPG)
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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Arm/Group Description	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose
Measure Participants	86	87	86
Least Squares Mean (95% Confidence Interval) [mg/dL]	-8.6	-13.7	5.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg, Placebo
	Comments	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
	Method	ANCOVA
	Comments	with treatment group (all treatment groups included) and stratum (HbA1c at randomization by gender) as effect and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.4
	Confidence Interval	(2-Sided) 95%; -20.1 to -8.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.902
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
	Method	ANCOVA
	Comments	with treatment group (all treatment groups included) and stratum (HbA1c at randomization by gender) as effect and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.5
	Confidence Interval	(2-Sided) 95%; -25.2 to -13.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.892
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change in Body Weight
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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Dapagliflozin 5 mg	Dapagliflozin 10 mg	Placebo
Arm/Group Description	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose	Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose	Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose
Measure Participants	86	88	87
Least Squares Mean (95% Confidence Interval) [kg]	-2.13	-2.22	-0.84

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg, Placebo
	Comments	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
	Method	ANCOVA
	Comments	with treatment group (all treatment groups included) and stratum (HbA1c at randomization by gender) as effect and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95%; -1.98 to -0.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3533
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	The null hypothesis is given as H0: mean(treat) minus mean(placebo) = 0 versus HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure within treatment group.
	Method	ANCOVA
	Comments	with treatment group (all treatment groups included) and stratum (HbA1c at randomization by gender) as effect and baseline value as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.38
	Confidence Interval	(2-Sided) 95%; -2.08 to -0.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3540
	Estimation Comments

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.
Adverse Event Reporting 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.
Arm/Group Title	Dapagliflozin 5 mg		Dapagliflozin 10 mg		Placebo
Arm/Group Description	Dapagliflozin : Dapagliflozin 5mg/matching placebo for Dapagliflozin 10mg oral dose		Dapagliflozin : Dapagliflozin 10mg/matching placebo for Dapagliflozin 5mg oral dose		Placebo : Matching placebo for Dapagliflozin 5mg/10mg oral dose
All Cause Mortality
	Dapagliflozin 5 mg		Dapagliflozin 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dapagliflozin 5 mg		Dapagliflozin 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/86 (0%)		1/88 (1.1%)		1/87 (1.1%)
Injury, poisoning and procedural complications
RIB FRACTURE	0/86 (0%)		1/88 (1.1%)		0/87 (0%)
Nervous system disorders
PUTAMEN HAEMORRHAGE	0/86 (0%)		0/88 (0%)		1/87 (1.1%)
Other (Not Including Serious) Adverse Events
	Dapagliflozin 5 mg		Dapagliflozin 10 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/86 (12.8%)		15/88 (17%)		14/87 (16.1%)
Infections and infestations
NASOPHARYNGITIS	9/86 (10.5%)		15/88 (17%)		9/87 (10.3%)
Vascular disorders
HYPERTENSION	2/86 (2.3%)		1/88 (1.1%)		5/87 (5.7%)

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.