Safety and Efficacy of Combination Saxagliptin & Dapagliflozin Added to Metformin to Treat Subjects With Type 2 Diabetes

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01606007
• Collaborator: (none)
• Enrollment: 1,282
• Locations: 139
• Arms: 3
• Duration (Months): 18
• Patients Per Site: 9.2
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to learn if a combination of BMS-477118 (Saxagliptin) and BMS -512148 (Dapagliflozin) added to Metformin can improve (decrease) Glycosylated Hemoglobin (Hemoglobin A1c) in patients with type 2 diabetes after 24 weeks of treatment. The safety of this treatment will also be studied.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 1282 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, 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 Add-On Therapy With Saxagliptin and Dapagliflozin Added to Metformin Compared to Add-On Therapy With Saxagliptin in Combination With Metformin or Dapagliflozin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin Alone.
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Jan 1, 2014
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm 1: Saxagliptin+Metformin XR+Placebo	Drug: Saxagliptin; Tablets, Oral, 5mg , Once daily, 24 weeks; Other Names: Onglyza ; Drug: Metformin XR; Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks; Other Names: Glucophage XR ; Drug: Placebo matching with Dapagliflozin; Tablets, Oral, 0mg, Once daily, 24 weeks
Active Comparator: Arm 2: Dapagliflozin+Metformin XR+Placebo	Drug: Metformin XR; Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks; Other Names: Glucophage XR ; Drug: Dapagliflozin; Tablets, Oral, 10mg , Once daily, 24 weeks; Other Names: BMS-512148 ; Drug: Placebo matching with Saxagliptin; Tablets, Oral, 0mg, Once daily, 24 weeks
Experimental: Arm 3: Saxagliptin+Dapagliflozin+Metformin XR	Drug: Saxagliptin; Tablets, Oral, 5mg , Once daily, 24 weeks; Other Names: Onglyza ; Drug: Metformin XR; Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks; Other Names: Glucophage XR ; Drug: Dapagliflozin; Tablets, Oral, 10mg , Once daily, 24 weeks; Other Names: BMS-512148

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 [Baseline (Week 0) and at Week 24]

   HbA1c was measured as percent of hemoglobin by a central laboratory. 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 at Week 24 in the double-blind period, including observations prior to rescue.

Secondary Outcome Measures

1. Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF]) [Baseline (Week 0) and at Week 24]

   Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained at week 24 in the doubleblind period, including observations prior to rescue.

2. Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Baseline (Week 0) and at Week 24]

   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 at Week 24 in the doubleblind period, including observations prior to rescue.

3. Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) [At Week 24]

   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.

4. Adjusted Mean Change From Baseline in Body Weight at Week 24 [Baseline (Week 0) and at Week 24]

   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 at Week 24 in the doubleblind period, including observations prior to rescue.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with Type 2 diabetes mellitus (T2DM) with HbA1c ≥ 8.0% and ≤ 12.0%

• Stable metformin therapy dose of ≥ 1500mg for at least 8 weeks prior to screening

• Body mass index (BMI) ≤ 45.0kg/m2

Exclusion Criteria:

• Estimated glomerular filtration rate (eGFR) < 60mL/min/1,73m2 and Serum Creatinine (Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females

• Uncontrolled hypertension Systolic Blood Pressure (SBP) ≥ 160mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100mmHg

• Hepatic disease

• Cardiovascular disease within 3 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Alabama Research	Birmingham	Alabama	United States	35209
2	Central Alabama Research	Homewood	Alabama	United States	35244
3	Terence T. Hart, Md	Muscle Shoals	Alabama	United States	35662
4	International Institute Of Clinical Research	Ozark	Alabama	United States	36360
5	Clinical Research Advantage	Mesa	Arizona	United States	85206
6	Elite Clinical Studies, Llc	Phoenix	Arizona	United States	85018
7	Genova Clinical Research	Tucson	Arizona	United States	85704
8	Medical Investigations, Inc.	Little Rock	Arkansas	United States	72205
9	Aureus Research, Inc.	Little Rock	Arkansas	United States	72211
10	Southland Clinical Research Center, Inc.	Fountain Valley	California	United States	92708
11	Torrance Clinical Research	Lomita	California	United States	90717
12	National Research Inst	Los Angeles	California	United States	90057
13	Providence Clinical Research	North Hollywood	California	United States	91606
14	Diabetes Medical Center Of California	Northridge	California	United States	91325
15	Mehrdad Kevin Ariani Md, Inc.	Northridge	California	United States	91325
16	Lucita M. Cruz,Md.,Inc.	Norwalk	California	United States	90650
17	Center For Clinical Trials, Llc.	Paramount	California	United States	90723
18	Center For Clinical Trials Of Sacramento, Inc.	Sacramento	California	United States	95823
19	Trinitas Research, Inc	San Jose	California	United States	95116
20	Orange County Research Center	Tustin	California	United States	92780
21	Clinical Research Advantage	Colorado Springs	Colorado	United States	80906
22	Infocus Clinical Research	Denver	Colorado	United States	80211
23	Lynn Institute Of Denver	Denver	Colorado	United States	80246
24	Southeast Clinical Research, Llc	Chiefland	Florida	United States	32626
25	Clinical Therapeutics Corporation	Coral Gables	Florida	United States	33134
26	Southeast Clinical Research, Llc	Jacksonville	Florida	United States	32216
27	Fpa Clinical Research	Kissimmee	Florida	United States	34741
28	Newphase Clinical Trials, Inc.	Miami Beach	Florida	United States	33140
29	Clinical Research Of Miami, Inc.	Miami	Florida	United States	33126
30	Advanced Pharma Cr, Llc	Miami	Florida	United States	33136
31	Omega Research Consultants, Llc	Orlando	Florida	United States	32804
32	Palm Harbor Medical Associates	Palm Harbor	Florida	United States	34684
33	Andres Patron, Do Pa	Pembroke Pines	Florida	United States	33026
34	Endocrine Research Solutions, Inc.	Roswell	Georgia	United States	30076
35	Cedar Crosse Research Center	Chicago	Illinois	United States	60607-4559
36	Deerbrook Medical Associates	Vernon Hills	Illinois	United States	60061
37	Clinical Research Advantage	Council Bluffs	Iowa	United States	51503
38	Horizon Research Group Of Opelousas, Llc	Eunice	Louisiana	United States	70535
39	Associated Internal Medicine Specialists	Battle Creek	Michigan	United States	49015
40	Harris And Associates, P.C.	Detroit	Michigan	United States	48235
41	Patterson Medical Clinic	Florissant	Missouri	United States	63031
42	Bellevue Family Practice	Bellevue	Nebraska	United States	68005
43	Clinical Research Advantage	Elkhorn	Nebraska	United States	68022
44	Clinical Research Advantage	Fremont	Nebraska	United States	68025
45	Clinical Research Advantage	Omaha	Nebraska	United States	68130
46	South Jersey Medical Associates, P.A.	Blackwood	New Jersey	United States	08012
47	Central Jersey Health And Medical Research	Elizabeth	New Jersey	United States	07205
48	Southgate Medical Group	West Seneca	New York	United States	14224
49	Metrolina Internal Medicine	Charlotte	North Carolina	United States	28204
50	Triad Clinical Trials, Llc	Greensboro	North Carolina	United States	27410
51	Diabetes & Endocrinology Consultants	Morehead City	North Carolina	United States	28557
52	Pmg Research Of Winston-Salem, Llc	Winston-salem	North Carolina	United States	27103
53	Daystar Clinical Resarch, Inc.	Akron	Ohio	United States	44313
54	Sterling Research Grp, Ltd.	Cincinnati	Ohio	United States	45246
55	Rapid Medical Research, Inc.	Cleveland	Ohio	United States	44122
56	Primed Clinical Research	Dayton	Ohio	United States	45419
57	Physicians Research, Inc.	Zanesville	Ohio	United States	43701
58	Lynn Institute Of Norman	Norman	Oklahoma	United States	73069
59	Willamette Valley Clinical Studies	Eugene	Oregon	United States	97404
60	Oregon Clinical Research	Portland	Oregon	United States	97220
61	Heritage Valley Medical Group	Beaver	Pennsylvania	United States	15009
62	Wellmon Family Practice	Shippensburg	Pennsylvania	United States	17257
63	Tlm Medical Services	Columbia	South Carolina	United States	29204
64	Palmetto Clinical Trial Services Llc	Fountain Inn	South Carolina	United States	29644
65	Holston Medical Group	Bristol	Tennessee	United States	37620
66	Holston Medical Group	Kingsport	Tennessee	United States	37660
67	Pmg Research Of Knoxville	Knoxville	Tennessee	United States	37912
68	Arlington Family Research Center, Inc.	Arlington	Texas	United States	76012
69	Padre Coast Clinical Research	Corpus Christi	Texas	United States	78404
70	Dallas Diabetes & Endocrine Center	Dallas	Texas	United States	75230-2548
71	Excel Clinical Research, Llc	Houston	Texas	United States	77035
72	North Hills Medical Research, Inc.	North Richland Hills	Texas	United States	76180
73	Med-Olam Clinical Research	Pasadena	Texas	United States	77504
74	Sam Clinical Research Center	San Antoinio	Texas	United States	78229
75	Covenant Clinical Research, Pa	San Antonio	Texas	United States	78229
76	Hillcrest Family Health Center	Waco	Texas	United States	76710
77	Val R. Hansen, M.D.	Bountiful	Utah	United States	84010
78	Highland Clinical Research	Salt Lake City	Utah	United States	84124
79	Southwestern Vermont Med Cntr	Bennington	Vermont	United States	05201
80	Hampton Roads Center For Clinical Research, Inc.	Suffolk	Virginia	United States	23435
81	Local Institution	Coquitlam	British Columbia	Canada	V3K 3V9
82	Local Institution	Winnipeg	Manitoba	Canada	R3E3P4
83	Local Institution	Brampton	Ontario	Canada	L6T 0G1
84	Local Institution	Smiths Falls	Ontario	Canada	K7A 4W8
85	Local Institution	Toronto	Ontario	Canada	M9W 4L6
86	Local Institution	Granby	Quebec	Canada	J2G 8Z9
87	Local Institution	Saskatoon	Saskatchewan	Canada	S7K 3H3
88	Local Institution	Quebec		Canada	G1N 4V3
89	Local Institution	Bucheon	Gyeonggi-do	Korea, Republic of	420-717
90	Local Institution	Sungnam-si	Gyeonggi-do	Korea, Republic of	463-712
91	Local Institution	Daegu		Korea, Republic of	700-721
92	Local Institution	Incheon		Korea, Republic of	405-760
93	Local Institution	Seoul		Korea, Republic of	110-774
94	Local Institution	Seoul		Korea, Republic of	120-752
95	Local Institution	Seoul		Korea, Republic of	137-701
96	Local Institution	Guadalajara	Jalisco	Mexico	44670
97	Local Institution	Cuautla	Morelos	Mexico	62744
98	Local Institution	Monterrey	Nuevo Leon	Mexico	64460
99	Local Institution	Monterrey	Nuevo Leon	Mexico	64710
100	Local Institution	Merida	Yucatan	Mexico	97070
101	Local Institution	Aguascalientes		Mexico	20230
102	Local Institution	Chihuahua		Mexico	31217
103	Local Institution	Durango		Mexico	34000
104	Local Institution	Gdansk		Poland	80-546
105	Local Institution	Katowice		Poland	40-057
106	Local Institution	Katowice		Poland	40954
107	Local Institution	Krakow		Poland	30-015
108	Local Institution	Lodz		Poland	90-242
109	Local Institution	Opole		Poland	45-367
110	Local Institution	Poznan		Poland	61-655
111	Local Institution	Pulawy		Poland	24-100
112	Local Institution	Warszawa		Poland	03-580
113	Local Institution	Cidra		Puerto Rico	00739
114	Local Institution	Manati		Puerto Rico	00674
115	Local Institution	Ponce		Puerto Rico	00716
116	Local Institution	San Juan		Puerto Rico	00909
117	Local Institution	San Juan		Puerto Rico	00926
118	Local Institution	San Juan		Puerto Rico	00935
119	Local Institution	Villa Fontana		Puerto Rico	00983
120	Local Institution	Ploiesti	Prahova	Romania	100018
121	Local Institution	Ploiesti	Prahova	Romania	100163
122	Local Institution	Timisoara	Timis	Romania	300736
123	Local Institution	Bucharest		Romania	050538
124	Local Institution	Bucuresti		Romania	020359
125	Local Institution	Bucuresti		Romania	020475
126	Local Institution	Bucuresti		Romania	11794
127	Local Institution	Cluj Napoca Cluj		Romania	400006
128	Local Institution	Craiova		Romania	200349
129	Local Institution	Galati		Romania	800098
130	Local Institution	Soweto	Gauteng	South Africa	2013
131	Local Institution	Gauteng	Johannesburg	South Africa	1818
132	Local Institution	Durban	Kwa-Zulu Natal	South Africa	4001
133	Local Institution	Cape Town	Western Cape	South Africa	7500
134	Local Institution	Goodwood	Western Cape	South Africa	7460
135	Local Institution	Paarl	Western Cape	South Africa	7646
136	Local Institution	Rondebosch	Western Cape	South Africa	7700
137	Local Institution	Somerset West	Western Cape	South Africa	7130
138	Local Institution	Johannesburg		South Africa	1829
139	Local Institution	Johannesburg		South Africa	2129

Sponsors and Collaborators

• AstraZeneca

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource
• CV_181169_Protocol_Redacted
• CV181169_Synopsis

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01606007
• Other Study ID Numbers: CV181-169; 2012-000679-18
• First Posted: May 25, 2012
• Last Update Posted: May 15, 2017
• Last Verified: Mar 1, 2017

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

Study Results

Participant Flow

Pre-assignment Detail	Of 1282 participants enrolled subjects, 534 eligible subjects entered the randomized, double-blind treatment period. Of 534 randomized and treated subjects, 490 subjects completed the study.

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
Period Title: Overall Study
STARTED	176	179	179
COMPLETED	161	160	169
NOT COMPLETED	15	19	10

Baseline Characteristics

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR	Total
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148	Total of all reporting groups
Overall Participants	176	179	179	534
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.6 (9.6)	53.5 (9.7)	53.4 (9.8)	53.8 (9.7)
Age, Customized (participants) [Number]
<65 years	148 84.1%	158 88.3%	160 89.4%	466 87.3%
>=65 years	28 15.9%	21 11.7%	19 10.6%	68 12.7%
Sex: Female, Male (Count of Participants)
Female	82 46.6%	90 50.3%	94 52.5%	266 49.8%
Male	94 53.4%	89 49.7%	85 47.5%	268 50.2%
Race/Ethnicity, Customized (participants) [Number]
White	121 68.8%	131 73.2%	120 67%	372 69.7%
Black african/american	22 12.5%	16 8.9%	22 12.3%	60 11.2%
Asian	11 6.3%	10 5.6%	12 6.7%	33 6.2%
Other	22 12.5%	22 12.3%	25 14%	69 12.9%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.8 (5.142)	31.46 (5.321)	31.76 (4.787)	31.67 (5.080)
T2DM duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.2 (5.52)	7.4 (5.40)	7.1 (5.04)	7.6 (5.33)
HbA1c (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	9.03 (1.05)	8.87 (1.16)	8.92 (1.18)	8.94 (1.13)

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24
Description	HbA1c was measured as percent of hemoglobin by a central laboratory. 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 at Week 24 in the double-blind period, including observations prior to rescue.
Time Frame	Baseline (Week 0) and at Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing HbA1c values at baseline and Week 24

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
Measure Participants	143	151	158
Mean (95% Confidence Interval) [% HbA1c]	-0.88	-1.20	-1.47

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Saxagliptin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+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 Saxagliptin+Dapagliflozin+Metformin was superior to both Saxagliptin+Metformin and Dapagliflozin+Metformin.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.59
	Confidence Interval	(2-Sided) 95%; -0.81 to -0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1112
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Dapagliflozin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0166
	Comments	Primary endpoint was tested at alpha=0.05; significance was claimed only if Saxagliptin+Dapagliflozin+Metformin was superior to both Saxagliptin+Metformin and Dapagliflozin+Metformin.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.48 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1108
	Estimation Comments

2. Secondary Outcome

Title	Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24 (Last Observation Carried Forward [LOCF])
Description	Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained at week 24 in the doubleblind period, including observations prior to rescue.
Time Frame	Baseline (Week 0) and at Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
Measure Participants	147	144	154
Mean (95% Confidence Interval) [MG/DL PPG]	-35.6 (3.510)	-70.4 (3.538)	-79.6 (3.426)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Saxagliptin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
	Comments	LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Each secondary endpoint was tested at alpha=0.05; significance was claimed only if Saxagliptin+Dapagliflozin+Metformin was superior to both Saxagliptin+Metformin and Dapagliflozin+Metformin.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-44.0
	Confidence Interval	(2-Sided) 95%; -53.7 to -34.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.914
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Dapagliflozin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
	Comments	LOCF
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0639
	Comments	Each secondary endpoint was tested at alpha=0.05; significance testing stops at the endpoint where p-value>0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.1
	Confidence Interval	(2-Sided) 95%; -18.8 to 0.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.923
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Description	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 at Week 24 in the doubleblind period, including observations prior to rescue.
Time Frame	Baseline (Week 0) and at Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing PPG values at baseline and Week 24

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
Measure Participants	142	148	155
Mean (95% Confidence Interval) [mg/dL]	-14.0	-31.7	-37.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Saxagliptin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+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	-23.8
	Confidence Interval	(2-Sided) 95%; -31.6 to -15.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.988
	Estimation Comments	ANCOVA was applied for comparison, but p-value was not reported because at least one prior test in the hierarchical testing procedure yielded p-value>0.05.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Dapagliflozin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+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	-6.1
	Confidence Interval	(2-Sided) 95%; -13.8 to 1.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.957
	Estimation Comments	ANCOVA was applied for comparison, but p-value was not reported because at least one prior test in the hierarchical testing procedure yielded p-value>0.05.

4. Secondary Outcome

Title	Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
Description	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.
Time Frame	At Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and were not missing baseline and Week 24 (LOCF) values

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
Measure Participants	175	173	177
Number (95% Confidence Interval) [% of Participants]	18.3 10.4%	22.2 12.4%	41.4 23.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Saxagliptin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+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 in percentages
	Estimated Value	23.1
	Confidence Interval	(2-Sided) 95%; 14.7 to 31.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.282
	Estimation Comments	Modified Logistic Regression was applied for comparison, but p-value was not reported because at least one prior test in the hierarchical testing procedure yielded p-value>0.05.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 2: Dapagliflozin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+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 in percentages
	Estimated Value	19.1
	Confidence Interval	(2-Sided) 95%; 10.1 to 28.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 4.587
	Estimation Comments	Modified Logistic Regression was applied for comparison, but p-value was not reported because at least one prior test in the hierarchical testing procedure yielded p-value>0.05.

5. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Body Weight at Week 24
Description	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 at Week 24 in the doubleblind period, including observations prior to rescue.
Time Frame	Baseline (Week 0) and at Week 24

Outcome Measure Data

Analysis Population Description

All randomized participants who received study medication and had nonmissing body weight values at baseline and Week 24

Arm/Group Title	Arm 1: Saxagliptin+Metformin XR+Placebo	Arm 2: Dapagliflozin+Metformin XR+Placebo	Arm 3: Saxagliptin+Dapagliflozin+Metformin XR
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
Measure Participants	145	152	159
Mean (95% Confidence Interval) [Body weight Kg]	0.00	-2.39	-2.05

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Saxagliptin+Metformin XR+Placebo, Arm 3: Saxagliptin+Dapagliflozin+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	-2.05
	Confidence Interval	(2-Sided) 95%; -2.73 to -1.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3451
	Estimation Comments	ANCOVA was applied for comparison, but p-value was not reported because at least one prior test in the hierarchical testing procedure yielded p-value>0.05.

Adverse Events

Time Frame	24 weeks
Arm/Group Title	SAXA + MET		DAPA + MET		SAXA + DAPA + MET
Arm/Group Description	Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Placebo matching with Dapagliflozin Tablets, Oral, 0mg, Once daily, 24 weeks		Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148 Drug: Placebo matching with Saxagliptin Tablets, Oral, 0mg, Once daily, 24 weeks		Drug: Saxagliptin Tablets, Oral, 5mg , Once daily, 24 weeks Other Names: Onglyza Drug: Metformin XR Tablets, Oral, ≥ 1500mg/≤ 2000mg, Once daily, 24 weeks Other Names: Glucophage XR Drug: Dapagliflozin Tablets, Oral, 10mg , Once daily, 24 weeks Other Names: BMS512148
All Cause Mortality
	SAXA + MET		DAPA + MET		SAXA + DAPA + MET
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	SAXA + MET		DAPA + MET		SAXA + DAPA + MET
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/176 (3.4%)		2/179 (1.1%)		2/179 (1.1%)
Cardiac disorders
ACUTE MYOCARDIAL INFARCTION	0/176 (0%)	0	0/179 (0%)	0	1/179 (0.6%)	1
Gastrointestinal disorders
PANCREATITIS CHRONIC	0/176 (0%)	0	0/179 (0%)	0	1/179 (0.6%)	1
UMBILICAL HERNIA	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
General disorders
CHEST PAIN	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Infections and infestations
TOOTH INFECTION	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Injury, poisoning and procedural complications
PATELLA FRACTURE	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Metabolism and nutrition disorders
HYPERKALAEMIA	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Musculoskeletal and connective tissue disorders
ARTHRITIS	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
GASTRIC NEOPLASM	0/176 (0%)	0	0/179 (0%)	0	1/179 (0.6%)	1
Nervous system disorders
TRANSIENT ISCHAEMIC ATTACK	0/176 (0%)	0	1/179 (0.6%)	1	0/179 (0%)	0
Reproductive system and breast disorders
BENIGN PROSTATIC HYPERPLASIA	0/176 (0%)	0	1/179 (0.6%)	1	0/179 (0%)	0
Respiratory, thoracic and mediastinal disorders
PULMONARY EMBOLISM	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Vascular disorders
DEEP VEIN THROMBOSIS	1/176 (0.6%)	1	0/179 (0%)	0	0/179 (0%)	0
Other (Not Including Serious) Adverse Events
	SAXA + MET		DAPA + MET		SAXA + DAPA + MET
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/176 (0%)		0/179 (0%)		0/179 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.