A Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes and Inadequately Controlled Hypertension on an Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01137474
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 2,996
• Locations: 329
• Arms: 4
• Duration (Months): 31.1
• Patients Per Site: 9.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to learn whether 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 or an angiotensin receptor blocker. 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: 2996 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 Inhibitor (ACEI) or Angiotensin Receptor Blocker (ARB)
• Study Start Date: Jul 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 Oral tablets administered as 10 mg once daily for up to 12 weeks	Drug: Dapagliflozin; Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks; Other Names: BMS-512148
Placebo Comparator: Placebo-matching dapagliflozin Oral tablets administered once daily in the morning	Drug: Placebo-matching dapagliflozin; Oral tablets administered as 0 mg once daily for up to 12 weeks
Experimental: Dapagliflozin, 2. 5 mg Oral tablets administered as 2.5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)	Drug: Dapagliflozin; Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks; Other Names: BMS-512148
Experimental: Dapagliflozin, 5 mg Oral tablets administered as 5 mg once daily for up to 12 weeks (Arm discontinued as of Protocol Amendment 8)	Drug: Dapagliflozin; Oral tablets administered as 2.5, 5, or 10 mg, once daily for up to 12 weeks; Other Names: BMS-512148

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12 [From Baseline to Week 12]

   Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained 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 to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.

2. Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12 [From Baseline to Week 12]

   HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.

Secondary Outcome Measures

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

   Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24-hrs each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hr ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.

2. Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12 [From Baseline to Week 12]

   All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.

3. Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF]) [From Baseline to Week 12]

   Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24 hours each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hour ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.

4. Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12 [From Baseline to Week 12]

   Central laboratory serum uric acid levels will be determined at the Enrollment, Day -28, Day 1, and at Week 4, 8, 12, and 13 visits. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.

Eligibility Criteria

Criteria

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

Key inclusion criteria

• Participants willing and able to give signed and written informed consent

• Males and females, aged 18 to 89 years, who have type 2 diabetes with inadequate glycemic control (hemoglobin A1c between 7% and 10.5%) and uncontrolled hypertension (seated systolic blood pressure of 140 to 165 mm Hg and seated diastolic blood pressure 85 to 105 mm Hg)

• Mean 24-hour BP>=130/80 mmHg determined by ABPM

• Stable dose of oral antidiabetic agent (OAD) for at least 6 weeks (12 weeks for thiazolidinedione) or a stable daily dose of insulin as monotherapy or in combination with another OAD, for 8 weeks, and a stable dose of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for at least 4 weeks

• C-peptide level ≥0.8 ng/mL

• Body mass index ≤ 45.0 kg/m^2

Key exclusion criteria

• Aspartate aminotransferase or alanine aminotransferase level >3*upper limit of normal (ULN)

• Serum total bilirubin level >1.5*ULN

• Serum creatinine ≥2.0 mg/dL unless subject was on metformin, where exclusionary limits were serum creatinine ≥1.50 mg/dL for men and ≥1.40 mg/dL for women

• Estimated creatinine clearance of <60 mL/min

• Hemoglobin ≤10.0 g/dL for men and ≤9.0 g/dL for women

• Creatine kinase >3*ULN

• Positive for hepatitis B surface antigen

• Positive for antihepatitis C virus antibody

• Abnormal free T4 value

• History of diabetes insipidus

• Symptoms of poorly controlled diabetes that would preclude participation in this trial, including but not limited to, marked polyuria and polydipsia with greater than 10% weight loss during the 3 months prior to enrollment.

• History of diabetic ketoacidosis or hyperosmolar nonketotic coma

• History of malignant and accelerated hypertension

• Known or suspected secondary hypertension

• Any of the following within 6 months of enrollment visit:

• Myocardial infarction

• Cardiac surgery or revascularization (coronary artery bypass surgery /percutaneous transluminal coronary angioplasty)

• Unstable angina

• Unstable congestive heart disease or New York Heart Association Class III or IV

• Transient ischemic attack or significant cerebrovascular disease

• Unstable or previously undiagnosed arrhythmia

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Of Alabama At Birmingham	Birmingham	Alabama	United States	35294
2	Horizon Research Group, Inc.	Mobile	Alabama	United States	36608
3	Iicr, Inc. (International Institute Of Clinical Research)	Ozark	Alabama	United States	36360
4	Hope Research Institute	Phoenix	Arizona	United States	85050
5	43rd Medical Associates	Phoenix	Arizona	United States	85051
6	Central Phoenix Medical Clinic, Llc	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	Orange County Research Institute	Anaheim	California	United States	92801
13	Cmp Research	Anaheim	California	United States	92805
14	Med Center	Carmichael	California	United States	95608
15	Catalina Research Institute, Llc	Chino	California	United States	91710
16	Southland Clinical Research Center, Inc.	Fountain Valley	California	United States	92708
17	Marin Endocrine Care & Research, Inc.	Greenbrae	California	United States	94904
18	Del Rosario Medical Clinic, Inc.	Huntington Park	California	United States	90255
19	Time Clinical Research Inc.	Huntington Park	California	United States	90255
20	Marina Raikhel, M.D., F.A.A.F.P	Lomita	California	United States	90717
21	Clinica Medica San Miguel	Los Angeles	California	United States	90015
22	American Institute Of Research	Los Angeles	California	United States	90017
23	Randall G. Shue, D.O.	Los Angeles	California	United States	90023
24	National Research Inst	Los Angeles	California	United States	90057
25	Quest Diagnostics West Hills	Los Angeles	California	United States	90057
26	Diabetes Medical Center Of California	Northridge	California	United States	91325
27	Valley Clinical Trials	Northridge	California	United States	91325
28	Lucita M. Cruz,Md.,Inc.	Norwalk	California	United States	90650
29	Sds Clinical Trials	Orange	California	United States	92868
30	Integrated Research Group, Inc.	Riverside	California	United States	92506
31	Quality Control Research, Inc	Sacramento	California	United States	95842
32	Crest Clinical Trials, Inc.	Santa Ana	California	United States	92701
33	Orrin M. Troum, Md And Medical Associates	Santa Monica	California	United States	90404
34	Orange County Research Center	Tustin	California	United States	92780
35	University Clinical Investigators, Inc.	Tustin	California	United States	92780
36	Infosphere Clinical Research, Inc.	West Hills	California	United States	91307
37	Aurora Family Medicine, P.C.	Aurora	Colorado	United States	80012
38	Horizons Clinical Research Center, Llc	Denver	Colorado	United States	80220
39	Chase Medical Research, Llc	Waterbury	Connecticut	United States	06708
40	Zasa Clinical Research	Boynton Beach	Florida	United States	33472
41	Bradenton Research Center, Inc.	Bradenton	Florida	United States	34205
42	Meridien Research	Brooksville	Florida	United States	34601
43	Family Care Associates Of Nw Fl	Chipley	Florida	United States	32428
44	Innovative Research Of West Florida, Inc	Clearwater	Florida	United States	33756
45	Clinical Research Of South Florida	Coral Gables	Florida	United States	33134
46	Avail Clinical Research, Llc	Deland	Florida	United States	32720
47	In Vivo Clinical Research	Doral	Florida	United States	33166
48	Palm Springs Research Institute	Hialeah	Florida	United States	33012
49	The Community Research Of South Florida	Hialeah	Florida	United States	33016
50	Newphase Clinical Trials, Inc.	Miami Beach	Florida	United States	33140
51	Ocean Blue Medical Research Center, Inc.	Miami Springs	Florida	United States	33166
52	San Marcus Research Clinic, Inc.	Miami	Florida	United States	33015
53	Flcri Global Research, Llc	Miami	Florida	United States	33125
54	International Research Associates, Llc	Miami	Florida	United States	33125
55	Clinical Research Of Miami, Inc.	Miami	Florida	United States	33126
56	Apf Research, Llc	Miami	Florida	United States	33135
57	Community Research Foundation, Inc.	Miami	Florida	United States	33155
58	Medical Research Marseilles	Miami	Florida	United States	33155
59	Baptist Diabetes Associates, Pa	Miami	Florida	United States	33156
60	Suncoast Clinical Research, Inc.	New Port Richey	Florida	United States	34652
61	Compass Research, Llc	Orlando	Florida	United States	32806
62	Florida Institute For Clinical Research, Llc	Orlando	Florida	United States	32822
63	South Miami Clinical Research, Llc	South Miami	Florida	United States	33143
64	Meridien Research	St Petersburg	Florida	United States	33709
65	Meridien Research	Tampa	Florida	United States	33606
66	Perimeter Institute For Clinical Research	Atlanta	Georgia	United States	30338
67	Bainbridge Medical Associates	Bainbridge	Georgia	United States	39819
68	River Birch Research Alliance, Llc	Blue Ridge	Georgia	United States	30513
69	In-Quest Medical Research, Llc	Duluth	Georgia	United States	30096
70	Middle Georgia Clinical Research Center, Llc	Perry	Georgia	United States	31069
71	Endocrine Research Solutions, Inc.	Roswell	Georgia	United States	30076
72	Cedar Crosse Research Center	Chicago	Illinois	United States	60607
73	James R. Herron, Md, Ltd	Chicago	Illinois	United States	60610
74	So. Illinois Clin Res Ctr @ Div Of Kevin L Pritchett Md, Pc	O?Fallon	Illinois	United States	62269
75	Springfield Diabetes And Endocrine Center	Springfield	Illinois	United States	62704
76	American Health Network Of Indiana Llc	Avon	Indiana	United States	46123
77	Investigators Research Group, Llc	Brownsburg	Indiana	United States	46112
78	American Health Network Of In Llc	Franklin	Indiana	United States	46131
79	Laporte County Institute For Clinical Research, Inc.	Michigan City	Indiana	United States	46360
80	American Health Network Of In Llc	Muncie	Indiana	United States	47304
81	Medical Development Centers, Llc	Baton Rouge	Louisiana	United States	70808
82	Crescent City Clinical Research Center	Metairie	Louisiana	United States	70006
83	Acadia Clinical Research, Llc	Bangor	Maine	United States	04401
84	Alternative Primary Care	Silver Spring	Maryland	United States	20910
85	Neurocare, Inc.	Brookline	Massachusetts	United States	02446
86	Genesis Clinical Research, Llc	Fall River	Massachusetts	United States	02720
87	Hci-Metromedic Walk-In Medical Office	New Bedford	Massachusetts	United States	02740
88	Atlantic Clinical Trials, Llc	Watertown	Massachusetts	United States	02472
89	Providence Park Clinical Research	Novi	Michigan	United States	48374
90	The Center For Clinical Trials	Biloxi	Mississippi	United States	39531
91	Phillips Medical Services, Pllc	Jackson	Mississippi	United States	39209
92	Jackson Clinic	Rolling Fork	Mississippi	United States	39159
93	Jefferson City Medical Group	Jefferson City	Missouri	United States	65109
94	St. Louis Center For Clinical Research	St. Louis	Missouri	United States	63128
95	Kcumb Dybedal Clinical Research Center	Kansas City	Montana	United States	64106
96	Clin Research Advantage, Inc. James Meli, Do Family Pracice	Henderson	Nevada	United States	89014
97	Office Of Ted Thorp, Md	Las Vegas	Nevada	United States	89102
98	Independent Clinical Researchers@ Wolfson Medical Center	Las Vegas	Nevada	United States	89103
99	Clinical Research Advantage, Inc.	Las Vegas	Nevada	United States	89128
100	Palm Medical Research Center	Las Vegas	Nevada	United States	89148
101	Joslin Diabetes Center Affiliate Of Snhmc	Nashua	New Hampshire	United States	03063
102	Central Jersey Medical Research Center	Elizabeth	New Jersey	United States	07202
103	Premier Research	Trenton	New Jersey	United States	08611
104	Medex Healthcare Research, Inc.	New York	New York	United States	10022
105	Digiovanna Institute For Medical Education & Research	North Massapequa	New York	United States	11758
106	Southgate Medical Group	West Seneca	New York	United States	14224
107	Barat Research Group, Inc.	Charlotte	North Carolina	United States	28262
108	Pharmquest	Greensboro	North Carolina	United States	27408
109	Burke Primary Care	Morganton	North Carolina	United States	28655
110	Pmg Research Of Wilmington Llc	Wilmington	North Carolina	United States	28401
111	Lillestol Research	Fargo	North Dakota	United States	58103
112	Community Health Care, Inc.	Canal Fulton	Ohio	United States	44614
113	Community Research	Cincinnati	Ohio	United States	45227
114	Cleveland Sleep Research Center	Middleburg Heights	Ohio	United States	44130
115	Clinical Research Source, Inc	Perrysburg	Ohio	United States	43551
116	Integris Family Care Central	Oklahoma City	Oklahoma	United States	73112
117	Sooner Clinical Research	Oklahoma City	Oklahoma	United States	73112
118	Integris Family Care Yukon	Yukon	Oklahoma	United States	73099
119	Willamette Valley Clinical Studies	Eugene	Oregon	United States	97404
120	Fanno Creek Clinic	Portland	Oregon	United States	97219
121	Southeastern Pa Medical Institute	Broomall	Pennsylvania	United States	19008
122	Abington Memorial Hos/Feasterville Family Health Care Center	Feasterville Trevose	Pennsylvania	United States	19053
123	The Clinical Trial Center, Llc	Jenkintown	Pennsylvania	United States	19046
124	Arcuri Clinical Research Llc	Philadelphia	Pennsylvania	United States	19142
125	Philadelphia Health Associates - Adult Medicine	Philadelphia	Pennsylvania	United States	19146
126	Banksville Medical Pc	Pittsburgh	Pennsylvania	United States	15216
127	Research Across America	Reading	Pennsylvania	United States	19606
128	Pish Medical Associates	Uniontown	Pennsylvania	United States	15401
129	Greater Providence Clinical Research, Llc	Warwick	Rhode Island	United States	02888
130	Southeastern Research Associates, Inc.	Anderson	South Carolina	United States	29621
131	Southeastern Research Associates, Inc.	Greenville	South Carolina	United States	29605
132	Hillcrest Clinical Reseach, Llc	Simpsonville	South Carolina	United States	29681
133	Palmetto Clinical Research	Summerville	South Carolina	United States	29485
134	Chattanooga Research & Medicine, Pllc	Chattanooga	Tennessee	United States	37404
135	Complete Family Care Of Knoxville, Pllc	Knoxville	Tennessee	United States	37923
136	Premier Internal Medicine	Memphis	Tennessee	United States	38119
137	Arlington Family Research Center, Inc.	Arlington	Texas	United States	76012
138	Krk Medical Research	Dallas	Texas	United States	75230
139	Research Institute Of Dallas	Dallas	Texas	United States	75231
140	Internal Medicine Clinical Research	Dallas	Texas	United States	75235
141	Renaissance Clinical Research And Hypertension Pllc	Dallas	Texas	United States	75235
142	Sergio F. Rovner, M.D.	El Paso	Texas	United States	79925
143	Mercury Clinical Research	Houston	Texas	United States	77036
144	Southwest Clinical Trials	Houston	Texas	United States	77074
145	Excel Clinical Research, Llc	Houston	Texas	United States	77081
146	Lone Star Clinical Research	Houston	Texas	United States	77088
147	Hill Country Medical Associates	New Braunfels	Texas	United States	78130
148	North Hills Medical Research, Inc.	North Richland Hills	Texas	United States	76180
149	Med-Olam Clinical Research	Pasadena	Texas	United States	77504
150	Lisa E. Medwedeff, Md, Pa	Plano	Texas	United States	75024
151	Sun Research Institute	San Antonio	Texas	United States	78215
152	Abbott Clinical Research Group, Inc.	San Antonio	Texas	United States	78224
153	Covenant Clinical Research, Pa	San Antonio	Texas	United States	78229
154	Breco Research, Ltd	Sugarland	Texas	United States	77479
155	Pioneer Research Solutions, Inc.	Sugarland	Texas	United States	77479
156	Exodus Healthcare Network	Magna	Utah	United States	84044
157	Wasatch Endocrinology And Diabetes Specialists	Salt Lake City	Utah	United States	84102
158	Wasatch Clinical Research	Salt Lake City	Utah	United States	84107
159	Millennium Clinical Trials Llc	Arlington	Virginia	United States	22203
160	Burke Internal Medicine And Research	Burke	Virginia	United States	22015
161	Manassas Clinical Research Center	Manassas	Virginia	United States	20110
162	Hampton Roads Center For Clinical Research, Inc.	Suffolk	Virginia	United States	23435
163	Tidewater Integrated Medical Research	Virginia Beach	Virginia	United States	23454
164	Sound Medical Research	Port Orchard	Washington	United States	98366
165	Local Institution	Kelowona	British Columbia	Canada	V1Y 3G8
166	Local Institution	Victoria	British Columbia	Canada	V8V 3N7
167	Local Institution	Brampton	Ontario	Canada	L6T 0G1
168	Local Institution	Granby	Quebec	Canada	J2G 8Z9
169	Local Institution	Montreal	Quebec	Canada	H2R 1V6
170	Local Institution	Saskatoon	Saskatchewan	Canada	S7K 3H3
171	Local Institution	Medellin	Antioquia	Colombia	0000
172	Local Institution	Bogota	Cundinamarca	Colombia	0000
173	Local Institution	Armenia	Quindio	Colombia	0000
174	Local Institution	Cali	Valle	Colombia	0000
175	Local Institution	Barranquilla		Colombia	0000
176	Local Institution	Barranquilla		Colombia
177	Local Institution	Bogota		Colombia	0000
178	Local Institution	Beroun		Czech Republic	266 01
179	Local Institution	Cheb		Czech Republic	350 02
180	Local Institution	Havirov		Czech Republic	736 01
181	Local Institution	Liberec		Czech Republic	460 01
182	Local Institution	Ostrava		Czech Republic	702 00
183	Local Institution	Prague 1		Czech Republic	116 94
184	Local Institution	Praha 4		Czech Republic	149 00
185	Local Institution	Copenhagen		Denmark	2300
186	Local Institution	Copenhagen		Denmark	2400
187	Local Institution	Frederiksberg		Denmark	DK-2000
188	Local Institution	Slagelse		Denmark	4200
189	Local Institution	Kokkola		Finland	67100
190	Local Institution	Oulu		Finland	90100
191	Local Institution	Aschaffenburg	Bavaria	Germany	63739
192	Local Institution	Vellmar	Hessen	Germany	34246
193	Local Institution	Duisburg	Nordrhein-Westfalen	Germany	47051
194	Local Institution	Bad Kreuznach		Germany	55545
195	Local Institution	Berlin		Germany	10787
196	Local Institution	Karlsruhe		Germany	76199
197	Local Institution	Kothen		Germany	06366
198	Local Institution	Kronshagen		Germany	24119
199	Local Institution	Langenfeld		Germany	40764
200	Local Institution	Lueneburg		Germany	21339
201	Local Institution	Magdeburg		Germany	39112
202	Local Institution	Mainz		Germany	55116
203	Local Institution	Mannheim		Germany	68161
204	Local Institution	Pirna		Germany	01796
205	Local Institution	Saarbruecken		Germany	66121
206	Local Institution	Gyongyos	Heves	Hungary	3200
207	Local Institution	Eger		Hungary	3300
208	Local Institution	Hatvan		Hungary	3000
209	Local Institution	Miskolc		Hungary	3530
210	Local Institution	Nagykanizsa		Hungary	8800
211	Local Institution	Nyiregyhaza		Hungary	4400
212	Local Institution	Satoraljaujhely		Hungary	3980
213	Local Institution	Sopron		Hungary	9400
214	Local Institution	Szeged		Hungary	6720
215	Local Institution	Szekszard		Hungary	H-7100
216	Local Institution	Szentes		Hungary	6600
217	Local Institution	Hyderabad	Andhra Pradesh	India	500 034
218	Local Institution	Vijayawada	Andhra Pradesh	India	520008
219	Local Institution	New Delhi	Delhi	India	110070
220	Local Institution	Bangalore	Karnataka	India	560 043
221	Local Institution	Bangalore	Karnataka	India	560043
222	Local Institution	Belgaum	Karnatka	India	590010
223	Local Institution	Indore	Madhya Pradesh	India	452010
224	Local Institution	Nagpur	Maharashtra	India	440010
225	Local Institution	Nagpur	Maharashtra	India	440012
226	Local Institution	Nagpur	Maharashtra	India	440033
227	Local Institution	Delhi	New Delhi	India	110007
228	Local Institution	Jaipur	Rajasthan	India	202023
229	Local Institution	Jaipur	Rajasthan	India	302 001
230	Local Institution	Jaipur	Rajasthan	India	302004
231	Local Institution	Coimbatore	Tamil Nadu	India	641018
232	Local Institution	Madurai	Tamilnadu	India	625020
233	Local Institution	Bangalore		India	560092
234	Local Institution	Hyderabad		India	500063
235	Local Institution	Manipal		India	576104
236	Local Institution	Nagpur		India	440012
237	Local Institution	Torreon	Coahuila	Mexico	27000
238	Local Institution	Del. Benito Juarez	Distrito Federal	Mexico	03100
239	Local Institution	Mexico City	Distrito Federal	Mexico	07760
240	Local Institution	Mexico, Df	Distrito Federal	Mexico	06700
241	Local Institution	Tlalpan	Distrito Federal	Mexico	14000
242	Local Institution	Guadalajara	Jalisco	Mexico	44100
243	Local Institution	Guadalajara	Jalisco	Mexico	44600
244	Local Institution	Guadalajara	Jalisco	Mexico	44670
245	Local Institution	Cuautla	Morelos	Mexico	62744
246	Local Institution	Monterrey	Nuevo Leon	Mexico	64460
247	Local Institution	Culiacan	Sinaloa	Mexico	80020
248	Local Institution	Merida	Yucatan	Mexico	97070
249	Local Institution	Chihuahua		Mexico	31217
250	Local Institution	Durango		Mexico	34000
251	Local Institution	Guadalajara		Mexico	44680
252	Local Institution	Puebla		Mexico	72000
253	Local Institution	Queretaro		Mexico	76000
254	Local Institution	Veracruz		Mexico	91910
255	Local Institution	Chiclayo	Lambayeque	Peru
256	Local Institution	Lince	Lima	Peru	LIMA14
257	Local Institution	Arequipa		Peru	54
258	Local Institution	Arequipa		Peru
259	Local Institution	Cusco		Peru
260	Local Institution	Ica		Peru	ICA01
261	Local Institution	Lima		Peru	17
262	Local Institution	Lima		Peru	LIMA 10
263	Local Institution	Lima		Peru	LIMA 11
264	Local Institution	Lima		Peru	LIMA 31
265	Local Institution	Lima		Peru	LIMA 33
266	Local Institution	Piura		Peru
267	Local Institution	Bialystok		Poland	15-404
268	Local Institution	Bydgoszcz		Poland	85-822
269	Local Institution	Chrzanow		Poland	32-500
270	Local Institution	Gdansk		Poland	80-847
271	Local Institution	Gdynia		Poland	80-384
272	Local Institution	Golub-Dobrzyn		Poland	87-400
273	Local Institution	Kamieniec Zabkowicki		Poland	57-230
274	Local Institution	Katowice		Poland	40-748
275	Local Institution	Krakow		Poland	30-015
276	Local Institution	Krakow		Poland	31-159
277	Local Institution	Krakow		Poland	31-949
278	Local Institution	Lodz		Poland	90-242
279	Local Institution	Lodz		Poland	91-078
280	Local Institution	Lodz		Poland	92-003
281	Local Institution	Ostroda		Poland	14-100
282	Local Institution	Poznan		Poland	61-251
283	Local Institution	Szczecin		Poland	70-506
284	Local Institution	Warsaw		Poland	01-231
285	Local Institution	Warsaw		Poland	02-097
286	Local Institution	Warszawa		Poland	01-868
287	Local Institution	Warszawa		Poland	02-507
288	Local Institution	Warszawa		Poland	02-679
289	Local Institution	Warszawa		Poland	03-580
290	Local Institution	Wroc#Aw		Poland	50-088
291	Local Institution	WrocB Aw		Poland	50-349
292	Local Institution	Zamosc		Poland	22-400
293	Local Institution	Cidra		Puerto Rico	00739
294	Local Institution	Ponce		Puerto Rico	00716
295	Local Institution	Ponce		Puerto Rico	00717
296	Local Institution	San Juan		Puerto Rico	00918
297	Local Institution	Oradea	Bihor	Romania	410169
298	Local Institution	Oradea	Jud. Bihor	Romania	410469
299	Local Institution	Timisoara	Jud. Timis	Romania	300125
300	Local Institution	Targu Mures	Mures	Romania	540098
301	Local Institution	Targu Mures	Mures	Romania	540142
302	Local Institution	Ploiesti	Prahova	Romania	100163
303	Local Institution	Ploiesti	Prahova	Romania	100342
304	Local Institution	Timisoara	Timis	Romania	300456
305	Local Institution	Bucuresti		Romania	010496
306	Local Institution	Bucuresti		Romania	011478
307	Local Institution	Bucuresti		Romania	020359
308	Local Institution	Bucuresti		Romania	020475
309	Local Institution	Satu Mare		Romania	440055
310	Local Institution	Sibiu		Romania	550245
311	Local Institution	Sibiu		Romania	550371
312	Local Institution	Dzerzhinskiy		Russian Federation	140091
313	Local Institution	Krasnoyarsk		Russian Federation	660022
314	Local Institution	Moscow		Russian Federation	115093
315	Local Institution	Moscow		Russian Federation	119992
316	Local Institution	Moscow		Russian Federation	125367
317	Local Institution	Novosibirsk		Russian Federation	630076
318	Local Institution	Saint Petersburg		Russian Federation	197022
319	Local Institution	Saratov		Russian Federation	410028
320	Local Institution	Smolensk		Russian Federation	214018
321	Local Institution	St. Petersburg		Russian Federation	191119
322	Local Institution	St.Petersburg		Russian Federation	195112
323	Local Institution	Yaroslavl		Russian Federation	150003
324	Local Institution	Yaroslavl		Russian Federation	150062
325	Local Institution	Yaroslav		Russian Federation	150062
326	Local Institution	Santiago De Compostela	A Coruna	Spain	15706
327	Local Institution	Barcelona		Spain	08036
328	Local Institution	La Roca Del Valles		Spain	08430
329	Local Institution	Peralada		Spain	17491

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:

• Redacted_Protocol

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01137474
• Other Study ID Numbers: MB102-073 ST; 2010-019797-32
• First Posted: Jun 4, 2010
• Last Update Posted: Jan 26, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by AstraZeneca: Diabetes Mellitus, Type 2; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Hypoglycemic Agents; Pharmacologic Actions; Physiological Effects of Drugs
• Additional relevant MeSH terms: Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	This study was originally designed with 2 additional double-blind treatment arms, dapagliflozin 2.5 and 5 mg, but randomization of new patients into these arms stopped with implementation of Protocol Amendment 8 on 1-11-11. Patients randomized to dapagliflozin 2.5 or 5 mg remained on their blinded medication until study completion.
Pre-assignment Detail	Of 2996 participants enrolled, 944 were randomized and received double-blind treatment.

Arm/Group Title	Placebo	Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)	Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)	Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 2.5 mg, daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 5 mg, daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Period Title: Overall Study
STARTED	311	166	165	302
Received Treatment	311	166	165	302
COMPLETED	287	154	158	281
NOT COMPLETED	24	12	7	21

Baseline Characteristics

Arm/Group Title	Placebo	Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)	Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)	Dapagliflozin 10 mg	Total
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 2.5 mg, daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 5 mg, daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.	Total of all reporting groups
Overall Participants	311	166	165	302	944
Age, Customized (Number) [Number]
Younger than 65 years	259 83.3%	141 84.9%	142 86.1%	260 86.1%	802 85%
65 years and older to younger than 75 years	46 14.8%	25 15.1%	21 12.7%	42 13.9%	134 14.2%
75 years and older	6 1.9%	0 0%	2 1.2%	0 0%	8 0.8%
Gender (Count of Participants)
Female	140 45%	76 45.8%	76 46.1%	123 40.7%	415 44%
Male	171 55%	90 54.2%	89 53.9%	179 59.3%	529 56%
Race/Ethnicity, Customized (Number) [Number]
White	241 77.5%	105 63.3%	108 65.5%	239 79.1%	693 73.4%
Black or African American	14 4.5%	11 6.6%	8 4.8%	12 4%	45 4.8%
Asian	54 17.4%	49 29.5%	49 29.7%	49 16.2%	201 21.3%
Other	2 0.6%	1 0.6%	0 0%	2 0.7%	5 0.5%
Body Mass Index (Number) [Number]
Less than 25 kg/m^2	28 9%	20 12%	18 10.9%	34 11.3%	100 10.6%
25 kg/m^2 to 30 kg/m^2	131 42.1%	67 40.4%	63 38.2%	95 31.5%	356 37.7%
30 kg/m^2 and greater	152 48.9%	79 47.6%	84 50.9%	173 57.3%	488 51.7%

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change From Baseline in Seated Systolic Blood Pressure (BP) at Week 12
Description	Seated BP was to be measured at every visit. Data after rescue medication was excluded. The patient first rested for at least 10 minutes in the seated position. Seated blood BP was determined from the mean of 3 replicated measurements obtained 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 to be obtained (total=5) and incorporated into the calculated mean for systolic BP and diastolic BP. For the initial BP recording, BP was measured in both arms. If the BP was higher in 1 arm, that arm was used for BP measurement. If there was no difference in BP measurements between arms, the dominant arm was used for all future BP measurements. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Arm/Group Title	Dapagliflozin 10 mg	Placebo
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.
Measure Participants	280	279
Mean (Standard Error) [mm Hg]	-10.40 (0.8822)	-7.34 (0.8812)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	Change from baseline to week 12 calculated using a 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 value and baseline value by week interaction. Data after rescue were not included in the analysis. With 253 patients per group, there is >80% power to detect a difference of 3.5 mm Hg at alpha=0.05, assuming a common SD of 14 mm Hg.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	Endpoint tested following a sequential testing procedure at two-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
	Method	Longitudinal repeated measures analysis
	Comments	Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.05
	Confidence Interval	(2-Sided) 95%; -4.87 to -1.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.9251
	Estimation Comments

2. Primary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin (HbA1c) at Week 12
Description	HbA1c was measured as percent of hemoglobin by a central laboratory. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis. SD=standard deviation.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Arm/Group Title	Placebo	Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Measure Participants	279	278
Mean (Standard Error) [Percent]	-0.10 (0.0631)	-0.56 (0.0633)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	Change from baseline to week 12 was calculated using a 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 value and baseline value by week interaction. With 253 subjects per group, there is >98% power to detect a difference of 0.4% at a=0.05, assuming a common SD of 1.1%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Endpoint tested following a sequential testing procedure at two-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
	Method	Longitudinal repeated measures analysis
	Comments	Only Week 12 data are presented; data from all weeks in the double-blind treatment period were included in the longitudinal repeated measures model
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0673
	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)
Description	Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24-hrs each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hr ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Arm/Group Title	Placebo	Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Measure Participants	263	267
Mean (Standard Error) [mm Hg]	-6.73 (1.2427)	-9.62 (1.2277)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	Change from baseline to week 12 LOCF was calculated using an ANCOVA model with treatment group as an effect and baseline value and randomization strata as covariate. Data after rescue are excluded from blood pressure analyses.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0043
	Comments	Endpoint tested following a sequential testing procedure at 2-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
	Method	ANCOVA
	Comments	Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.89
	Confidence Interval	(2-Sided) 95%; -4.88 to -0.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.0091
	Estimation Comments

4. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Seated Diastolic Blood Pressure at Week 12
Description	All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Arm/Group Title	Placebo	Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Measure Participants	279	280
Mean (Standard Error) [mm Hg]	-4.79 (0.5418)	-5.79 (0.5425)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	Change from baseline to week 12 was calculated using a 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 value and baseline value by week interaction. Data after rescue were not included in the analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0843
	Comments	Endpoint tested following a sequential testing procedure at two-sided alpha=0.05 to control the family-wise Type I error rate related to primary and secondary efficacy endpoints. Test performed since previous tests were significant.
	Method	Longitudinal repeated measures analysis
	Comments	Only Week 12 data are presented; data from all weeks in double-blind period were included in the longitudinal repeated measures model.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -2.15 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5811
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Mean Change in 24-Hour Ambulatory Diastolic Blood Pressure at Week 12 (Last Observation Carried Forward [LOCF])
Description	Ambulatory blood pressure monitoring was performed twice during the study, at baseline and at the end of study, for a duration of 24 hours each time. If the patient met the criteria for rescue due to hypertension, a second monitoring was performed prior to the first dose of rescue medication. Initiation of the 24-hour ambulatory blood pressure monitoring began between 6 and 11 am to ensure trough blood pressure measurements were obtained. Patients were instructed to withhold all medication on the morning of the study visit and to bring their medications to the visit with them.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Arm/Group Title	Placebo	Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Measure Participants	263	267
Mean (Standard Error) [mm Hg]	-5.53 (0.8458)	-6.15 (0.8353)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	Change from baseline to week 12 LOCF was calculated using an ANCOVA model with treatment group as an effect and baseline value and randomization strata as covariate. Data after rescue are excluded from blood pressure analyses.
	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	-0.62
	Confidence Interval	(2-Sided) 95%; -1.96 to 0.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.6866
	Estimation Comments

6. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Serum Uric Acid Levels at Week 12
Description	Central laboratory serum uric acid levels will be determined at the Enrollment, Day -28, Day 1, and at Week 4, 8, 12, and 13 visits. All randomized participants who received at least 1 dose of study drug and who had nonmissing baseline and at least 1 postbaseline value during the double-blind treatment period were used for analysis.
Time Frame	From Baseline to Week 12

Outcome Measure Data

Analysis Population Description

This study originally had 2 additional arms-dapagliflozin 2.5 and 5 mg-but randomization to these arms stopped when Protocol Amendment 8 (1-11-11) was implemented. Because endpoints focused only on 10-mg and placebo data, only patients in these arms who received study drug and who had nonmissing baseline and Week 12 values were included.

Arm/Group Title	Placebo	Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
Measure Participants	279	278
Mean (Standard Error) [mg/dL]	0.05 (0.0747)	-0.27 (0.0754)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dapagliflozin 10 mg, Placebo
	Comments	Change from baseline to week 12 was calculated using a 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 value and baseline value by week interaction.
	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	-0.32
	Confidence Interval	(2-Sided) 95%; -0.46 to -0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0717
	Estimation Comments

Adverse Events

Arm/Group Title	Placebo		Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin 10 mg
Arm/Group Description	Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an oral antidiabetic drug (OAD) with or without insulin and an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), received dapagliflozin-matching placebo daily with a morning meal.		Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 2.5 mg, daily with a morning meal.		Participants with type 2 diabetes and inadequate glycemic control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 5 mg, daily with a morning meal.		Participants with type 2 diabetes and inadequate glycemic and hypertension control while taking an OAD with or without insulin and an ACE inhibitor or ARB, received dapagliflozin, 10 mg, daily with a morning meal.
All Cause Mortality
	Placebo		Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/311 (1.3%)		3/166 (1.8%)		2/165 (1.2%)		2/302 (0.7%)
General disorders
Chest pain	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Hepatobiliary disorders
Cholecystitis acute	0/311 (0%)		0/166 (0%)		1/165 (0.6%)		0/302 (0%)
Infections and infestations
Mastoiditis	0/311 (0%)		0/166 (0%)		0/165 (0%)		1/302 (0.3%)
Abscess intestinal	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Appendiceal abscess	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Appendicitis	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Otitis media	0/311 (0%)		0/166 (0%)		0/165 (0%)		1/302 (0.3%)
Injury, poisoning and procedural complications
Craniocerebral injury	0/311 (0%)		0/166 (0%)		1/165 (0.6%)		0/302 (0%)
Fall	0/311 (0%)		0/166 (0%)		1/165 (0.6%)		0/302 (0%)
Lumbar vertebral fracture	0/311 (0%)		1/166 (0.6%)		0/165 (0%)		0/302 (0%)
Rib fracture	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Road traffic accident	1/311 (0.3%)		1/166 (0.6%)		0/165 (0%)		0/302 (0%)
Cervical vertebral fracture	0/311 (0%)		1/166 (0.6%)		0/165 (0%)		0/302 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder	0/311 (0%)		1/166 (0.6%)		0/165 (0%)		0/302 (0%)
Intervertebral disc protrusion	0/311 (0%)		1/166 (0.6%)		0/165 (0%)		0/302 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal adenoma	0/311 (0%)		0/166 (0%)		0/165 (0%)		1/302 (0.3%)
Nervous system disorders
Ischaemic stroke	1/311 (0.3%)		1/166 (0.6%)		0/165 (0%)		0/302 (0%)
Syncope	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Skin and subcutaneous tissue disorders
Subcutaneous emphysema	1/311 (0.3%)		0/166 (0%)		0/165 (0%)		0/302 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Dapagliflozin, 2.5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin, 5 mg (Randomized Before Protocol Amendment 8)		Dapagliflozin 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/311 (0%)		0/166 (0%)		0/165 (0%)		0/302 (0%)

Limitations/Caveats

Study originally had 2 additional arms, dapagliflozin 2.5 and 5 mg, but enrolment stopped after Protocol Amendment 8 (1-11-11) implemented. Because endpoints focused on comparison of dapagliflozin 10 mg with placebo, only these arms were summarized.

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.