Efficacy and Safety in Patients With Type 2 Diabetes Mellitus, Cardiovascular Disease and Hypertension

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01031680
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 922
• Locations: 141
• Arms: 2
• Duration (Months): 34
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study is carried out to assess whether dapagliflozin lowers blood glucose, body weight and blood pressure, when added to patients existing medications and how it compares with their usual treatment without added dapagliflozin. Safety data will be collected and analysed to confirm that treatment with dapagliflozin is safe and well tolerated in patients who have diabetes, cardiovascular disease and hypertension.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus; Cardiovascular Disease; Hypertension; Inadequate Glycaemic Control	Drug: Dapagliflozin; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 922 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 24-week, Multicentre, Randomised, Double-blind, Age-stratified, Placebo Controlled, Phase III Study With a 80-week Extension Period to Evaluate the Efficacy and Safety of Dapagliflozin 10 mg Once Daily in Pts With T2DM, CV Disease and Hypertension Who Exhibit Inadequate Glycaemic Control on Usual Care
• Study Start Date: Feb 1, 2010
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Dapagliflozin 10 mg tablet	Drug: Dapagliflozin; 10 mg tablet, oral, once daily, 24- week treatment and 80-week extension period
Placebo Comparator: 2 Matching placebo tablet	Drug: Placebo; Matching placebo tablet, oral, once daily, 24- week treatment and 80-week extension period

Outcome Measures

Primary Outcome Measures

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

   To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease and hypertension, measured as the mean change in HbA1c from baseline to week 24.

2. Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit [Baseline to week 24]

   To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease and hypertension at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.

Secondary Outcome Measures

1. Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) [Baseline to Week 8]

   To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.

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

   To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.

3. Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 24 (LOCF) [Baseline to Week 24]

   To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.

4. Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m² [Baseline to Week 24]

   To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Type 2 diabetes mellitus.

• Cardiovascular disease

• Hypertension

Exclusion Criteria:

• Patients with type 1 diabetes or diabetes insipidus

• Patients with 3 or more oral anti-hyperglycaemic drugs with or without insulin and/or poorly controlled diabetes

• Any clinically significant illness, which would compromise the patient's safety and their participation in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Gulf Shores	Alabama	United States
2	Research Site	Phoenix	Arizona	United States
3	Research Site	Burbank	California	United States
4	Research Site	Garden Grove	California	United States
5	Research Site	Huntington Park	California	United States
6	Research Site	Lancaster	California	United States
7	Research Site	Salinas	California	United States
8	Research Site	San Marino	California	United States
9	Research Site	San Ramon	California	United States
10	Research Site	Tustin	California	United States
11	Research Site	Colorado Springs	Colorado	United States
12	Research Site	Waterbury	Connecticut	United States
13	Research Site	Clearwater	Florida	United States
14	Research Site	Deerfield Beach	Florida	United States
15	Research Site	Hialeah	Florida	United States
16	Research Site	Hollywood	Florida	United States
17	Research Site	Jacksonville	Florida	United States
18	Research Site	Miami	Florida	United States
19	Research Site	Port Charlotte	Florida	United States
20	Research Site	Port Orange	Florida	United States
21	Research Site	Tampa	Florida	United States
22	Research Site	Winter Park	Florida	United States
23	Research Site	Columbus	Georgia	United States
24	Research Site	Decatur	Georgia	United States
25	Research Site	Stone Mountain	Georgia	United States
26	Research Site	Honolulu	Hawaii	United States
27	Research Site	Chicago	Illinois	United States
28	Research Site	Wichita	Kansas	United States
29	Research Site	Baton Rouge	Louisiana	United States
30	Research Site	Lake Charles	Louisiana	United States
31	Research Site	West Monroe	Louisiana	United States
32	Research Site	Baltimore	Maryland	United States
33	Research Site	Kansas City	Missouri	United States
34	Research Site	St Louis	Missouri	United States
35	Research Site	Las Vegas	Nevada	United States
36	Research Site	Brick	New Jersey	United States
37	Research Site	Oradell	New Jersey	United States
38	Research Site	Bronx	New York	United States
39	Research Site	New Hyde Park	New York	United States
40	Research Site	Cincinnati	Ohio	United States
41	Research Site	Dayton	Ohio	United States
42	Research Site	Oklahoma City	Oklahoma	United States
43	Research Site	Philadelphia	Pennsylvania	United States
44	Research Site	Phoenixville	Pennsylvania	United States
45	Research Site	Pittsburgh	Pennsylvania	United States
46	Research Site	Reading	Pennsylvania	United States
47	Research Site	Charleston	South Carolina	United States
48	Research Site	Kingsport	Tennessee	United States
49	Research Site	Carrollton	Texas	United States
50	Research Site	Dallas	Texas	United States
51	Research Site	Fort Worth	Texas	United States
52	Research Site	Houston	Texas	United States
53	Research Site	North Richland Hills	Texas	United States
54	Research Site	Plano	Texas	United States
55	Research Site	San Antonio	Texas	United States
56	Research Site	Tomball	Texas	United States
57	Research Site	Ogden	Utah	United States
58	Research Site	Danville	Virginia	United States
59	Research Site	Spokane	Washington	United States
60	Research Site	Tacoma	Washington	United States
61	Research Site	La Plata	Buenos Aires	Argentina
62	Research Site	Buenos Aires	Caba	Argentina
63	Research Site	Buenos Aires		Argentina
64	Research Site	Caba		Argentina
65	Research Site	Ciudad de Buenos Aires		Argentina
66	Research Site	Cordoba		Argentina
67	Research Site	Mendoza		Argentina
68	Research Site	Santa Fe		Argentina
69	Research Site	Calgary	Alberta	Canada
70	Research Site	New Westminster	British Columbia	Canada
71	Research Site	Winnipeg	Manitoba	Canada
72	Research Site	Carbonear	Newfoundland and Labrador	Canada
73	Research Site	Mount Pearl	Newfoundland and Labrador	Canada
74	Research Site	St. John's	Newfoundland and Labrador	Canada
75	Research Site	Courtice	Ontario	Canada
76	Research Site	Hamilton	Ontario	Canada
77	Research Site	Mississauga	Ontario	Canada
78	Research Site	Ottawa	Ontario	Canada
79	Research Site	Smiths Falls	Ontario	Canada
80	Research Site	Toronto	Ontario	Canada
81	Research Site	Lachine	Quebec	Canada
82	Research Site	Laval	Quebec	Canada
83	Research Site	Montreal	Quebec	Canada
84	Research Site	Saint-marc-des-carrieres	Quebec	Canada
85	Research Site	Sherbrooke	Quebec	Canada
86	Research Site	Potsdam	BR	Germany
87	Research Site	Bad Nauheim		Germany
88	Research Site	Berlin		Germany
89	Research Site	Erdmannhausen		Germany
90	Research Site	Frankfurt		Germany
91	Research Site	Hamburg		Germany
92	Research Site	Heilbronn		Germany
93	Research Site	Hildesheim		Germany
94	Research Site	Mainz		Germany
95	Research Site	Munster		Germany
96	Research Site	Potsdam		Germany
97	Research Site	Speyer		Germany
98	Research Site	Wahlstedt		Germany
99	Research Site	Braila		Romania
100	Research Site	Brasov		Romania
101	Research Site	Bucharest		Romania
102	Research Site	Bucuresti		Romania
103	Research Site	Constanta		Romania
104	Research Site	Iasi		Romania
105	Research Site	Sibiu		Romania
106	Research Site	Suceava		Romania
107	Research Site	Banska Bystrica		Slovakia
108	Research Site	Bratislava		Slovakia
109	Research Site	Dolny Kubin		Slovakia
110	Research Site	Komarno		Slovakia
111	Research Site	Kosice		Slovakia
112	Research Site	Kysucke Nove Mesto		Slovakia
113	Research Site	Liptovsky Hradok		Slovakia
114	Research Site	Lucenec		Slovakia
115	Research Site	Nitra		Slovakia
116	Research Site	Povazska Bystrica		Slovakia
117	Research Site	Prievidza		Slovakia
118	Research Site	Rimavska Sobota		Slovakia
119	Research Site	Ruzomberok		Slovakia
120	Research Site	Zilina		Slovakia
121	Research Site	Cordoba	Andalucia	Spain
122	Research Site	Granada	Andalucia	Spain
123	Research Site	Sevilla	Andalucia	Spain
124	Research Site	Oviedo	Asturias	Spain
125	Research Site	Barcelona	Cataluna	Spain
126	Research Site	Lerida	Cataluna	Spain
127	Research Site	Olot (girona)	Cataluna	Spain
128	Research Site	Majadahonda	Comunidad de Madrid	Spain
129	Research Site	San Juan (alicante)	Comunidad Valenciana	Spain
130	Research Site	Valencia	Comunidad Valenciana	Spain
131	Research Site	A Coruna	Galicia	Spain
132	Research Site	Santiago de Compostela	Galicia	Spain
133	Research Site	Palma de Mallorca	Islas Baleares	Spain
134	Research Site	Changhua		Taiwan
135	Research Site	Kaohsiung		Taiwan
136	Research Site	Taichung		Taiwan
137	Research Site	Tainan County		Taiwan
138	Research Site	Taipei		Taiwan
139	Research Site	Tao-yuan		Taiwan
140	Research Site	Hanoi		Vietnam
141	Research Site	Ho Chi Minh		Vietnam

Sponsors and Collaborators

• AstraZeneca
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Dr. William Cefalu, Pennington Biomedical Research Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01031680
• Other Study ID Numbers: D1690C00018
• First Posted: Dec 14, 2009
• Last Update Posted: Oct 29, 2013
• Last Verified: Sep 1, 2013

• Keywords provided by AstraZeneca: dapagliflozin; diabetes; cardiovascular disease; hypertension
• Additional relevant MeSH terms: Hypertension; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	First participant enrolled: 10 Feb 2010, last participant for last visit for the 24-week period: 26 May 2011. This study was conducted in 4 European countries, 2 countries in Asia/the Pacific Region, The United States, Canada, and Argentina. In total 1429 participants were enrolled and 922 participants were randomized.
Pre-assignment Detail	During a placebo lead-in period, participants were counselled on dietary and life-style modifications.

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Period Title: Overall Study
STARTED	460	462
COMPLETED	403	404
NOT COMPLETED	57	58

Baseline Characteristics

Arm/Group Title	Experimental	Placebo Comparator	Total
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily	Total of all reporting groups
Overall Participants	455	459	914
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.8 (6.97)	63.0 (7.66)	62.9 (7.32)
Age, Customized (Number) [Number]
<55	58 12.7%	74 16.1%	132 14.4%
>=55 and <65	205 45.1%	189 41.2%	394 43.1%
>=65 and <75	164 36%	165 35.9%	329 36%
>=75	28 6.2%	31 6.8%	59 6.5%
Sex: Female, Male (Count of Participants)
Female	146 32.1%	144 31.4%	290 31.7%
Male	309 67.9%	315 68.6%	624 68.3%
Haemoglobin A1c (HbA1c) (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	8.18 (0.841)	8.08 (0.802)	8.13 (0.823)
Seated Systolic Blood Pressure (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	133.5 (13.48)	133.0 (13.81)	133.2 (13.64)
Total Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	92.63 (20.504)	93.59 (19.467)	93.11 (19.985)
Body Mass Index (BMI) (Number) [Number]
< 25 kg/m²	29 6.4%	30 6.5%	59 6.5%
>= 25 kg/m²	426 93.6%	429 93.5%	855 93.5%
>= 27 kg/m²	388 85.3%	397 86.5%	785 85.9%
>= 30 kg/m²	291 64%	304 66.2%	595 65.1%

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change in HbA1c Levels
Description	To compare the glycemic efficacy of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease and hypertension, measured as the mean change in HbA1c from baseline to week 24.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Measure Participants	448	451
Least Squares Mean (95% Confidence Interval) [Percent]	-0.38	0.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental, Placebo Comparator
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.025 (2-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate for each endpoint
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0473
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

2. Primary Outcome

Title	Proportion of Responders Meeting All Criteria of a 3-item Endpoint of Clinical Benefit
Description	To compare the clinical benefit of dapagliflozin 10 mg versus placebo when added to usual care in type 2 diabetes patients with cardiovascular disease and hypertension at week 24, measured as the proportion of responders for a 3-item endpoint of clinical benefit, defined as an absolute drop of 0.5% or more from baseline HbA1c, and a relative drop of 3% or more from baseline for total body weight, and an absolute drop of 3 mmHg or more from baseline in seated systolic blood pressure.
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Measure Participants	444	451
Number (95% Confidence Interval) [Percentage of participants]	11.7 2.6%	0.9 0.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental, Placebo Comparator
	Comments	H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.025 (2-sided). A hierarchical closed testing procedure was used to control Type I error across the primary & key secondary objectives
	Method	Cochran-Mantel-Haenszel
	Comments	with age-by-insulin use-by-time from most recent qualifying CV event as stratum
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	9.9
	Confidence Interval	(2-Sided) 95%; 7.0 to 12.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change in Seated Systolic Blood Pressure (SBP)
Description	To compare the mean change in seated systolic blood pressure from baseline to week 8 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 8

Outcome Measure Data

Analysis Population Description

Full Analysis Set, participants with non-missing baseline and Week 8 (LOCF) values

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Measure Participants	451	459
Least Squares Mean (95% Confidence Interval) [mmHg]	-2.96	-0.99

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental, Placebo Comparator
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0126
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.97
	Confidence Interval	(2-Sided) 95%; -3.52 to -0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7898
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

4. Secondary Outcome

Title	Adjusted Mean Percent Change in Body Weight
Description	To compare the mean percent change in body weight from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Measure Participants	455	459
Least Squares Mean (95% Confidence Interval) [Percentage of Body Weight]	-2.56	-0.30

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental, Placebo Comparator
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.27
	Confidence Interval	() 95%; -2.64 to -1.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1910
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

5. Secondary Outcome

Title	Adjusted Mean Change in Seated Systolic Blood Pressure (SBP) at Week 24 (LOCF)
Description	To compare the mean change in seated systolic blood pressure from baseline to week 24 between dapagliflozin 10 mg versus placebo.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Measure Participants	451	459
Least Squares Mean (95% Confidence Interval) [mmHg]	-2.99	-1.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental, Placebo Comparator
	Comments	H0: mean(treat) minus mean(placebo) = 0 versus the alternative HA: mean(treat) minus mean(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0174
	Comments	Significant at alpha=0.05 (2-sided). Key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	ANCOVA
	Comments	with treatment group and stratum as effects and baseline value as covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.95
	Confidence Interval	(2-Sided) 95%; -3.56 to -0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8203
	Estimation Comments	with stratum = age-by-insulin use-by-time from most recent qualifying CV event

6. Secondary Outcome

Title	Proportion of Participants With a Reduction From Baseline of 5% or More in Body Weight in Participants With Baseline BMI ≥27 kg/m²
Description	To compare the proportion of participants with BMI baseline ≥27 kg/m2 with a reduction from baseline of 5% or more in body weight with dapagliflozin 10 mg versus placebo from baseline to week 24. Least Squares Mean represents the percent of participants adjusted for baseline body weight and age stratum.
Time Frame	Baseline to Week 24

Outcome Measure Data

Analysis Population Description

Full analysis set; participants with baseline BMI ≥27 kg/m² and Week 24 (LOCF) body weight value

Arm/Group Title	Experimental	Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily	Placebo, Matching placebo tablet, oral, once daily
Measure Participants	388	397
Least Squares Mean (95% Confidence Interval) [Percentage of participants]	16.5 3.6%	4.0 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Experimental, Placebo Comparator
	Comments	H0: proportion(treat) minus proportion(placebo) = 0 versus the alternative HA: proportion(treat) minus proportion(placebo) =/= 0
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Significant at alpha=0.05 (2-sided). Primary and key secondary endpoints are tested following a hierarchical closed testing procedure
	Method	Regression, Logistic
	Comments	Based on methodology of Zhang, Tsiatis & Davidian and Davidian, Tsiatis, Zhang & Lu, with adjustment for baseline value and stratum (gender)
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	12.5
	Confidence Interval	(2-Sided) 95%; 8.3 to 16.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.126
	Estimation Comments

Adverse Events

Time Frame	Non-serious / serious adverse events on or after the first day and on or prior to the last day of the 24-week double-blind treatment plus 4/30 days or up to follow-up visit if earlier, or up to and including the start date of extension period if earlier.
Adverse Event Reporting Description	Participants were questioned at each study visit about the occurrence of any health problems and any examination conducted at a study visit was assessed in comparison to the status at study entry.
Arm/Group Title	Experimental		Placebo Comparator
Arm/Group Description	Dapagliflozin, 10 mg tablet, oral, once daily		Placebo, Matching placebo tablet, oral, once daily
All Cause Mortality
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/460 (5.9%)		26/462 (5.6%)
Cardiac disorders
Acute Coronary Syndrome	1/460 (0.2%)		0/462 (0%)
Acute Myocardial Infarction	1/460 (0.2%)		1/462 (0.2%)
Angina Pectoris	1/460 (0.2%)		0/462 (0%)
Angina Unstable	1/460 (0.2%)		3/462 (0.6%)
Cardiogenic Shock	1/460 (0.2%)		0/462 (0%)
Coronary Artery Disease	1/460 (0.2%)		1/462 (0.2%)
Atrial Flutter	0/460 (0%)		1/462 (0.2%)
Cardiac Failure Congestive	0/460 (0%)		1/462 (0.2%)
Gastrointestinal disorders
Diarrhoea	1/460 (0.2%)		0/462 (0%)
Gastric Ulcer	1/460 (0.2%)		0/462 (0%)
Peptic Ulcer	1/460 (0.2%)		0/462 (0%)
Peritonitis	1/460 (0.2%)		0/462 (0%)
Gastritis	0/460 (0%)		1/462 (0.2%)
Nausea	0/460 (0%)		1/462 (0.2%)
General disorders
Chest Pain	1/460 (0.2%)		2/462 (0.4%)
Sudden Death	1/460 (0.2%)		0/462 (0%)
Unassigned	0/460 (0%)		1/462 (0.2%)
Hepatobiliary disorders
Cholelithiasis	1/460 (0.2%)		0/462 (0%)
Infections and infestations
Gastroenteritis	2/460 (0.4%)		1/462 (0.2%)
Anal Abscess	1/460 (0.2%)		0/462 (0%)
Diarrhoea Infectious	1/460 (0.2%)		0/462 (0%)
Diverticulitis	1/460 (0.2%)		0/462 (0%)
Gangrene	1/460 (0.2%)		1/462 (0.2%)
Localised Infection	1/460 (0.2%)		0/462 (0%)
Nasopharyngitis	1/460 (0.2%)		0/462 (0%)
Otitis Media	1/460 (0.2%)		0/462 (0%)
Pneumonia	1/460 (0.2%)		1/462 (0.2%)
Septic Shock	1/460 (0.2%)		0/462 (0%)
Urinary Tract Infection	1/460 (0.2%)		0/462 (0%)
Abscess Limb	0/460 (0%)		1/462 (0.2%)
Lung Infection	0/460 (0%)		1/462 (0.2%)
Injury, poisoning and procedural complications
Epicondylitis	1/460 (0.2%)		0/462 (0%)
Alcohol Poisoning	0/460 (0%)		1/462 (0.2%)
Ankle Fracture	0/460 (0%)		1/462 (0.2%)
Patella Fracture	0/460 (0%)		1/462 (0.2%)
Metabolism and nutrition disorders
Diabetic Foot	1/460 (0.2%)		0/462 (0%)
Hyperkalaemia	1/460 (0.2%)		0/462 (0%)
Hypoglycaemia	1/460 (0.2%)		0/462 (0%)
Musculoskeletal and connective tissue disorders
Osteitis	1/460 (0.2%)		0/462 (0%)
Osteoarthritis	0/460 (0%)		1/462 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder Transitional Cell Carcinoma	2/460 (0.4%)		0/462 (0%)
Basal Cell Carcinoma	1/460 (0.2%)		1/462 (0.2%)
Nervous system disorders
Cerebrovascular Accident	1/460 (0.2%)		1/462 (0.2%)
Ischaemic Stroke	1/460 (0.2%)		1/462 (0.2%)
Psychiatric disorders
Depression	1/460 (0.2%)		0/462 (0%)
Renal and urinary disorders
Renal Failure Acute	1/460 (0.2%)		0/462 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory Failure	1/460 (0.2%)		0/462 (0%)
Vascular disorders
Hypertensive Crisis	1/460 (0.2%)		0/462 (0%)
Arteriosclerosis Obliterans	0/460 (0%)		1/462 (0.2%)
Hypertension	0/460 (0%)		1/462 (0.2%)
Vascular Occlusion	0/460 (0%)		1/462 (0.2%)
Other (Not Including Serious) Adverse Events
	Experimental		Placebo Comparator
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	89/460 (19.3%)		84/462 (18.2%)
Endocrine disorders
Hypoglycemia	89/460 (19.3%)		84/462 (18.2%)

Limitations/Caveats

For participants who did not complete 8 and/or 24 weeks, respectively, LOCF was used. For HbA1c: excluding data after glycemic rescue, Weight: including data after rescue, SBP: excluding data after anti-hypertensive rescue.

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Certain Agreements

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

If an Investigator requests permission to publish data from this study any such publication is to be agreed with AstraZeneca (AZ) in advance. The investigator agrees to provide AZ as soon as possible with drafts of proposed publications. Unless otherwise agreed, AZ shall have a period of 60 days from receipt of the proposed final manuscript to review it and may within such time require that submission for publication of the manuscript be delayed in order for AZ to file patent applications.