A Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes With Inadequately Controlled Hypertension on an ACEI or ARB and an Additional Antihypertensive Medication

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01195662
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 2,245
• Locations: 298
• Arms: 2
• Duration (Months): 28.1
• Patients Per Site: 7.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to learn if BMS-512148 (Dapagliflozin), after 12 weeks, can improve (decrease) blood pressure in patients with type 2 diabetes with uncontrolled hypertension who are on an Angiotensin-converting enzyme inhibitor (ACEI) or an Angiotensin Receptor Blocker (ARB).The safety of this treatment will also be studied

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 2245 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin in Subjects With Type 2 Diabetes With Inadequately Controlled Hypertension on an Angiotensin-Converting Enzyme (ACE) Inhibitor or Angiotensin Receptor Blocker (ARB) and an Additional Antihypertensive Medication
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin 10 mg Dapagliflozin 10 mg tablets	Drug: Dapagliflozin; Tablets, Oral, 10 mg, once daily, Up to 12 weeks; Other Names: BMS-512148 Farxiga™
Placebo Comparator: Placebo matching Dapagliflozin Placebo tablets matching dapagliflozin tablets	Drug: Placebo matching Dapagliflozin; Tablets, Oral, 0 mg, once daily, Up to 12 weeks

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure for 12 Week Double-Blind Treatment Period - Randomized Participants [Baseline to Week 12]

   Systolic blood pressure (SBP) was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Blood pressure (BP) values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the BP was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured.

2. Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) for 12 Week Double-Blind Treatment Period - Randomized Participants [Baseline to Week 12]

   Adjusted mean change in glycosylated hemoglobin ( HbA1c) from baseline at Week 12 was calculated. HbA1c was measured as percent of hemoglobin 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. HbA1c values were obtained at enrollment and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period.

Secondary Outcome Measures

1. Adjusted Mean Change From Baseline in 24-hour Ambulatory Systolic Blood Pressure at Week 12 Last Observation Carried Forward (LOCF) [Baseline, Week 12]

   Ambulatory 24 hour (hr) blood pressure monitoring (ABPM) was performed at baseline, which was during the lead-in period (between Day -7 and Day -1 prior to randomization) and 1 week prior to the Week 12 visit/end of treatment visit. If no Week 12 measurement was available, the last available earlier post-baseline measurement was used (LOCF) for analysis. Initiation of the 24-hr ABPM began between 6am and 11am to ensure trough BP measurements were obtained.The ABPM units were calibrated, and used per the manufacturer's and central ABPM vendor instructions. BP was measured in mmHg. Participants had to have a mean 24-hour ABPM ≥ 130/80 mmHg prior to randomization. All medication was withheld on the morning of the study visit and brought to the visit site by the participant. Once the ABPM cuff was in place, all morning medication was taken while at the site.

2. Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure (DBP) for 12 Week Double-Blind Treatment Period - Randomized Participants [Baseline to Week 12]

   Diastolic BP was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Diastolic BP values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the pressure was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured.

3. Adjusted Mean Change From Baseline in 24-hr Ambulatory Diastolic Blood Pressure at Week 12 (LOCF) [Baseline, Week 12]

   Ambulatory 24 hour (hr) BP monitoring (ABPM) was performed at baseline, which was during the lead-in period (between Day -7 and Day -1 prior to randomization) and 1 week prior to the Week 12 visit/end of treatment visit. If no Week 12 measurement was available, the last available earlier post-baseline measurement was used (LOCF). Initiation of the 24-hr ABPM began between 6am and 11am to ensure trough BP measurements were obtained. The ABPM units were calibrated, and used per the manufacturer's and central ABPM vendor instructions. BP was measured in mmHg. Participants had to have a mean 24-hour ABPM ≥ 130/80 mmHg prior to randomization. All medication was withheld on the morning of the study visit and brought to the visit site by the participant. Once the ABPM cuff was in place, all morning medication was taken while at the site.

4. Adjusted Mean Change From Baseline in Serum Uric Acid at Week 12 in Double-Blind Treatment Period - Randomized Participants [Baseline, Week 12]

   Adjusted mean change in serum uric acid from baseline at Week 12 was calculated. Serum uric acid was measured in 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. Serum uric acid measurements were obtained at qualification and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period but only the change from baseline at Week 12 was considered a secondary endpoint and is presented.

5. Number of Participants With Deaths,Serious Adverse Events (SAEs), Adverse Events (AEs), Hypoglycemia Events, Discontinuation Due to AEs, SAEs and Hypoglycemia, During the 12 Week Double Blind Period, Including Data After Rescue [Baseline to last dose of 12 weeks of double blind medication plus 30 days if SAE or plus 4 days if AE/hypoglycemic event]

   Medical Dictionary for Regulatory Activities (MedDRA), version 15.1 AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Events captured from baseline to last double blind dose plus 4 days for AEs, plus 30 days for SAEs during the Double Blind 12 Week Period. Only hypoglycemia reported as an SAE is included in AE/SAE categories . All reported hypoglycemia events within 4 days of last day of treatment are included as hypoglycemic events.

6. Number of Participants With Marked Chemistry Laboratory Abnormalities in 12 Week Double Blind Treatment Period, Including Data After Rescue [Baseline (Day 1) to last dose double blind medication (Week 12) plus 4 days]

   Samples obtained: Day 1, Weeks 4, 8,12 in Double Blind Period. Baseline: last assessment prior to start of first dose of double-blind treatment. Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); greater than (>) less than (<); Units per liter (U/L), Marked abnormality Low (High): hemoglobin <6 (>18 females or >20 males) g/dL; creatinine (>=1.5*preRX, >=2.5 mg/dL); glucose < 54 or (> 350) mg/dL; albumin <= 2 or (> 6) g/dL; creatine kinase >5*ULN; albumin/creatinine ratio (>1800 mg/G); calcium <7.5 (>1 and >0.5 from PreRX) mg/dL; bicarbonate <=13 meq/dL; potassium <=2.5 (>6) meq/L; magnesium <1 (>4) mEq/L; sodium < 130 mEq/L (>150 mEq/L; phosphorus (>=5.6 mg/dL age 17-65, >=5.1 is >=66 years); Albumin/creatinine ratio (>1800 mg/g). Note: Hepatic tests are presented separately in next outcome measure.

7. Number of Participants With Elevated Liver Laboratory Tests in Participants Treated With Double Blind 10 mg Dapagliflozin or Placebo , Including Data After Rescue [Baseline (Day 1) to last dose double blind medication (Week 12) Plus 30 days]

   Laboratories were obtained at Day 1, Weeks 4, 8 and 12 in the Double Blind Period. Baseline: last assessment prior to start of first dose of double-blind treatment. Includes laboratory values measured after the first date of double-blind treatment and up to and including the last day of double blind treatment plus 30 days. Upper limit of normal (ULN);, alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). Marked abnormality (High): AST and ALT (>3*ULN); ALP (>1.5*ULN); bilirubin (>1.5*ULN). Participants with abnormally elevated liver laboratory tests were followed 30 days after the last dose of study drug.

8. Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 12 (LOCF), Including Data After Rescue [Baseline, Week 12]

   12-Lead electrocardiograms (ECGs) were performed at Enrollment, Day 1 of Double Blind Period and Week 12/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator as normal or abnormal. Baseline (BL) was Day 1 prior to dosing or last observation prior to dosing.

9. Proportion of Participants With Orthostatic Hypotension at Baseline and Week 12, Including Data After Rescue [Baseline (Day 1), Week 12]

   Orthostatic hypotension was defined as a decrease from supine to standing of > 20 mmHg in systolic BP or >10 mmHg in diastolic BP. Proportion was calculated from number of participants with orthostatic hypotension (n) divided by the number of treated participants (N). n/N presented as a percent (%). Baseline was Day 1 of the double blind Period. Measurements for orthostatic hypotension were taken on Day 1 and at Week 12 visit and does not reflect AEs reported by the investigator.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 89 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent

• Males and females, 18 to 89 years old, with type 2 diabetes with inadequate glycemic control HbA1c between 7-10.5% and uncontrolled hypertension Systolic Blood Pressure (SBP) 140-165 and Diastolic Blood Pressure (DBP) 85-105

• Subjects must have a mean 24 hr blood pressure ≥ 130/80 determined by Ambulatory Blood Pressure Monitoring (ABPM) within 1 week prior to Day 1 visit

• Stable dose of oral antidiabetic agent (OAD) for at least 6 weeks [12 wks for Thiazolidinedione (TZD)] or a stable daily dose of insulin, as a monotherapy or in combination with another OAD, for 8 weeks, and a stable dose of ACEI or ARB and 1 additional antihypertensive medication for at least 4 weeks

• C-peptide ≥ 0.8 ng/mL

• Body Mass Index ≤ 45.0 kg/m2

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

Exclusion Criteria:

• Aspartate aminotransferase (AST) and /or Alanine aminotransferase (ALT) > 3.0*upper limit of normal (ULN)

• Serum total bilirubin ≥ 1.5*ULN

• Creatinine kinase > 3*ULN

• Symptoms of severely uncontrolled diabetes

• History of malignant or accelerated hypertension

• 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	University Of Alabama At Birmingham	Birmingham	Alabama	United States	35294
2	Medical Affiliated Research Center, Inc.	Huntsville	Alabama	United States	35801
3	Wilmax Clinical Research, Inc.	Mobile	Alabama	United States	36608
4	43rd Medical Associates	Phoenix	Arizona	United States	85051
5	Central Phoenix Medical Center	Tempe	Arizona	United States	85282
6	Clinical Research Advantage, Inc./Mesa Family Med Ctr, Pc	Tempe	Arizona	United States	85282
7	Clinical Research Advantage/Desert Clinical Research	Tempe	Arizona	United States	85282
8	Visions Clinical Research - Tucson	Tucson	Arizona	United States	85712
9	Eclipse Clinical Research	Tucson	Arizona	United States	85745
10	Aureus Research, Inc.	Little Rock	Arkansas	United States	72211
11	Preferred Research Partners, Inc.	Little Rock	Arkansas	United States	72211
12	Cmp Research	Anaheim	California	United States	92805
13	Catalina Research Institute, Llc	Chino	California	United States	91710
14	Southland Clinical Research Center, Inc.	Fountain Valley	California	United States	92708
15	Marin Endocrine Care & Research, Inc.	Greenbrae	California	United States	94904
16	Del Rosario Medical Clinic, Inc.	Huntington Park	California	United States	90255
17	Time Clinical Research Inc.	Huntington Park	California	United States	90255
18	Clinica Medica San Miguel	Los Angeles	California	United States	90015
19	American Institute Of Research	Los Angeles	California	United States	90017
20	Randall G. Shue, D.O.	Los Angeles	California	United States	90023
21	Mcs Clinical Trials	Los Angeles	California	United States	90057
22	National Research Inst	Los Angeles	California	United States	90057
23	Diabetes Medical Center Of California	Northridge	California	United States	91325
24	Valley Clinical Trials	Northridge	California	United States	91325
25	Lucita M. Cruz,Md.,Inc.	Norwalk	California	United States	90650
26	Sds Clinical Trials	Orange	California	United States	92868
27	Bayview Research Group, Llc	Paramount	California	United States	90723
28	San Diego Managed Care Group	Poway	California	United States	92064
29	Integrated Research Group, Inc.	Riverside	California	United States	92506
30	Quality Control Research, Inc	Sacramento	California	United States	95842
31	Wetlin Research Associates, Inc.	San Diego	California	United States	92120
32	Crest Clinical Trials, Inc.	Santa Ana	California	United States	92701
33	Neurological Research Institute	Santa Monica	California	United States	90404
34	Orrin M. Troum, Md And Medical Associates	Santa Monica	California	United States	90404
35	Torrance Clinical Research	Torrance	California	United States	90505
36	Orange County Research Center	Tustin	California	United States	92780
37	University Clinical Investigators, Inc.	Tustin	California	United States	92780
38	Chase Medical Research, Llc	Waterbury	Connecticut	United States	06708
39	Christiana Care Health Services, Inc	Newark	Delaware	United States	19713
40	Zasa Clinical Research	Boynton Beach	Florida	United States	33472
41	Bradenton Research Center, Inc.	Bradenton	Florida	United States	34205
42	Innovative Research Of West Florida, Inc	Clearwater	Florida	United States	33756
43	Clinical Research Of South Florida	Coral Gables	Florida	United States	33134
44	Avail Clinical Research, Llc	Deland	Florida	United States	32720
45	International Research Associates, Llc	Hialeah	Florida	United States	33012
46	Palm Springs Research Institute	Hialeah	Florida	United States	33012
47	The Community Research Of South Florida	Hialeah	Florida	United States	33016
48	Central Florida Internists	Kissimmee	Florida	United States	34741
49	Newphase Clinical Trials, Inc.	Miami Beach	Florida	United States	33140
50	Ocean Blue Medical Research Center, Inc.	Miami Springs	Florida	United States	33166
51	Flcri Global Research, Llc	Miami	Florida	United States	33125
52	Clinical Research Of Miami, Inc.	Miami	Florida	United States	33126
53	Pharmax Research Clinic, Inc.	Miami	Florida	United States	33126
54	Apf Research, Llc	Miami	Florida	United States	33135
55	Community Research Foundation, Inc.	Miami	Florida	United States	33155
56	Baptist Diabetes Associates, Pa	Miami	Florida	United States	33156
57	Suncoast Clinical Research, Inc.	New Port Richey	Florida	United States	34652
58	Florida Institute For Clinical Research, Llc	Orlando	Florida	United States	32822
59	Michele A. Morrison Internal Medicine, Inc.	Pembroke Pines	Florida	United States	33026
60	Medsol Clinical Research Center	Port Charlotte	Florida	United States	33952
61	Meridien Research	Tampa	Florida	United States	33606
62	Perimeter Institute For Clinical Research	Atlanta	Georgia	United States	30338
63	Bainbridge Medical Associates	Bainbridge	Georgia	United States	39819
64	River Birch Research Alliance, Llc	Blue Ridge	Georgia	United States	30513
65	In-Quest Medical Research, Llc	Duluth	Georgia	United States	30096
66	Middle Georgia Drug Study Center, Llc	Perry	Georgia	United States	31069
67	Cedar Crosse Research Center	Chicago	Illinois	United States	60607
68	So. Illinois Clin Res Ctr @ Div Of Kevin L Pritchett Md, Pc	O?Fallon	Illinois	United States	62269
69	Springfield Diabetes And Endocrine Center	Springfield	Illinois	United States	62704
70	American Health Network Of Indiana Llc	Avon	Indiana	United States	46123
71	Investigators Research Group, Llc	Brownsburg	Indiana	United States	46112
72	American Health Network Of In Llc	Franklin	Indiana	United States	46131
73	Laporte County Institute For Clinical Research, Inc.	Michigan City	Indiana	United States	46360
74	American Health Network Of In Llc	Muncie	Indiana	United States	47304
75	Medical Development Centers, Llc	Baton Rouge	Louisiana	United States	70808
76	Omega Clinical Research, Llc	Metairie	Louisiana	United States	70006
77	Acadia Clinical Research, Llc	Bangor	Maine	United States	04401
78	Alternative Primary Care	Silver Spring	Maryland	United States	20910
79	Hci-Metromedic Walk-In Medical Office	New Bedford	Massachusetts	United States	02740
80	Neurocare, Inc.	Newton	Massachusetts	United States	02459
81	Atlantic Clinical Trials, Llc	Watertown	Massachusetts	United States	02472
82	Providence Park Clinical Research	Novi	Michigan	United States	48374
83	The Center For Clinical Trials	Biloxi	Mississippi	United States	39531
84	Phillips Medical Services, Pllc	Jackson	Mississippi	United States	39209
85	Jefferson City Medical Group	Jefferson City	Missouri	United States	65109
86	Kcumb Dybedal Clinical Research Center	Kansas City	Missouri	United States	64106
87	Clin Research Advantage, Inc. James Meli, Do Family Pracice	Henderson	Nevada	United States	89014
88	Office Of Ted Thorp, Md	Las Vegas	Nevada	United States	89102
89	Independent Clinical Researchers@ Wolfson Medical Center	Las Vegas	Nevada	United States	89103
90	Clinical Research Advantage, Inc.	Las Vegas	Nevada	United States	89128
91	Palm Medical Research Center	Las Vegas	Nevada	United States	89148
92	Comprehensive Clinical Research	Berlin	New Jersey	United States	08009
93	Premier Research	Trenton	New Jersey	United States	08611
94	Medex Healthcare Research, Inc.	New York	New York	United States	10022
95	Digiovanna Institute For Medical Education & Research	North Massapequa	New York	United States	11758
96	Southgate Medical Group	West Seneca	New York	United States	14224
97	Diabetes & Endocrinology Consultants	Morehead City	North Carolina	United States	28557
98	Burke Primary Care	Morganton	North Carolina	United States	28655
99	Lillestol Research	Fargo	North Dakota	United States	58103
100	Community Health Care, Inc.	Canal Fulton	Ohio	United States	44614
101	Community Research	Cincinnati	Ohio	United States	45227
102	Parsons Avenue Medical Clinical	Columbus	Ohio	United States	43207
103	Clinical Research Source, Inc	Perrysburg	Ohio	United States	43551
104	Sooner Clinical Research	Oklahoma City	Oklahoma	United States	73112
105	Integris Family Care Yukon	Yukon	Oklahoma	United States	73099
106	Willamette Valley Clinical Studies	Eugene	Oregon	United States	97404
107	Southeastern Pa Medical Institute	Broomall	Pennsylvania	United States	19008
108	Abington Memorial Hos/Feasterville Family Health Care Center	Feasterville	Pennsylvania	United States	19053
109	The Clinical Trial Center, Llc	Jenkintown	Pennsylvania	United States	19046
110	Arcuri Clinical Research Llc	Philadelphia	Pennsylvania	United States	19142
111	Philadelphia Health Associates - Adult Medicine	Philadelphia	Pennsylvania	United States	19146
112	Research Across America	Reading	Pennsylvania	United States	19606
113	Pish Medical Associates	Uniontown	Pennsylvania	United States	15401
114	Greater Providence Clinical Research, Llc	Warwick	Rhode Island	United States	02888
115	Medical Research South	Charleston	South Carolina	United States	29407
116	Southeastern Research Associates, Inc.	Greenville	South Carolina	United States	29605
117	North Myrtle Beach Family Practice	North Myrtle Beach	South Carolina	United States	29582
118	Pawleys Pediatrics And Adult Medicine	Pawleys Island	South Carolina	United States	29585
119	Hillcrest Clinical Reseach, Llc	Simpsonville	South Carolina	United States	29681
120	Palmetto Clinical Research	Summerville	South Carolina	United States	29485
121	Southwind Medical Specialists	Memphis	Tennessee	United States	38125
122	Tn Medical Research	Spring Hill	Tennessee	United States	37174
123	Arlington Family Research Center, Inc.	Arlington	Texas	United States	76012
124	3rd Coast Research Associates	Corpus Christi	Texas	United States	78414
125	Krk Medical Research	Dallas	Texas	United States	75230
126	Research Institute Of Dallas	Dallas	Texas	United States	75231
127	Internal Medicine Clinical Reaseach	Dallas	Texas	United States	75235
128	Renaissance Clinical Research And Hypertension Pllc	Dallas	Texas	United States	75235
129	Sergio F. Rovner, M.D.	El Paso	Texas	United States	79925
130	Pioneer Research Solutions, Inc.	Houston	Texas	United States	77008
131	Village Family Practice	Houston	Texas	United States	77024
132	Dependable Clinical Research, Llc	Houston	Texas	United States	77074
133	Southwest Clinical Trials	Houston	Texas	United States	77074
134	Bellaire Medical Care Group	Houston	Texas	United States	77081
135	Excel Clinical Research, Llc	Houston	Texas	United States	77081
136	Hill Country Medical Associates	New Braunfels	Texas	United States	78130
137	North Hills Medical Research, Inc.	North Richland Hills	Texas	United States	76180
138	Med-Olam Clinical Research	Pasadena	Texas	United States	77504
139	Lisa E. Medwedeff, Md, Pa	Plano	Texas	United States	75024
140	Sun Research Institute	San Antonio	Texas	United States	78215
141	Abbott Clinical Research Group, Inc.	San Antonio	Texas	United States	78224
142	Covenant Clinical Research, Pa	San Antonio	Texas	United States	78229
143	Innovative Clinical Trials	San Antonio	Texas	United States	78229
144	Breco Research, Ltd	Sugarland	Texas	United States	77479
145	Exodus Healthcare Network	Magna	Utah	United States	84044
146	Wasatch Endocrinology And Diabetes Specialists	Salt Lake City	Utah	United States	84102
147	Wasatch Clinical Research	Salt Lake City	Utah	United States	84107
148	Alexandria Health Care Center	Alexandria	Virginia	United States	22314
149	Millennium Clinical Trials Llc	Arlington	Virginia	United States	22203
150	Burke Internal Medicine And Research	Burke	Virginia	United States	22015
151	Manassas Clinical Research Center	Manassas	Virginia	United States	20110
152	Hampton Roads Center For Clinical Research, Inc.	Suffolk	Virginia	United States	23435
153	Larry D. Stonesifer, Md	Federal Way	Washington	United States	98003
154	Sound Medical Research	Port Orchard	Washington	United States	98366
155	Clinical Investigation Specialists, Inc.	Kenosha	Wisconsin	United States	53142
156	Local Institution	Camperdown	New South Wales	Australia	2050
157	Local Institution	Heidelberg	Victoria	Australia	3081
158	Local Institution	Nedlands	Western Australia	Australia	6009
159	Local Institution	Kelowona	British Columbia	Canada	V1Y 3G8
160	Local Institution	Victoria	British Columbia	Canada	V8V 3N7
161	Local Institution	Monction	New Brunswick	Canada	E1G 1A7
162	Local Institution	Brampton	Ontario	Canada	L6T 3J1
163	Local Institution	Granby	Quebec	Canada	J2G 8Z9
164	Local Institution	Montreal	Quebec	Canada	H2R 1V6
165	Local Institution	Saskatoon	Saskatchewan	Canada	S7K 3H3
166	Local Institution	Armenia	Quindio	Colombia	0000
167	Local Institution	Bucaramanga	Santander	Colombia	0000
168	Local Institution	Barranquilla		Colombia	0000
169	Local Institution	Barranquilla		Colombia
170	Local Institution	Bogota		Colombia	0000
171	Local Institution	Beroun		Czech Republic	266 01
172	Local Institution	Cheb		Czech Republic	350 02
173	Local Institution	Havirov		Czech Republic	736 01
174	Local Institution	Krnov		Czech Republic	794 01
175	Local Institution	Liberec		Czech Republic	460 01
176	Local Institution	Ostrava		Czech Republic	702 00
177	Local Institution	Prague 1		Czech Republic	116 94
178	Local Institution	Praha 4		Czech Republic	149 00
179	Local Institution	Copenhagen		Denmark	DK 2400
180	Local Institution	Frederiksberg		Denmark	2000
181	Local Institution	Gentofte		Denmark	2820
182	Local Institution	Slagelse		Denmark	4200
183	Local Institution	Helsinki		Finland	09200
184	Local Institution	Kerava		Finland	04200
185	Local Institution	Kokkola		Finland	67100
186	Local Institution	Oulu		Finland	90100
187	Local Institution	Aschaffenburg	Bavaria	Germany	63739
188	Local Institution	Augsburg	Bavaria	Germany	86150
189	Local Institution	Duisburg	Nordrhein-Westfalen	Germany	47051
190	Local Institution	Bad Kreuznach		Germany	55545
191	Local Institution	Berlin		Germany	10787
192	Local Institution	Dortmund		Germany	44137
193	Local Institution	Dresden		Germany	01307
194	Local Institution	Karlsruhe		Germany	76199
195	Local Institution	Kothen		Germany	06366
196	Local Institution	Kronshagen		Germany	24119
197	Local Institution	Langenfeld		Germany	40764
198	Local Institution	Lueneburg		Germany	21339
199	Local Institution	Magdeburg		Germany	39112
200	Local Institution	Mainz		Germany	55116
201	Local Institution	Mannheim		Germany	68161
202	Local Institution	Saarbruecken		Germany	66121
203	Local Institution	Wuestensachsen		Germany	36115
204	Local Institution	Gyongyos	Heves	Hungary	3200
205	Local Institution	Budapest		Hungary	1134
206	Local Institution	Budapest		Hungary	H-1171
207	Local Institution	Eger		Hungary	3300
208	Local Institution	Kisvarda		Hungary	4600
209	Local Institution	Miskolc		Hungary	3530
210	Local Institution	Nyiregyhaza		Hungary	4400
211	Local Institution	Satoraljaujhely		Hungary	3980
212	Local Institution	Sopron		Hungary	9400
213	Local Institution	Szeged		Hungary	6720
214	Local Institution	Szekszard		Hungary	H-7100
215	Local Institution	Hyderabad	Andhra Pradesh	India	5000 18
216	Local Institution	Bangalore	Karnataka	India	560 043
217	Local Institution	Bangalore	Karnataka	India	560043
218	Local Institution	Bangalore	Karnataka	India	560092
219	Local Institution	Mangalore	Karnataka	India	575001
220	Local Institution	Belgaum	Karnatka	India	590010
221	Local Institution	Indore	Madhya Pradesh	India	452010
222	Local Institution	Nagpur	Maharashtra	India	440010
223	Local Institution	Nagpur	Maharashtra	India	440012
224	Local Institution	Nagpur	Maharashtra	India	440033
225	Local Institution	Delhi	New Delhi	India	110007
226	Local Institution	Jaipur	Rajasthan	India	202023
227	Local Institution	Chennai	Tamil Nadu	India	600013
228	Local Institution	Coimbatore	Tamil Nadu	India	641 018
229	Local Institution	Madurai	Tamilnadu	India	625020
230	Local Institution	Chennai Tamilnadu		India	6000081
231	Local Institution	Hyderabad		India	500063
232	Local Institution	Nagpur		India	440012
233	Local Institution	Trivandrum		India	695011
234	Local Institution	Dublin 15	Dublin	Ireland
235	Local Institution	Galway		Ireland
236	Local Institution	Torreon	Coahuila	Mexico	27000
237	Local Institution	Mexico City	Distrito Federal	Mexico	03300
238	Local Institution	Mexico City	Distrito Federal	Mexico	07760
239	Local Institution	Guadalajara	Jalisco	Mexico	44100
240	Local Institution	Guadalajara	Jalisco	Mexico	44130
241	Local Institution	Guadalajara	Jalisco	Mexico	44670
242	Local Institution	Cuautla	Morelos	Mexico	62744
243	Local Institution	Monterrey	Nuevo Leon	Mexico	64000
244	Local Institution	Monterrey	Nuevo Leon	Mexico	64460
245	Local Institution	Culiacan	Sinaloa	Mexico	80020
246	Local Institution	Merida	Yucatan	Mexico	97070
247	Local Institution	Chihuahua		Mexico	31217
248	Local Institution	Del. Benito Juarez		Mexico	03100
249	Local Institution	Delegacion Tlalpan		Mexico	14000
250	Local Institution	Distrito Federal		Mexico	07020
251	Local Institution	San Luis Potosi		Mexico	78200
252	Local Institution	Bialystok		Poland	15-404
253	Local Institution	Bialystok		Poland	15-879
254	Local Institution	Chrzanow		Poland	32-500
255	Local Institution	Elblag		Poland	82-300
256	Local Institution	Gdansk		Poland	80-847
257	Local Institution	Gdynia		Poland	81-384
258	Local Institution	Kamieniec Zabkowicki		Poland	57-230
259	Local Institution	Katowice		Poland	40-748
260	Local Institution	Kielce		Poland	25-364
261	Local Institution	Krakow		Poland	30-015
262	Local Institution	Krakow		Poland	31-159
263	Local Institution	Lodz		Poland	90-242
264	Local Institution	Lodz		Poland	92-525
265	Local Institution	Lublin		Poland	20-044
266	Local Institution	Ostroda		Poland	14-100
267	Local Institution	Poznan		Poland	61-251
268	Local Institution	Warsaw		Poland	02-097
269	Local Institution	Warsaw		Poland	02-507
270	Local Institution	Warszawa		Poland	01-192
271	Local Institution	Warszawa		Poland	01-337
272	Local Institution	Warszawa		Poland	01-868
273	Local Institution	Wroclaw		Poland	50-088
274	Local Institution	Wroclaw		Poland	50-349
275	Local Institution	Zabrze		Poland	41-800
276	Local Institution	Fajard		Puerto Rico	00738
277	Local Institution	Ponce		Puerto Rico	00717
278	Local Institution	San Juan		Puerto Rico	00920
279	Local Institution	Oradea	Bihor	Romania	410169
280	Local Institution	Oradea	Jud. Bihor	Romania	410469
281	Local Institution	Timisoara	Jud. Timis	Romania	300125
282	Local Institution	Targu Mures	Mures	Romania	540098
283	Local Institution	Targu Mures	Mures	Romania	540142
284	Local Institution	Ploiesti	Prahova	Romania	100163
285	Local Institution	Ploiesti	Prahova	Romania	100342
286	Local Institution	Timisoara	Timis	Romania	300456
287	Local Institution	Bucuresti		Romania	010507
288	Local Institution	Bucuresti		Romania	010719
289	Local Institution	Bucuresti		Romania	020475
290	Local Institution	Bucuresti		Romania	020725
291	Local Institution	Cluj-Napoca		Romania	400006
292	Local Institution	Satu Mare		Romania	440055
293	Local Institution	Sibiu		Romania	550245
294	Local Institution	Sibiu		Romania	550371
295	Local Institution	Irvine	Ayrshire	United Kingdom	KA11 1JU
296	Local Institution	Ely	Cambridgeshire	United Kingdom	CB7 5JD
297	Local Institution	Birmingham	West Midlands	United Kingdom	B9 5SS
298	Local Institution	Bath	Wiltshire	United Kingdom	BA2 3HT

Sponsors and Collaborators

• AstraZeneca
• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• BMS clinical trial educational resource

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01195662
• Other Study ID Numbers: MB102-077 ST; 2010-019798-13
• First Posted: Sep 6, 2010
• Last Update Posted: Dec 29, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by AstraZeneca: Diabetes Mellitus, Type 2; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Angiotensin Receptor Inhibitors; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Pharmacological Actions
• Additional relevant MeSH terms: Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	Recruitment: 29-Oct-2010 to 04-Oct-2012. Original study had 3 arms but 5 mg dapagliflozin arm was discontinued with Protocol Amendment 8 (implemented 01-Nov-2011) because totality of data in development program showed that once daily 10-mg dapagliflozin provides optimal efficacy with safety and tolerance. Study continued to enroll with 2 arms.
Pre-assignment Detail	2245 enrolled. 1213 completed enrollment;1032 not completed:1 adverse event (AE), 65 withdrew consent (WC), 7 lost to follow up (LTF), 2 administrative (admin), 934 criteria not met, 2 non-compliant, 21 other. Lead-In: 588 randomized; 625 not randomized: 6 AE, 69 WC, 13 LTF, 8 admin, 2 at request, 497 criteria not met, 11 non-compliant, 19 other.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg	Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 5 mg, once a day for up to12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor. This arm was discontinued with Amendment 8 to the protocol (implemented 1 November 2011) and the other 2 arms continued to enroll. This arm is not included in primary and secondary efficacy analysis.
Period Title: Double Blind Treatment Period
STARTED	224	225	133
COMPLETED	202	211	119
NOT COMPLETED	22	14	14
Period Title: Double Blind Treatment Period
STARTED	203	209	120
COMPLETED	200	209	119
NOT COMPLETED	3	0	1

Baseline Characteristics

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg	Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)	Total
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 5 mg, once daily, Up to 12 weeks. This arm discontinued with implementation of Amendment 8 to the protocol (1 November 2011). Study continued to enroll participants in other 2 arms post Amendment 8. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Total of all reporting groups
Overall Participants	224	225	133	582
Age, Customized (participants) [Number]
Less than (<) 65 years	198 88.4%	198 88%	118 88.7%	514 88.3%
Greater than, equal (>=) to 65 and < 75 years	25 11.2%	23 10.2%	14 10.5%	62 10.7%
>= 75 years	1 0.4%	4 1.8%	1 0.8%	6 1%
Gender (Count of Participants)
Female	95 42.4%	107 47.6%	52 39.1%	254 43.6%
Male	129 57.6%	118 52.4%	81 60.9%	328 56.4%
Race/Ethnicity, Customized (participants) [Number]
White	157 70.1%	160 71.1%	84 63.2%	401 68.9%
Black or African American	17 7.6%	19 8.4%	9 6.8%	45 7.7%
Asian	38 17%	34 15.1%	36 27.1%	108 18.6%
Other Race	12 5.4%	12 5.3%	4 3%	28 4.8%
Ethnicity Hispanic/Latino	41 18.3%	47 20.9%	21 15.8%	109 18.7%
Ethnicity Not Hispanic/Latino	40 17.9%	38 16.9%	16 12%	94 16.2%
Ethnicity Not Reported	143 63.8%	140 62.2%	96 72.2%	379 65.1%
Body Mass Index (BMI) (participants) [Number]
< 25 kg/m^2	21 9.4%	17 7.6%	9 6.8%	47 8.1%
>=25 kg/m^2	203 90.6%	208 92.4%	124 93.2%	535 91.9%
>=27 kg/m^2	179 79.9%	178 79.1%	101 75.9%	458 78.7%
>=30 kg/m^2	147 65.6%	141 62.7%	73 54.9%	361 62%
Hypertension Medication (participants) [Number]
Thiazide or thiazide-like diuretics, no insulin	94 42%	95 42.2%	54 40.6%	243 41.8%
Calcium channel and beta blockers, no insulin	114 50.9%	112 49.8%	79 59.4%	305 52.4%
Thiazide or thiazide-like diuretics, insulin	5 2.2%	6 2.7%	0 0%	11 1.9%
Calcium channel and beta blockers, insulin	11 4.9%	12 5.3%	0 0%	23 4%

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure for 12 Week Double-Blind Treatment Period - Randomized Participants
Description	Systolic blood pressure (SBP) was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Blood pressure (BP) values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the BP was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All randomized participants who received double-blind medication and had non-missing Baseline and on-study measurement. Data after rescue excluded from analyses

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	218	221
Week 2 (N=218, 221)	-5.13 (0.9489)	-7.93 (0.9357)
Week 4 (N=213, 220)	-6.05 (1.0232)	-9.69 (1.0097)
Week 8 (N=205, 212)	-6.80 (1.0374)	-11.38 (1.0251)
Week 12 (N=199, 205)	-7.62 (1.0701)	-11.90 (1.0585)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Dapagliflozin, Dapagliflozin 10 mg
	Comments	Longitudinal repeated measures analysis using 'direct likelihood', with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata, as well as continuous fixed covariates of baseline SBP value and baseline SBP value-by-week interaction. Unstructured matrix for within-subject error variance-covariance used. 80% power to detect a difference of 4 mmHg in mean change from baseline, 75% power to meet both co-primary endpoints with overall Type I error.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Endpoint was tested at alpha=0.05. Hierarchical closed testing procedure used.
	Method	Longitudinal repeated measures
	Comments	Data from all weeks during the double-blind treatment period were included.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.28
	Confidence Interval	(2-Sided) 95%; -6.54 to -2.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.1485
	Estimation Comments

2. Primary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) for 12 Week Double-Blind Treatment Period - Randomized Participants
Description	Adjusted mean change in glycosylated hemoglobin ( HbA1c) from baseline at Week 12 was calculated. HbA1c was measured as percent of hemoglobin 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. HbA1c values were obtained at enrollment and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All randomized participants who received double-blind medication and had non-missing Baseline and on-study measurement. Data after rescue included.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	214	219
Week 4 (N=214, 219)	-0.06 (0.0498)	-0.41 (0.0496)
Week 8 (N=207, 211)	-0.07 (0.0606)	-0.58 (0.0602)
Week 12 (N=197, 204)	-0.02 (0.0673)	-0.63 (0.0668)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Dapagliflozin, Dapagliflozin 10 mg
	Comments	A longitudinal repeated measures analysis used, with fixed categorical effects of treatment, week, treatment-by-week interaction, and randomization strata, continuous fixed covariates of baseline HbA1c value and baseline HbA1c value-by-week interaction. Only data up to Week 12 included. All data used in the model even if participants discontinued prior to Week 12. A heirarchical closed testing procedure (sequential) was used and testing performed since first primary endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Longitudinal repeated measures
	Comments	Endpoint was tested at alpha=0.05. Hierarchical closed testing procedure was used.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -0.76 to -0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0773
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change From Baseline in 24-hour Ambulatory Systolic Blood Pressure at Week 12 Last Observation Carried Forward (LOCF)
Description	Ambulatory 24 hour (hr) blood pressure monitoring (ABPM) was performed at baseline, which was during the lead-in period (between Day -7 and Day -1 prior to randomization) and 1 week prior to the Week 12 visit/end of treatment visit. If no Week 12 measurement was available, the last available earlier post-baseline measurement was used (LOCF) for analysis. Initiation of the 24-hr ABPM began between 6am and 11am to ensure trough BP measurements were obtained.The ABPM units were calibrated, and used per the manufacturer's and central ABPM vendor instructions. BP was measured in mmHg. Participants had to have a mean 24-hour ABPM ≥ 130/80 mmHg prior to randomization. All medication was withheld on the morning of the study visit and brought to the visit site by the participant. Once the ABPM cuff was in place, all morning medication was taken while at the site.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

All randomized participants who received double-blind medication and had non-missing Baseline and Week 12 (LOCF) values. Data after rescue excluded from analyses.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	186	187
Mean (Standard Error) [mmHg]	-6.88 (1.5793)	-11.33 (1.6031)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Dapagliflozin, Dapagliflozin 10 mg
	Comments	ANCOVA model with treatment group as an effect and baseline value and randomization strata as a covariate was used. By applying sequential testing procedure, the testing was performed since the prior endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments	Endpoint tested following a sequential testing procedure at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.45
	Confidence Interval	(2-Sided) 95%; -7.14 to -1.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.3680
	Estimation Comments

4. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure (DBP) for 12 Week Double-Blind Treatment Period - Randomized Participants
Description	Diastolic BP was measured in millimeters of mercury (mmHg) on Day -1, Day 1, Weeks 2, 4, 8, and 12 of the Double Blind Period. Diastolic BP values were obtained after the participant was seated for quietly for 10 minutes; a mean of 3 replicate measurements was taken at least 1 minute apart. However, if the 3 consecutive seated BP readings were not within 8 mm Hg of each other, an additional 2 BP readings were obtained (total = 5) and incorporated into the calculated mean. BP was measured in both arms. If the pressure was higher in one arm than the other, then this arm was used; if no difference, the participant's dominant arm was used for all future BP measurements. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. Participants refrained from ingestion of caffeine, alcohol, or nicotine at least 10 hours prior to their visit and having their BP measured.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

All randomized participants who received double-blind medication and had non-missing Baseline and on-study measurement. Data after rescue excluded from analyses

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks.Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	218	221
Week 2 (N=218, 221)	-3.84 (0.5691)	-5.22 (0.5613)
Week 4 (N=213, 220)	-4.28 (0.5894)	-5.57 (0.5818)
Week 8 (N=205, 212)	-4.76 (0.6247)	-6.53 (0.6170)
Week 12 (N=199, 205)	-5.33 (0.6377)	-6.30 (0.6308)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Dapagliflozin, Dapagliflozin 10 mg
	Comments	Longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by week interaction, and randomization strata and continuous fixed covariates of baseline seated diastolic BP value and baseline seated diastolic BP value by week interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1619
	Comments	Endpoint tested following a sequential testing procedure at alpha=0.05.
	Method	Longitudinal repeated measures
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.97
	Confidence Interval	(2-Sided) 95%; -2.32 to 0.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.6900
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Mean Change From Baseline in 24-hr Ambulatory Diastolic Blood Pressure at Week 12 (LOCF)
Description	Ambulatory 24 hour (hr) BP monitoring (ABPM) was performed at baseline, which was during the lead-in period (between Day -7 and Day -1 prior to randomization) and 1 week prior to the Week 12 visit/end of treatment visit. If no Week 12 measurement was available, the last available earlier post-baseline measurement was used (LOCF). Initiation of the 24-hr ABPM began between 6am and 11am to ensure trough BP measurements were obtained. The ABPM units were calibrated, and used per the manufacturer's and central ABPM vendor instructions. BP was measured in mmHg. Participants had to have a mean 24-hour ABPM ≥ 130/80 mmHg prior to randomization. All medication was withheld on the morning of the study visit and brought to the visit site by the participant. Once the ABPM cuff was in place, all morning medication was taken while at the site.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

All randomized participants who received double-blind medication and had non-missing Baseline and on-study measurement (Week 12 LOCF). Data after rescue excluded from analyses.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	186	187
Mean (Standard Error) [mmHg]	-5.57 (1.0042)	-7.56 (1.0183)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Dapagliflozin, Dapagliflozin 10 mg
	Comments	ANCOVA model with treatment group as an effect and baseline value and randomization strata as a covariate. A hierarchical closed testing procedure was implemented to control the family-wise type I error rate related to the co-primary and secondary endpoints at the 2-sided 0.05 level. Statistical testing of this endpoint was not performed since the prior secondary endpoint was not statistically significant.
	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	-1.99
	Confidence Interval	(2-Sided) 95%; -3.68 to -0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8635
	Estimation Comments

6. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Serum Uric Acid at Week 12 in Double-Blind Treatment Period - Randomized Participants
Description	Adjusted mean change in serum uric acid from baseline at Week 12 was calculated. Serum uric acid was measured in 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. Serum uric acid measurements were obtained at qualification and lead-in (Day -28) periods, and at Day 1, Weeks 4, 8, and 12, in the double-blind period but only the change from baseline at Week 12 was considered a secondary endpoint and is presented.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

All randomized participants who received double-blind medication and had non-missing Baseline and on-study measurement. Data after rescue was included.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	210	219
Mean (Standard Error) [mg/dL]	-0.03 (0.0890)	-0.43 (0.0883)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo Matching Dapagliflozin, Dapagliflozin 10 mg
	Comments	Longitudinal repeated measures analysis using direct likelihood with fixed categorical effects of treatment, week, treatment-by week interaction, and randomization strata and continuous fixed covariates of baseline serum uric acid value and baseline seated serum uric acid value by week interaction. By applying sequential testing procedure at alpha=0.05, no testing was performed since the prior secondary endpoint was not significant.
	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	-0.40
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0858
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With Deaths,Serious Adverse Events (SAEs), Adverse Events (AEs), Hypoglycemia Events, Discontinuation Due to AEs, SAEs and Hypoglycemia, During the 12 Week Double Blind Period, Including Data After Rescue
Description	Medical Dictionary for Regulatory Activities (MedDRA), version 15.1 AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Events captured from baseline to last double blind dose plus 4 days for AEs, plus 30 days for SAEs during the Double Blind 12 Week Period. Only hypoglycemia reported as an SAE is included in AE/SAE categories . All reported hypoglycemia events within 4 days of last day of treatment are included as hypoglycemic events.
Time Frame	Baseline to last dose of 12 weeks of double blind medication plus 30 days if SAE or plus 4 days if AE/hypoglycemic event

Outcome Measure Data

Analysis Population Description

Randomized participants who received double-blind study medication in the double-blind period.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg	Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 5 mg, once a day for up to12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor. This arm was discontinued with Amendment 8 to the protocol (implemented 1 November 2011) and the other 2 arms continued to enroll. This arm is not included in primary and secondary efficacy analysis.
Measure Participants	224	225	133
Deaths	0 0%	0 0%	0 0%
SAEs	2 0.9%	6 2.7%	1 0.8%
Related SAEs	1 0.4%	0 0%	0 0%
AEs	93 41.5%	98 43.6%	60 45.1%
Hypoglycemia AEs	6 2.7%	13 5.8%	2 1.5%
Related AEs	12 5.4%	15 6.7%	8 6%
Discontinued due to AE	4 1.8%	1 0.4%	2 1.5%
Discontinued due to SAE	1 0.4%	0 0%	1 0.8%
Discontinued due to Hypoglycemia	0 0%	0 0%	0 0%

8. Secondary Outcome

Title	Number of Participants With Marked Chemistry Laboratory Abnormalities in 12 Week Double Blind Treatment Period, Including Data After Rescue
Description	Samples obtained: Day 1, Weeks 4, 8,12 in Double Blind Period. Baseline: last assessment prior to start of first dose of double-blind treatment. Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); greater than (>) less than (<); Units per liter (U/L), Marked abnormality Low (High): hemoglobin <6 (>18 females or >20 males) g/dL; creatinine (>=1.5*preRX, >=2.5 mg/dL); glucose < 54 or (> 350) mg/dL; albumin <= 2 or (> 6) g/dL; creatine kinase >5*ULN; albumin/creatinine ratio (>1800 mg/G); calcium <7.5 (>1 and >0.5 from PreRX) mg/dL; bicarbonate <=13 meq/dL; potassium <=2.5 (>6) meq/L; magnesium <1 (>4) mEq/L; sodium < 130 mEq/L (>150 mEq/L; phosphorus (>=5.6 mg/dL age 17-65, >=5.1 is >=66 years); Albumin/creatinine ratio (>1800 mg/g). Note: Hepatic tests are presented separately in next outcome measure.
Time Frame	Baseline (Day 1) to last dose double blind medication (Week 12) plus 4 days

Outcome Measure Data

Analysis Population Description

N=All randomized participants who received at least one dose of double-blind medication. n=all treated participants who had non-missing Baseline and on-study measurement. Data after rescue included.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	218	223
Hemoglobin High >18 g/dL (n=218, 223)	1 0.4%	0 0%
Creatinine >=1.5PreRx (n=218,223)	1 0.4%	3 1.3%
Glucose, plasma unspecif <54 mg/dL (n=218,222)	0 0%	1 0.4%
Glucose, plasma unspecif >350 mg/dL (n=218,222)	2 0.9%	1 0.4%
Creatine Kinase >5*ULN (n=218,223)	2 0.9%	0 0%
Creatine Kinase >10*ULN (n=218,223)	1 0.4%	0 0%
Calcium, total <7.5 mg (n=218,223)	0 0%	1 0.4%
Potassium, serum≥6 mEq/L (n=218,222)	0 0%	4 1.8%
Magnesium <1 mEq/L (n=218,223)	0 0%	2 0.9%
Sodium, serum <130 mEq/L (n=218,222)	1 0.4%	0 0%
Sodium, serum >150 mEq/L (n=218,222)	1 0.4%	1 0.4%
Phosphorus inorganic High (n=218,223)	0 0%	2 0.9%
Albumin/Creatinine Ratio High (n=218, 223)	5 2.2%	3 1.3%

9. Secondary Outcome

Title	Number of Participants With Elevated Liver Laboratory Tests in Participants Treated With Double Blind 10 mg Dapagliflozin or Placebo , Including Data After Rescue
Description	Laboratories were obtained at Day 1, Weeks 4, 8 and 12 in the Double Blind Period. Baseline: last assessment prior to start of first dose of double-blind treatment. Includes laboratory values measured after the first date of double-blind treatment and up to and including the last day of double blind treatment plus 30 days. Upper limit of normal (ULN);, alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). Marked abnormality (High): AST and ALT (>3*ULN); ALP (>1.5*ULN); bilirubin (>1.5*ULN). Participants with abnormally elevated liver laboratory tests were followed 30 days after the last dose of study drug.
Time Frame	Baseline (Day 1) to last dose double blind medication (Week 12) Plus 30 days

Outcome Measure Data

Analysis Population Description

N=All randomized participants who received at least 1 dose of study medication. n=number of participants treated with double blind study medication with at least one non-missing post-baseline value. Data after rescue included.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	221	224
AST >3*ULN (n=221, 224)	0 0%	3 1.3%
AST >5*ULN (n=221, 224)	0 0%	1 0.4%
AST >10*ULN (n=221, 224)	0 0%	1 0.4%
AST >20*ULN (n=221, 224)	0 0%	1 0.4%
ALT >3*ULN (n=221, 224)	0 0%	3 1.3%
ALT >5*ULN (n=221, 224)	0 0%	2 0.9%
ALT >10*ULN (n=221, 224)	0 0%	1 0.4%
ALT >20*ULN (n=221, 224)	0 0%	1 0.4%
Total Bilirubin >1.5*ULN (n=221, 224)	0 0%	2 0.9%
Total Bilirubin >2*ULN (n=221, 224)	0 0%	1 0.4%
ALP >1.5*ULN (n=221, 224)	5 2.2%	4 1.8%

10. Secondary Outcome

Title	Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 12 (LOCF), Including Data After Rescue
Description	12-Lead electrocardiograms (ECGs) were performed at Enrollment, Day 1 of Double Blind Period and Week 12/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator as normal or abnormal. Baseline (BL) was Day 1 prior to dosing or last observation prior to dosing.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

N= All randomized participants who received double-blind medication. Data after rescue included.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	224	225
Baseline normal/Week 12 normal	137 61.2%	130 57.8%
Baseline normal/Week 12 abnormal	9 4%	10 4.4%
Baseline normal/ Week 12 not reported	0 0%	0 0%
Baseline abnormal/Week 12 normal	10 4.5%	22 9.8%
Baselline abnormal/Week 12 abnormal	48 21.4%	50 22.2%
Baseline abnormal/Week 12 not reported	0 0%	0 0%
Baseline not reported/Week 12 normal	0 0%	0 0%
Baseline not reported/Week 12 abnormal	0 0%	0 0%
Baseline not reported/Week 12 not reported	20 8.9%	13 5.8%

11. Secondary Outcome

Title	Proportion of Participants With Orthostatic Hypotension at Baseline and Week 12, Including Data After Rescue
Description	Orthostatic hypotension was defined as a decrease from supine to standing of > 20 mmHg in systolic BP or >10 mmHg in diastolic BP. Proportion was calculated from number of participants with orthostatic hypotension (n) divided by the number of treated participants (N). n/N presented as a percent (%). Baseline was Day 1 of the double blind Period. Measurements for orthostatic hypotension were taken on Day 1 and at Week 12 visit and does not reflect AEs reported by the investigator.
Time Frame	Baseline (Day 1), Week 12

Outcome Measure Data

Analysis Population Description

N= All randomized participants who received double-blind medication and had non-missing Week (t) values. Week 12 includes participants with orthostatic hypotension during Week 12 visit window. Data after rescue included.

Arm/Group Title	Placebo Matching Dapagliflozin	Dapagliflozin 10 mg
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.	Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.
Measure Participants	220	222
Baseline n/N (2/220, 2/222)	0.9 0.4%	0.9 0.4%
Week 12 n/N (4/199, 7/203)	2.0 0.9%	3.4 1.5%

Adverse Events

Time Frame	12 Weeks plus 30 days
Adverse Event Reporting Description	Baseline to last dose of 12 weeks of double blind medication plus 30 days if SAE or plus 4 days if AE/hypoglycemic event
Arm/Group Title	Placebo Matching Dapagliflozin		Dapagliflozin 10 mg		Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
Arm/Group Description	Placebo matching dapagliflozin: Tablets, Oral, 0 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.		Dapagliflozin: Tablets, Oral, 10 mg, once daily, Up to 12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor.		Dapagliflozin: Tablets, Oral, 5 mg, once a day for up to12 weeks. Non-investigational medications used in this study were antidiabetic drug(s), including oral antidiabetic drugs and insulin, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and an additional antihypertensive drug. All non-investigational medications were commercially available and were not supplied by the Sponsor. This arm was discontinued with Amendment 8 to the protocol (implemented 1 November 2011) and the other 2 arms continued to enroll. This arm is not included in primary and secondary efficacy analysis.
All Cause Mortality
	Placebo Matching Dapagliflozin		Dapagliflozin 10 mg		Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo Matching Dapagliflozin		Dapagliflozin 10 mg		Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/224 (0.9%)		6/225 (2.7%)		1/133 (0.8%)
Cardiac disorders
Angina pectoris	1/224 (0.4%)		0/225 (0%)		0/133 (0%)
Gastrointestinal disorders
Diverticular perforation	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Infections and infestations
Hepatitis E	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Osteomyelitis	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Bronchitis	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Injury, poisoning and procedural complications
Avulsion fracture	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Lumbar vertebral fracture	0/224 (0%)		0/225 (0%)		1/133 (0.8%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Dyspnoea exertional	0/224 (0%)		1/225 (0.4%)		0/133 (0%)
Skin and subcutaneous tissue disorders
Angioedema	1/224 (0.4%)		0/225 (0%)		0/133 (0%)
Other (Not Including Serious) Adverse Events
	Placebo Matching Dapagliflozin		Dapagliflozin 10 mg		Dagagliflozin 5 mg (Arm Discontinued With Amendment 8)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/224 (0%)		0/225 (0%)		0/133 (0%)

Limitations/Caveats

Totality of data from dapagliflozin development program as of 1 NOV 2011 showed 10 mg dapagliflozin dose provided optimal efficacy, was safe and well tolerated for the general Type 2 diabetes population, allowing the 5 mg arm to be discontinued.

More Information

Certain Agreements

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

Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.