An Efficacy & Safety Study of BMS-512148 in Combination With Metformin Extended Release Tablets

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00643851
• Collaborator: Astra Zeneca, Bristol-Myers Squibb (Other)
• Enrollment: 994
• Locations: 99
• Arms: 3
• Duration (Months): 14
• Patients Per Site: 10
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to learn if initiating treatment with BMS-51248 (Dapagliflozin) in combination with metformin XR can improve diabetes control in patients with Type 2 Diabetes who do not receive any pharmacological treatment for diabetes, when compared to initial treatment with monotherapy dapagliflozin or metformin XR. The safety of this treatment will also be studied

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Dapagliflozin; Drug: Metformin XR	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 994 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Active Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Combination With Metformin as Initial Therapy as Compared With Dapagliflozin Monotherapy and Metformin Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Aug 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 Dapagliflozin (5 mg) + Metformin XR (up to 2000 mg)	Drug: Dapagliflozin; Tablets, Oral, Once daily, 24 weeks; Other Names: BMS-512148 ; Drug: Metformin XR; Tablets, Oral, Once daily, 24 weeks
Experimental: Arm 2 Dapagliflozin (5 mg)	Drug: Dapagliflozin; Tablets, Oral, Once daily, 24 weeks; Other Names: BMS-512148
Active Comparator: Arm 3 Metformin XR (500 mg up to 2000 mg)	Drug: Metformin XR; Tablets, Oral, Once daily, 24 weeks

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double- blind period.

Secondary Outcome Measures

1. Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the double-blind period.

2. Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. Mean and standard error for percentage of participants estimated by modified logistic regression model.

3. Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.

4. Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.

5. Adjusted Mean Change From Baseline in Total Body Weight (kg) in Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 24]

   Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 77 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males & females, 18-77 years old inclusive, with type 2 diabetes and with inadequate glycemic control

• Drug naive or treated with anti-diabetic medication for < 24 weeks since original diagnosis

• C-peptide ≥ 1.0 ng/mL

• Body Mass Index ≤ 45.0 kg/m

• Serum creatinine < 1.50 mg/dL for men or < 1.40 mg/dL for women

Exclusion Criteria:

• AST and/or ALT >3.0 times the upper limit of normal (ULN)

• Serum total bilirubin > 2.0 mg/dL

• Creatine kinase > 3X the upper limit of normal (ULN)

• Symptoms of severely uncontrolled diabetes

• Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric or rheumatic diseases

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Greystone Medical Research, Llc	Birmingham	Alabama	United States	35242
2	Winston Technology Research, Llc	Haleyville	Alabama	United States	35565
3	Clinical Research Advantage, Inc.	Tempe	Arizona	United States	85282
4	John Muir Physician Network Clinical Research Center	Concord	California	United States	94520
5	Southland Clinical Research Center, Inc.	Fountain Valley	California	United States	92708
6	Valley Research	Fresno	California	United States	93720
7	Central Florida Clinical Trials, Inc.	Altamonte Springs	Florida	United States	32701
8	Clinical Therapeutics Corporation	Coral Gables	Florida	United States	33134
9	Florida Research Network, Llc	Gainesville	Florida	United States	32605
10	Fpa Clinical Research	Kissimmee	Florida	United States	34741
11	Nextphase Clinical Trials, Inc.	Miami	Florida	United States	33145
12	Middle Georgia Drug Study Center, Llc	Perry	Georgia	United States	31069
13	Cedar Crosse Research Center	Chicago	Illinois	United States	60607
14	Deerbrook Medical Associates	Vernon Hills	Illinois	United States	60061
15	Jackson Clinic	Rolling Fork	Mississippi	United States	39159
16	Mercy Medical Group/Dba Woodlake Research	Chesterfield	Missouri	United States	63017
17	Hudson Valley Clinical Research Center	Kingston	New York	United States	12401
18	Metrolina Medical Research	Charlotte	North Carolina	United States	28209
19	Crescent Medical Research	Salisbury	North Carolina	United States	28144
20	Community Health Care, Inc.	Canal Fulton	Ohio	United States	44614
21	Wells Institute For Health Awareness	Kettering	Ohio	United States	45429
22	Newark Physician Associates	Newark	Ohio	United States	43055
23	Physician Research, Inc.	Zanesville	Ohio	United States	43701
24	Gilbert Medical Research, Llc	Bethany	Oklahoma	United States	73008
25	Integris Family Care South Penn	Oklahoma City	Oklahoma	United States	73159
26	Integris Family Care Yukon	Yukon	Oklahoma	United States	73099
27	Willamette Valley Clinical Studies	Eugene	Oregon	United States	97404
28	Commonwealth Primary Care, Pc / Fleetwood Clinical Research	Fleetwood	Pennsylvania	United States	19522
29	Biomedical Research Associates, Llc	Shippensburg	Pennsylvania	United States	17257
30	Safe Harbor Clinical Research	East Providence	Rhode Island	United States	02914
31	Southeastern Research Associates, Inc.	Greenville	South Carolina	United States	29605
32	Spartanburg Medical Research	Spartanburg	South Carolina	United States	29303
33	Middle Tennessee Clinical Research	Fayetteville	Tennessee	United States	37334
34	Holston Medical Group	Kingsport	Tennessee	United States	37660
35	Endocrine Associates	Houston	Texas	United States	77004
36	Village Family Practice	Houston	Texas	United States	77024
37	Non-Invasive Cardiovascular, Pa	Houston	Texas	United States	77074
38	Excel Clinical Research, Llc	Houston	Texas	United States	77081
39	Texas Center For Drug Development	Houston	Texas	United States	77081
40	Inst. Of Clin. Research At The Diabetes Cntr. Of The Sw	Midland	Texas	United States	79705
41	Hill Country Medical Associates	New Braunfels	Texas	United States	78130
42	Southwest Clinical Research Center, Llc	Pearland	Texas	United States	77584
43	S.A.M. Clinical Research Center	San Antoinio	Texas	United States	78229
44	Covenant Clinical Research, Pa	San Antonio	Texas	United States	78229
45	Local Institution	Guri-Si	Gyeonggi-Do	Korea, Republic of	471-701
46	Local Institution	Seoul	Nowon-Gu	Korea, Republic of	471-701
47	Local Institution	Bucheon		Korea, Republic of	420-717
48	Local Institution	Incheon		Korea, Republic of	105-760
49	Local Institution	Incheon		Korea, Republic of	400-711
50	Local Institution	Seoul		Korea, Republic of	137-040
51	Local Institution	Sungnam-Si, Gyeonggi-Do		Korea, Republic of	463-070
52	Local Institution	Ciudad De Mexico	Distrito Federal	Mexico	14000
53	Local Institution	Pachuca	Hidelgo	Mexico	42090
54	Local Institution	Guadalajara	Jalisco	Mexico	44100
55	Local Institution	Guadalajara	Jalisco	Mexico	44650
56	Local Institution	Guadalajara	Jalisco	Mexico	44670
57	Local Institution	Morelia	Michioacan	Mexico	58070
58	Local Institution	Monterrey, Nl	Nuevo Leon	Mexico	64400
59	Local Institution	Monterrey	Nuevo Leon	Mexico	64000
60	Local Institution	Tampico	Tamaulipas	Mexico	89000
61	Local Institution	Merida	Yucatan	Mexico	97070
62	Local Institution	Aguascalientes		Mexico	20127
63	Local Institution	Durango		Mexico	34000
64	Local Institution	Veracruz		Mexico	91910
65	Local Institution	Cebu City		Philippines	6000
66	Local Institution	Jaro Iloilo City		Philippines	5000
67	Local Institution	Las Pinas City		Philippines	1740
68	Local Institution	Marikina City		Philippines	1800
69	Local Institution	Pasig City		Philippines	1600
70	Local Institution	Quezon City		Philippines	1100
71	Local Institution	Ponce		Puerto Rico	00716
72	Local Institution	Ponce		Puerto Rico	00717
73	Local Institution	San Juan		Puerto Rico	00920
74	Local Institution	San Juan		Puerto Rico	00926
75	Local Institution	Villa Fontana		Puerto Rico	00983
76	Local Institution	Moscow	Russia	Russian Federation	125299
77	Local Institution	Arkhangelsk		Russian Federation	163045
78	Local Institution	Dzerzhinskiy		Russian Federation	140091
79	Local Institution	Kemerovo		Russian Federation	650066
80	Local Institution	Moscov		Russian Federation	119048
81	Local Institution	Nizhniy Novgorod		Russian Federation	603018
82	Local Institution	Novosibirsk		Russian Federation	630091
83	Local Institution	Novosibirsk		Russian Federation	630117
84	Local Institution	Saint-Petersburg		Russian Federation	190068
85	Local Institution	Saratov		Russian Federation	410028
86	Local Institution	St. Petersburg		Russian Federation	191015
87	Local Institution	Volgograd		Russian Federation	400001
88	Local Institution	Voronezh		Russian Federation	394018
89	Local Institution	Yaroslav		Russian Federation	150003
90	Local Institution	Dnepropetrovsk		Ukraine	49023
91	Local Institution	Donetsk		Ukraine	83003
92	Local Institution	Kiev		Ukraine	04050
93	Local Institution	Kiev		Ukraine	4114
94	Local Institution	Lviv		Ukraine	79010
95	Local Institution	Odessa		Ukraine	65009
96	Local Institution	Odessa		Ukraine	65039
97	Local Institution	Odessa		Ukraine	65114
98	Local Institution	Vinnytsya		Ukraine	21010
99	Local Institution	Zhytomyr		Ukraine	10003

Sponsors and Collaborators

• AstraZeneca
• Astra Zeneca, Bristol-Myers Squibb

Investigators

• Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Publication

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00643851
• Other Study ID Numbers: MB102-021
• First Posted: Mar 26, 2008
• Last Update Posted: Feb 23, 2017
• Last Verified: Jan 1, 2017

• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Metformin; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	Of 994 participants enrolled, 632 completed a qualification period. Of these 632 participants, 603 were randomized. Of these 603 randomized, 598 received at least one dose of study medication treatment. Of these 598 randomized, 518 completed double-blind treatment period.

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Period Title: Overall Study
STARTED	194	203	201
COMPLETED	177	170	171
NOT COMPLETED	17	33	30

Baseline Characteristics

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR	Total
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks	Total of all reporting groups
Overall Participants	194	203	201	598
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.7 (9.31)	52.3 (10.20)	51.8 (9.80)	52.0 (9.77)
Age, Customized (Number) [Number]
Younger than 65 years	177 91.2%	183 90.1%	184 91.5%	544 91%
65 to younger than 75 years	17 8.8%	17 8.4%	16 8%	50 8.4%
75 years and older	0 0%	3 1.5%	1 0.5%	4 0.7%
Sex/Gender, Customized (Number) [Number]
Male	78 40.2%	92 45.3%	95 47.3%	265 44.3%
Female	116 59.8%	111 54.7%	106 52.7%	333 55.7%
Race/Ethnicity, Customized (Number) [Number]
White	153 78.9%	166 81.8%	158 78.6%	477 79.8%
Black/African American	8 4.1%	4 2%	6 3%	18 3%
Asian	32 16.5%	33 16.3%	35 17.4%	100 16.7%
Other	1 0.5%	0 0%	2 1%	3 0.5%

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 (Last Observation Carried Forward [LOCF])
Description	HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double- blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF)

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Measure Participants	185	196	195
Mean (Standard Error) [% of hemoglobin]	-2.05 (0.0892)	-1.19 (0.0866)	-1.35 (0.0868)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Primary endpoint was tested at alpha=0.05; significance was claimed only if DAPA 5MG + MET was superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.86
	Confidence Interval	(2-Sided) 95%; -1.11 to -0.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1243
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Primary endpoint was tested at alpha=0.05; significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.70
	Confidence Interval	(2-Sided) 95%; -0.94 to -0.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1245
	Estimation Comments

2. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Fasting plasma glucose was measured as milligrams per deciliter(mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing FPG values at baseline and Week 24 (LOCF)

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Measure Participants	192	203	200
Mean (Standard Error) [mg/dL]	-61.0 (2.783)	-42.0 (2.708)	-33.6 (2.728)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.1
	Confidence Interval	(2-Sided) 95%; -26.7 to -11.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.883
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-27.5
	Confidence Interval	(2-Sided) 95%; -35.1 to -19.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.897
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. Mean and standard error for percentage of participants estimated by modified logistic regression model.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF)

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Measure Participants	185	196	195
Mean (Standard Error) [Percentage of participants]	52.4 (3.581) 27%	22.5 (2.741) 11.1%	34.6 (3.296) 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	modified logistic regression
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	29.9
	Confidence Interval	(2-Sided) 95%; 20.8 to 39.0
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.633
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	17.8
	Confidence Interval	(2-Sided) 95%; 8.1 to 27.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.947
	Estimation Comments

4. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) in Subjects With Baseline HbA1c ≥ 9% at Week 24 (Last Observation Carried Forward [LOCF])
Description	HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF) in subjects with baseline HbA1c ≥ 9%

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Measure Participants	92	96	101
Mean (Standard Error) [% of hemoglobin]	-3.01 (0.1381)	-1.67 (0.1361)	-1.82 (0.1320)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.34
	Confidence Interval	(2-Sided) 95%; -1.72 to -0.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1938
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.19
	Confidence Interval	(2-Sided) 95%; -1.57 to -0.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1912
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Total Body Weight (kg) at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF)

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Measure Participants	192	203	200
Mean (Standard Error) [kg]	-2.66 (0.2428)	-2.61 (0.2361)	-1.29 (0.2378)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8769
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.72 to 0.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3388
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Secondary endpoints were tested following a sequential testing procedure at alpha=0.05. Significance was claimed only if DAPA 5MG + MET is superior to both controls.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.37
	Confidence Interval	(2-Sided) 95%; -2.04 to -0.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3399
	Estimation Comments

6. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Total Body Weight (kg) in Subjects With Baseline Body Mass Index (BMI) ≥ 27 kg/m^2 at Week 24 (Last Observation Carried Forward [LOCF])
Description	Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the double-blind period.
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing values at baseline and Week 24 (LOCF) in subjects with BMI ≥ 27 kg/m2

Arm/Group Title	Dapagliflozin 5 mg + Metformin XR	Dapagliflozin 5 mg	Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks	Dapagliflozin tablets, oral, once daily for 24 weeks	Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
Measure Participants	142	156	154
Mean (Standard Error) [kg]	-3.04 (0.3031)	-2.88 (0.2890)	-1.47 (0.2907)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.98 to 0.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4191
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 5 mg + Metformin XR, Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.57
	Confidence Interval	(2-Sided) 95%; -2.40 to -0.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.4201
	Estimation Comments

Adverse Events

Time Frame	Onset on or after the first date of double-blind treatment and on or prior to the last day of double-blind treatment 24 weeks plus 4 days for non-serious adverse event; plus 30 days for serious adverse event.
Arm/Group Title	Dapagliflozin 5 mg + Metformin XR		Dapagliflozin 5 mg		Metformin XR
Arm/Group Description	Dapagliflozin tablets, oral, once daily for 24 weeks plus metfomin XR tablets (up to 2000mg), oral, once daily for 24 weeks		Dapagliflozin tablets, oral, once daily for 24 weeks		Metfomin XR tablets (500mg up to 2000mg), oral, once daily for 24 weeks
All Cause Mortality
	Dapagliflozin 5 mg + Metformin XR		Dapagliflozin 5 mg		Metformin XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dapagliflozin 5 mg + Metformin XR		Dapagliflozin 5 mg		Metformin XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/194 (3.1%)		9/203 (4.4%)		7/201 (3.5%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	0/194 (0%)	0	1/203 (0.5%)	1	0/201 (0%)	0
ANGINA UNSTABLE	0/194 (0%)	0	1/203 (0.5%)	1	0/201 (0%)	0
CARDIOPULMONARY FAILURE	0/194 (0%)	0	1/203 (0.5%)	1	0/201 (0%)	0
MYOCARDIAL INFARCTION	0/194 (0%)	0	1/203 (0.5%)	1	0/201 (0%)	0
Gastrointestinal disorders
OESOPHAGITIS	1/194 (0.5%)	1	0/203 (0%)	0	0/201 (0%)	0
GASTROINTESTINAL OBSTRUCTION	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
Infections and infestations
PULMONARY TUBERCULOSIS	3/194 (1.5%)	3	1/203 (0.5%)	1	1/201 (0.5%)	1
HERPES ZOSTER	1/194 (0.5%)	1	0/203 (0%)	0	0/201 (0%)	0
PNEUMONIA	1/194 (0.5%)	1	0/203 (0%)	0	0/201 (0%)	0
CELLULITIS	0/194 (0%)	0	1/203 (0.5%)	1	1/201 (0.5%)	1
CYSTITIS	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
GANGRENE	0/194 (0%)	0	1/203 (0.5%)	1	0/201 (0%)	0
PYELONEPHRITIS	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
Injury, poisoning and procedural complications
GUN SHOT WOUND	1/194 (0.5%)	1	0/203 (0%)	0	0/201 (0%)	0
UPPER LIMB FRACTURE	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
Metabolism and nutrition disorders
DIABETES MELLITUS	0/194 (0%)	0	2/203 (1%)	2	0/201 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BREAST CANCER	0/194 (0%)	0	1/203 (0.5%)	1	0/201 (0%)	0
Nervous system disorders
CEREBROVASCULAR ACCIDENT	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
ISCHAEMIC NEUROPATHY	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
Vascular disorders
HYPERTENSIVE CRISIS	0/194 (0%)	0	0/203 (0%)	0	1/201 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Dapagliflozin 5 mg + Metformin XR		Dapagliflozin 5 mg		Metformin XR
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/194 (24.7%)		32/203 (15.8%)		40/201 (19.9%)
Gastrointestinal disorders
DIARRHOEA	15/194 (7.7%)	20	8/203 (3.9%)	9	14/201 (7%)	21
NAUSEA	11/194 (5.7%)	20	4/203 (2%)	5	8/201 (4%)	14
Infections and infestations
UPPER RESPIRATORY TRACT INFECTION	10/194 (5.2%)	11	10/203 (4.9%)	11	11/201 (5.5%)	11
URINARY TRACT INFECTION	10/194 (5.2%)	11	9/203 (4.4%)	9	10/201 (5%)	12
Metabolism and nutrition disorders
DYSLIPIDAEMIA	9/194 (4.6%)	9	11/203 (5.4%)	13	8/201 (4%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.