Safety and Efficacy of Dapagliflozin as Monotherapy in Subjects With Type 2 Diabetes

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00736879
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 497
• Locations: 62
• Arms: 4
• Actual Duration (Months): 15.2
• Patients Per Site: 8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this clinical research study is to learn if BMS-512148 (Dapagliflozin) can help reduce the blood sugar levels in subjects with Type 2 Diabetes who are not well controlled on diet and exercise alone. The safety of this treatment will also be studied

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 497 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase III Trial to Evaluate the Safety and Efficacy of Dapagliflozin as Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control With Diet and Exercise
• Actual Study Start Date: Sep 22, 2008
• Actual Primary Completion Date: Dec 29, 2009
• Actual Study Completion Date: Dec 29, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dapagliflozin 1 mg Dapagliflozin: 1 mg	Drug: Dapagliflozin; Tablets, Oral, Once Daily, Up to 24 weeks; Other Names: BMS-512148 Farxiga™
Experimental: Dapagliflozin 2.5 mg Dapagliflozin: 2.5 mg	Drug: Dapagliflozin; Tablets, Oral, Once Daily, Up to 24 weeks; Other Names: BMS-512148 Farxiga™
Experimental: Dapagliflozin 5 mg Dapagliflozin: 5 mg	Drug: Dapagliflozin; Tablets, Oral, Once Daily, Up to 24 weeks; Other Names: BMS-512148 Farxiga™
Placebo Comparator: Placebo Placebo: 0 mg	Drug: Placebo; Tablets, Oral, Once Daily, Up to 24 weeks

Outcome Measures

Primary Outcome Measures

1. Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 Last Observation Carried Forward (LOCF) - All Randomized Participants [Baseline (Day 1), Week 24]

   Adjusted mean change in HbA1c from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available was determined(LOCF). HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication (metformin) was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c values were obtained at enrollment, lead-in, and at Day 1, Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.

Secondary Outcome Measures

1. Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized Participants [Baseline (Day 1), Week 24]

   Adjusted mean change in total body weight from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available LOCF was determined. Data after rescue medication (metformin) was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight was measured in kilograms (kg) at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period.

2. Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 (LOCF) - Randomized Participants [Baseline (Day 1), Week 24]

   Adjusted mean change in fasting plasma glucose (FPG) from baseline at Week 24 (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. FPG was measured as milligrams per deciliter (mg/dL) by a central laboratory at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

3. Adjusted Mean Change From Baseline in Effect on 2-hour Post Liquid Meal Glucose at Week 24 (LOCF) - Randomized Participants [Baseline (Day 1), Week 24]

   Liquid meal tolerance tests (MTTs) were scheduled to occur at Day 1 visit (MTT was to be completed 2 hours prior to first dose of treatment) and at Week 24 / End of treatment visit, or Rescue visit for participants meeting criteria for rescue due to lack of glycemic control. At Week 24, study treatment was given 1 hour before MTT was administered. Participant fasted for at least 10 hours (h) prior to both visits and abstained from tobacco, alcohol, and caffeine for 24 h prior to the MTT. The liquid meal supplement was administered over 10 minutes, starting immediately after Time 0 blood sample was drawn. Blood samples for post-liquid meal Glucose were obtained at 30, 60, 120, and 180 minutes after ingesting the liquid supplement. Glucose 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 double-blind study medication.

4. Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized Participants [Baseline (Day 1), Week 24]

   Therapeutic glycemic response was defined as HbA1c less than 7.0%. n=Number of participants with HBA1c less than (<) 7 % at Week 24, last observation carried forward (LOCF) while N=number of randomized participants with non-missing baseline and Week 24 (LOCF) values. Percent=n/N and was adjusted for Baseline HbA1c. Data after rescue medication (metformin) was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.

5. Adjusted Mean Change From Baseline in Waist Circumference at Week 24 (LOCF) - Randomization Participants [Baseline (Day 1), Week 24]

   Adjusted mean waist circumference values from baseline to Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, last observation carried forward, (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. Waist circumference was measured centimeters (cm) and obtained at lead-in, Day 1, and Week 24 of the double-blind period. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

6. Number of Participants With Deaths, Serious AEs (SAEs), Adverse Events (AEs), Discontinuation Due to AEs, During the 12 Week Double Blind Period, Including Data After Rescue - All Treated Participants [Day 1 of Double Blind Period to end of Week 24 Plus 30 days]

   Medical Dictionary for Regulatory Activities (MedDRA), version 12.1 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. Treatment-related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Baseline to last dose plus 4 days for AEs, plus 30 days for SAEs. Data after rescue included.

7. Number of Participants With Adverse Events of Special Interest During the 12 Week Double Blind Period - All Treated Participants [Baseline to last dose plus 4 days in 12 Week Double Blind Period]

   Participants with AEs of hypoglycemia, cardiac/vascular disorders, renal impairment or failure, volume depletion (hypotension/dehydration/hypovolemia), fractures, urinary stones, and other reports suggestive of genital infection or urinary tract infection (UTI) were summarized using MedDRA version 12.1. Data after rescue included for all AEs of special interest except hypoglycemia; hypoglycemia AEs were prior to rescue. Major hypoglycemic episode: symptomatic requiring 3rd party assistance due to severe impairment in consciousness or behavior with a glucose value < 54 mg/dL and prompt recovery after glucose/glucagon; Minor: either symptomatic with glucose measurement < 63 mg/dL, regardless of need for 3rd party assistance, or asymptomatic with glucose < 63 mg/dL that does not qualify as major; Other: suggestive but not meeting criteria for major or minor.

8. Mean Change From Baseline in Seated Systolic and Diastolic Blood Pressure at Week 24, Including Data After Rescue - Treated Participants [Baseline (Day 1), Week 24]

   Blood pressure values were obtained on Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double blind period, after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Blood pressure was measured in millimeters of mercury (mmHg). Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

9. Mean Change From Baseline in Seated Heart Rate at Week 24 - Treated Participants [Baseline (Day 1), Week 24]

   Heart rate values were obtained after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Heart rate was measured in beats per minute (bpm). Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.

10. Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Treated Participants [Week 24]

    12-Lead electrocardiograms (ECGs) were performed at Day -14 and Week 24/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator. Baseline (BL) was Day -14 for this parameter.

11. Number of Participants With Marked Laboratory Abnormalities in 24 Week Double Blind Treatment Period - Treated Participants [Baseline to Week 24/end of treatment plus 4 days]

    Safety laboratory measurements were obtained at Day 1, Weeks 1, 2, 4, 8, 12, 20, and 24 in the double blind Period. Baseline was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from baseline up to and including the last day of treatment plus 4 days. Data after rescue was also included. Abbreviations; 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), alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP); blood urea nitrogen (BUN). Marked abnormality Low (High) defined: hemoglobin <6 (>18 females or >20 males) g/dL; hematocrit <20% ( >55% females or >60% males); BUN (>60 mg/dL) or Urea >21.4 mmol/L; creatinine (>=1.5*preRX, >=2.5 mg/dL); AST and ALT >3*ULN; bilirubin >1.5*ULN; ALP >1.5*ULN.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male and females, ≥18 to ≤77 years old, with type 2 diabetes mellitus

• Subjects must have central laboratory pre-randomization A1C ≥7.0 and ≤ 10.0%

• C-peptide ≥ 1.0 ng/mL (0.34 nmol/L)

• Body Mass Index ≤ 45 kg/m²

• Must be able to perform self monitoring of blood glucose

Exclusion Criteria:

• aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3* upper limit of normal (ULN)

• Serum Total bilirubin >2 mg/dL (34.2 µmol/L)

• Creatinine kinase >3* ULN

• Serum creatinine ≥1.50 mg/dL (133 µmol/L) for male subjects, ≥1.40 mg/dL (124 µmol/L) for female subjects

• 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	Dedicated Clinical Research	Litchfield Park	Arizona	United States	85340
2	43rd Medical Associates, P.C.	Phoenix	Arizona	United States	85051
3	Clinical Research Advantage, Inc.	Tempe	Arizona	United States	85282
4	Valley Research	Fresno	California	United States	93720
5	Marina Raikhel, Md, Faafp	Lomita	California	United States	90717
6	Richard S. Cherlin, Md	Los Gatos	California	United States	95032
7	Orange County Research Center	Tustin	California	United States	92780
8	Family Physicians Of Greeley	Greeley	Colorado	United States	80634
9	Coastal Connecticut Research, Llc	New London	Connecticut	United States	06320
10	Central Florida Clinical Trials, Inc.	Altamonte Springs	Florida	United States	32701
11	Westside Center For Clinical Research	Jacksonville	Florida	United States	32205
12	Panhandle Family Care Associates	Marianna	Florida	United States	32446
13	Endocrine Research Solutions, Inc.	Roswell	Georgia	United States	30076
14	Belzoni Clinical Research	Belzoni	Mississippi	United States	39038
15	R-Research	Hamilton	New Jersey	United States	08690
16	Internist Associates Of Central New York	Syracuse	New York	United States	13210
17	Southgate Medical Group	West Seneca	New York	United States	14224
18	Down East Medical Associates, Pa	Morehead City	North Carolina	United States	28557
19	James J. Brown, Md	Akron	Ohio	United States	44319
20	Integris Family Care South	Oklahoma	Oklahoma	United States	73170
21	Southeastern Research Associates, Inc.	Taylors	South Carolina	United States	29687
22	Abbott Clinical Research Group, Inc	San Antonio	Texas	United States	78224
23	Avastra Clinical Trials	Midvale	Utah	United States	84047
24	Optimum Clinical Research, Inc.	Salt Lake City	Utah	United States	84102
25	Capital Clinical Research Center	Olympia	Washington	United States	98502
26	Stephen G. Danley, Do	Spokane	Washington	United States	99216
27	Local Institution	Calgary	Alberta	Canada	T3C 3P1
28	Local Institution	Coquitlam	British Columbia	Canada	V3K 3V9
29	Local Institution	Winnipeg	Manitoba	Canada	R3E 3P4
30	Local Institution	Bathurst	New Brunswick	Canada	E2A 4X7
31	Local Institution	Ajax	Ontario	Canada	L1S 7J5
32	Local Institution	Toronto	Ontario	Canada	M9W 4L6
33	Local Institution	Waterloo	Ontario	Canada	N2T 2Z6
34	Local Institution	Drummondville	Quebec	Canada	J2B 7T1
35	Local Institution	L'Ancienne Lorette	Quebec	Canada	G2E 2X1
36	Local Institution	St-Leonard	Quebec	Canada	H1S 3A9
37	Local Institution	Ahmedabad		India	380 015
38	Local Institution	Bangalore		India	560 043
39	Local Institution	Bangalore		India	560 052
40	Local Institution	Jaipur		India	302001
41	Local Institution	Jaipur		India	302016
42	Local Institution	Df	Distrito Federal	Mexico	11800
43	Local Institution	Guadalajara	Jalisco	Mexico	44670
44	Local Institution	Monterrey	Nuevo Leon	Mexico	64060
45	Local Institution	Merida	Yucatan	Mexico	97070
46	Local Institution	Durango		Mexico	34000
47	Local Institution	Mexico City		Mexico	06700
48	Local Institution	Veracruz		Mexico	91910
49	Local Institution	Ponce		Puerto Rico	00716
50	Local Institution	Ponce		Puerto Rico	00717
51	Local Institution	Kursk		Russian Federation	305035
52	Local Institution	Saint-Petersburg		Russian Federation	191015
53	Local Institution	Saratov		Russian Federation	410012
54	Local Institution	Smolensk		Russian Federation	214018
55	Local Institution	St. Petersburg		Russian Federation	195112
56	Local Institution	St. Petersburg		Russian Federation	195257
57	Local Institution	St. Petersburg		Russian Federation	197341
58	Local Institution	St.Petersburg		Russian Federation	197022
59	Local Institution	Benoni	Gauteng	South Africa	1501
60	Local Institution	Soweto	Gauteng	South Africa	1818
61	Local Institution	Paarl	Western Cape	South Africa	7646
62	Local Institution	Tygerberg	Western Cape	South Africa	7505

Sponsors and Collaborators

• AstraZeneca
• Bristol-Myers Squibb

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00736879
• Other Study ID Numbers: MB102-032
• First Posted: Aug 18, 2008
• Last Update Posted: Apr 20, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by AstraZeneca: Diabetes Mellitus, Type 2; Diabetes Mellitus; Endocrine System Diseases; Glucose Metabolism Disorders; Metabolic Diseases
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Dapagliflozin

Study Results

Participant Flow

Recruitment Details	Study initiated 22 September 2008 and completed 29 December 2009 in drug naive participants with type 2 diabetes mellitus who had inadequate glycemic control, defined as an hemoglobin A1c (HbA1c) greater than, equal to ( ≥) 7.0% and less than equal to (≤) 10.0%, with diet and exercise.
Pre-assignment Detail	497 enrolled in Qualification Period: 297 completed: 13 withdrew consent, 1 lost to follow up (LTF), 1 pregnancy, 183 no longer met criteria, 2 other; 297 entered Placebo Lead-In Period: 282 completed: 3 withdrew consent, 4 LTF, 5 no longer met criteria, 3 other. 282 treated Double Blind; Follow Up visit: 4 weeks ± 5 days post treatment completion.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Period Title: Double Blind Treatment Period
STARTED	68	72	74	68
COMPLETED	65	68	67	63
NOT COMPLETED	3	4	7	5
Period Title: Double Blind Treatment Period
STARTED	66	70	66	62
COMPLETED	65	67	66	62
NOT COMPLETED	1	3	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg	Total
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	Total of all reporting groups
Overall Participants	68	72	74	68	282
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.5 (11.08)	53.7 (9.04)	53.5 (10.61)	51.3 (11.51)	53.0 (10.57)
Age, Customized (participants) [Number]
Less than (<) 65 years	55 80.9%	63 87.5%	61 82.4%	61 89.7%	240 85.1%
Greater than, equal to (>=) 65 and < 75 years	11 16.2%	9 12.5%	12 16.2%	6 8.8%	38 13.5%
>= 75 years	2 2.9%	0 0%	1 1.4%	1 1.5%	4 1.4%
Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Age, Customized (participants) [Number]
Female <= 50 years	10 14.7%	12 16.7%	11 14.9%	22 32.4%	55 19.5%
Female > 50 years	21 30.9%	22 30.6%	29 39.2%	14 20.6%	86 30.5%
Sex: Female, Male (Count of Participants)
Female	31 45.6%	34 47.2%	40 54.1%	36 52.9%	141 50%
Male	37 54.4%	38 52.8%	34 45.9%	32 47.1%	141 50%
Race/Ethnicity, Customized (participants) [Number]
White	57 83.8%	56 77.8%	61 82.4%	55 80.9%	229 81.2%
Black/African American	3 4.4%	4 5.6%	2 2.7%	3 4.4%	12 4.3%
Asian	7 10.3%	11 15.3%	10 13.5%	10 14.7%	38 13.5%
Other Race	1 1.5%	1 1.4%	1 1.4%	0 0%	3 1.1%
Ethnicity Hispanic/Latino	3 4.4%	1 1.4%	2 2.7%	3 4.4%	9 3.2%
Ethnicity Not Hispanic/Latino	10 14.7%	13 18.1%	11 14.9%	9 13.2%	43 15.2%
Ethnicity Not Reported	55 80.9%	58 80.6%	61 82.4%	56 82.4%	230 81.6%
Body Mass Index in Kg/m^2 (participants) [Number]
< 25 kg/m^2	3 4.4%	6 8.3%	10 13.5%	7 10.3%	26 9.2%
>=25 kg/m^2	65 95.6%	66 91.7%	64 86.5%	61 89.7%	256 90.8%
>=27 kg/m^2	60 88.2%	57 79.2%	54 73%	48 70.6%	219 77.7%
>=30 kg/m^2	41 60.3%	48 66.7%	45 60.8%	37 54.4%	171 60.6%
Hemoglobin A1c (HbA1c) % (Percent of Hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of Hemoglobin]	7.80 (1.117)	7.80 (0.984)	8.11 (1.072)	7.94 (1.029)	7.92 (1.054)
Waist Circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	105.24 (12.653)	104.14 (11.642)	101.48 (12.710)	103.29 (13.745)	103.50 (12.703)

Outcome Measures

1. Primary Outcome

Title	Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 Last Observation Carried Forward (LOCF) - All Randomized Participants
Description	Adjusted mean change in HbA1c from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available was determined(LOCF). HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication (metformin) was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c values were obtained at enrollment, lead-in, and at Day 1, Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

N= Number of randomized participants, who took at least 1 dose of double-blind study medication, with non missing baseline and Week 24 (LOCF) values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	72	66
Mean (Standard Error) [Percent Hemoglobin]	0.02 (0.1200)	-0.68 (0.1166)	-0.72 (0.1169)	-0.82 (0.1217)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 1mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Tested at alpha=0.019 applying Dunnett's adjustment
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.69
	Confidence Interval	(2-Sided) 95%; -1.02 to -0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1672
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Tested at alpha=0.019 applying Dunnett's adjustment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.74
	Confidence Interval	(2-Sided) 95%; -1.07 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1679
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Tested at alpha=0.019 applying Dunnett's adjustment.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.84
	Confidence Interval	(2-Sided) 95%; -1.17 to -0.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1710
	Estimation Comments

2. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized Participants
Description	Adjusted mean change in total body weight from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available LOCF was determined. Data after rescue medication (metformin) was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight was measured in kilograms (kg) at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

N= Number of randomized participants, who took at least 1 dose of double-blind study medication, with non missing baseline and Week 24 (LOCF) values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	74	67
Mean (Standard Error) [kg]	-0.96 (0.3942)	-2.69 (0.3820)	-2.64 (0.3776)	-2.69 (0.3961)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 1mg
	Comments	By applying sequential testing procedure, the testing was performed since the primary endpoint was significant.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.73
	Confidence Interval	(2-Sided) 95%; -2.81 to -0.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5481
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0024
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.68
	Confidence Interval	(2-Sided) 95%; -2.76 to -0.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5474
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0022
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.73
	Confidence Interval	(2-Sided) 95%; -2.83 to -0.63
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5598
	Estimation Comments

3. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 (LOCF) - Randomized Participants
Description	Adjusted mean change in fasting plasma glucose (FPG) from baseline at Week 24 (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. FPG was measured as milligrams per deciliter (mg/dL) by a central laboratory at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

Number analyzed = Number of randomized participants, who took at least 1 dose of double-blind study medication, with non missing baseline and Week 24 (LOCF) values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	74	67
Mean (Standard Error) [mg/dL]	4.1 (4.200)	-11.0 (4.082)	-21.6 (4.025)	-28.5 (4.230)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 1mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.1
	Confidence Interval	(2-Sided) 95%; -26.7 to -3.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.859
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-25.7
	Confidence Interval	(2-Sided) 95%; -37.2 to -14.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.816
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-32.6
	Confidence Interval	(2-Sided) 95%; -44.3 to -20.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 5.962
	Estimation Comments

4. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Effect on 2-hour Post Liquid Meal Glucose at Week 24 (LOCF) - Randomized Participants
Description	Liquid meal tolerance tests (MTTs) were scheduled to occur at Day 1 visit (MTT was to be completed 2 hours prior to first dose of treatment) and at Week 24 / End of treatment visit, or Rescue visit for participants meeting criteria for rescue due to lack of glycemic control. At Week 24, study treatment was given 1 hour before MTT was administered. Participant fasted for at least 10 hours (h) prior to both visits and abstained from tobacco, alcohol, and caffeine for 24 h prior to the MTT. The liquid meal supplement was administered over 10 minutes, starting immediately after Time 0 blood sample was drawn. Blood samples for post-liquid meal Glucose were obtained at 30, 60, 120, and 180 minutes after ingesting the liquid supplement. Glucose 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 double-blind study medication.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

Number of randomized participants, who took at least 1 dose of double-blind study medication, with non missing baseline and Week 24 (LOCF) values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	58	67	58	58
Mean (Standard Error) [mg/dL]	8.81 (6.4925)	-33.3 (6.0390)	-39.3 (6.5025)	-51.8 (6.4973)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 1mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-42.1
	Confidence Interval	(2-Sided) 95%; -59.56 to -24.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.8681
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 2.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-48.1
	Confidence Interval	(2-Sided) 95%; -66.27 to -30.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.1963
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-60.6
	Confidence Interval	(2-Sided) 95%; -78.67 to -42.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 9.1796
	Estimation Comments

5. Secondary Outcome

Title	Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized Participants
Description	Therapeutic glycemic response was defined as HbA1c less than 7.0%. n=Number of participants with HBA1c less than (<) 7 % at Week 24, last observation carried forward (LOCF) while N=number of randomized participants with non-missing baseline and Week 24 (LOCF) values. Percent=n/N and was adjusted for Baseline HbA1c. Data after rescue medication (metformin) was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

N=number of randomized participants with non-missing baseline and Week 24 (LOCF) values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	72	66
Number [Adjusted Percentage of participants]	34.6 50.9%	53.6 74.4%	43.4 58.6%	49.1 72.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 1mg
	Comments	The probability of response was modeled using a logistic regression model with baseline HbA1c as the covariate. Treatment group estimates of response rate were then obtained by integrating each group's modeled probability of response over the observed distribution of baseline covariate (combined across groups).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0157
	Comments	Test was performed at alpha=0.05.
	Method	Regression, Logistic
	Comments	Logistic regression based on the methodology of Zhang, Tsiatis and Davidian and Tsiatis, Davidian, Zhang and Lu, with adjustment for baseline HbA1c.
Method of Estimation	Estimation Parameter	percent difference
	Estimated Value	18.9
	Confidence Interval	(2-Sided) 95%; 3.6 to 34.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.380
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 2.5 mg
	Comments	The probability of response was modeled using a logistic regression model with baseline HbA1c as the covariate. Treatment group estimates of response rate were then obtained by integrating each group's modeled probability of response over the observed distribution of baseline covariate (combined across groups).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2512
	Comments	Test was performed at alpha=0.05.
	Method	Regression, Logistic
	Comments	Logistic regression based on the methodology of Zhang, Tsiatis and Davidian and Tsiatis, Davidian, Zhang and Lu, with adjustment for baseline HbA1c
Method of Estimation	Estimation Parameter	Percent Difference
	Estimated Value	8.8
	Confidence Interval	(2-Sided) 95%; -6.2 to 23.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 7.650
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 5 mg
	Comments	The probability of response was modeled using a logistic regression model with baseline HbA1c as the covariate. Treatment group estimates of response rate were then obtained by integrating each group's modeled probability of response over the observed distribution of baseline covariate (combined across groups).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0726
	Comments	Test was performed at alpha=0.05.
	Method	Regression, Logistic
	Comments	Logistic regression based on the methodology of Zhang, Tsiatis and Davidian and Tsiatis, Davidian, Zhang and Lu, with adjustment for baseline HbA1c
Method of Estimation	Estimation Parameter	Percent Difference
	Estimated Value	14.5
	Confidence Interval	(2-Sided) 95%; -1.3 to 30.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 8.069
	Estimation Comments

6. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Waist Circumference at Week 24 (LOCF) - Randomization Participants
Description	Adjusted mean waist circumference values from baseline to Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, last observation carried forward, (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. Waist circumference was measured centimeters (cm) and obtained at lead-in, Day 1, and Week 24 of the double-blind period. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

Number of randomized participants, who took at least 1 dose of double-blind study medication, with non missing baseline and Week 24 (LOCF) values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	66	70	65	61
Mean (Standard Error) [cm]	-1.70 (0.5718)	-2.50 (0.5540)	-2.31 (0.5775)	-3.17 (0.5933)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 1mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3163
	Comments	Test was performed at alpha=0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.80
	Confidence Interval	(2-Sided) 95%; -2.37 to 0.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7954
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 2.5 mg
	Comments	Following a sequential testing procedure, this comparison was not statistically tested, ie, the previous comparison did not meet the criterion for statistical significance.
	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	-0.61
	Confidence Interval	(2-Sided) 95%; -2.22 to 0.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8154
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Dapagliflozin 5 mg
	Comments	Following a sequential testing procedure, this comparison was not statistically tested, ie, the previous comparison did not meet the criterion for statistical significance.
	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	-1.47
	Confidence Interval	(2-Sided) 95%; -3.09 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.8238
	Estimation Comments

7. Secondary Outcome

Title	Number of Participants With Deaths, Serious AEs (SAEs), Adverse Events (AEs), Discontinuation Due to AEs, During the 12 Week Double Blind Period, Including Data After Rescue - All Treated Participants
Description	Medical Dictionary for Regulatory Activities (MedDRA), version 12.1 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. Treatment-related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Baseline to last dose plus 4 days for AEs, plus 30 days for SAEs. Data after rescue included.
Time Frame	Day 1 of Double Blind Period to end of Week 24 Plus 30 days

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of double-blind study medication during the double-blind treatment period. Data after rescue were also included.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	74	68
Death	0 0%	0 0%	0 0%	0 0%
Serious Adverse Event (SAE)	0 0%	2 2.8%	2 2.7%	0 0%
Related SAE	0 0%	2 2.8%	0 0%	0 0%
Adverse Event (AE)	41 60.3%	42 58.3%	43 58.1%	39 57.4%
Related Adverse Event	8 11.8%	5 6.9%	9 12.2%	5 7.4%
Discontinued due to AE	0 0%	1 1.4%	1 1.4%	0 0%

8. Secondary Outcome

Title	Number of Participants With Adverse Events of Special Interest During the 12 Week Double Blind Period - All Treated Participants
Description	Participants with AEs of hypoglycemia, cardiac/vascular disorders, renal impairment or failure, volume depletion (hypotension/dehydration/hypovolemia), fractures, urinary stones, and other reports suggestive of genital infection or urinary tract infection (UTI) were summarized using MedDRA version 12.1. Data after rescue included for all AEs of special interest except hypoglycemia; hypoglycemia AEs were prior to rescue. Major hypoglycemic episode: symptomatic requiring 3rd party assistance due to severe impairment in consciousness or behavior with a glucose value < 54 mg/dL and prompt recovery after glucose/glucagon; Minor: either symptomatic with glucose measurement < 63 mg/dL, regardless of need for 3rd party assistance, or asymptomatic with glucose < 63 mg/dL that does not qualify as major; Other: suggestive but not meeting criteria for major or minor.
Time Frame	Baseline to last dose plus 4 days in 12 Week Double Blind Period

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least one dose of study medication in the double-blind period. Data after rescue included for all AEs of special interest except hypoglycemia; hypoglycemia AEs summarized below were prior to rescue.

Arm/Group Title	Placebo	1mg Dapagliflozin	2.5 mg Dapagliflozin	5 mg Dapagliflozin
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	74	68
Cardiac Disorders AEs	0 0%	0 0%	4 5.4%	0 0%
Vascular Disorders AEs	4 5.9%	1 1.4%	2 2.7%	1 1.5%
Hypoglycemia AEs (excluding data after rescue)	0 0%	0 0%	1 1.4%	1 1.5%
Major hypoglycemic episode	0 0%	0 0%	0 0%	0 0%
Minor hypoglycemic episode	0 0%	0 0%	0 0%	0 0%
Other hypoglycemic episode	0 0%	0 0%	1 1.4%	1 1.5%
AE Suggestive of Genital Infection	2 2.9%	1 1.4%	5 6.8%	2 2.9%
AE Suggestive of UTI	1 1.5%	3 4.2%	1 1.4%	2 2.9%
AE of Renal Impairment (creatinine increased)	2 2.9%	0 0%	0 0%	0 0%
AE of Hypotension	0 0%	0 0%	0 0%	1 1.5%
AE of Fracture	3 4.4%	0 0%	0 0%	0 0%
AE of Urinary Stones	1 1.5%	0 0%	1 1.4%	0 0%

9. Secondary Outcome

Title	Mean Change From Baseline in Seated Systolic and Diastolic Blood Pressure at Week 24, Including Data After Rescue - Treated Participants
Description	Blood pressure values were obtained on Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double blind period, after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Blood pressure was measured in millimeters of mercury (mmHg). Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

Participants who took at least 1 dose of double-blind study medication were analyzed. n= number of treated participants with non-missing baseline and Week 24 values.

Arm/Group Title	Placebo	Dapagliflozin 1mg	Dapagliflozin 2.5 mg	Dapagliflozin 5 mg
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	65	68	65	62
Systolic Blood Pressure (n=65, 68, 65, 62)	0.8 (1.462)	-3.7 (1.449)	-3.1 (1.603)	-4.6 (1.531)
Diastolic Blood Pressure (n=65, 68, 65, 62)	0.2 (0.981)	-1.1 (1.040)	-2.0 (0.980)	-1.9 (1.036)

10. Secondary Outcome

Title	Mean Change From Baseline in Seated Heart Rate at Week 24 - Treated Participants
Description	Heart rate values were obtained after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Heart rate was measured in beats per minute (bpm). Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication.
Time Frame	Baseline (Day 1), Week 24

Outcome Measure Data

Analysis Population Description

N=number of participants who took at least 1 dose of double-blind study medication, with non missing baseline and Week 24 values.

Arm/Group Title	Placebo	1mg Dapagliflozin	2.5 mg Dapagliflozin	5 mg Dapagliflozin
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	65	68	65	62
Mean (Standard Error) [bpm]	-1.3 (1.178)	-2.0 (0.882)	-1.6 (0.845)	-1.4 (1.080)

11. Secondary Outcome

Title	Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Treated Participants
Description	12-Lead electrocardiograms (ECGs) were performed at Day -14 and Week 24/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator. Baseline (BL) was Day -14 for this parameter.
Time Frame	Week 24

Outcome Measure Data

Analysis Population Description

N= Number of randomized participants, who took at least 1 dose of double-blind study medication, with non missing baseline (BL) and Week 24 (LOCF) values.

Arm/Group Title	Placebo	1mg Dapagliflozin	2.5 mg Dapagliflozin	5 mg Dapagliflozin
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	74	68
Normal at BL, Normal at Week 24 (N=68, 72, 74, 68)	34 50%	38 52.8%	43 58.1%	38 55.9%
Abnormal BL, Normal at Week 24(N=68, 72, 74, 68)	10 14.7%	5 6.9%	4 5.4%	7 10.3%
Normal BL, Abnormal at Week 24(N=68, 72, 74, 68)	4 5.9%	3 4.2%	4 5.4%	1 1.5%
Abnormal BL, Abnormal at Week 24(N=68, 72, 74, 68)	16 23.5%	23 31.9%	14 18.9%	16 23.5%
Reported at BL, Not Reported at Week 24	4 5.9%	3 4.2%	9 12.2%	6 8.8%

12. Secondary Outcome

Title	Number of Participants With Marked Laboratory Abnormalities in 24 Week Double Blind Treatment Period - Treated Participants
Description	Safety laboratory measurements were obtained at Day 1, Weeks 1, 2, 4, 8, 12, 20, and 24 in the double blind Period. Baseline was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from baseline up to and including the last day of treatment plus 4 days. Data after rescue was also included. Abbreviations; 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), alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP); blood urea nitrogen (BUN). Marked abnormality Low (High) defined: hemoglobin <6 (>18 females or >20 males) g/dL; hematocrit <20% ( >55% females or >60% males); BUN (>60 mg/dL) or Urea >21.4 mmol/L; creatinine (>=1.5*preRX, >=2.5 mg/dL); AST and ALT >3*ULN; bilirubin >1.5*ULN; ALP >1.5*ULN.
Time Frame	Baseline to Week 24/end of treatment plus 4 days

Outcome Measure Data

Analysis Population Description

N=Number of participants who received at least 1 dose of study medication and had non-missing laboratory results.

Arm/Group Title	Placebo	1mg Dapagliflozin	2.5 mg Dapagliflozin	5 mg Dapagliflozin
Arm/Group Description	Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.	5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
Measure Participants	68	72	74	67
Hematocrit High >55% (N=68, 72, 74, 67)	0 0%	0 0%	1 1.4%	0 0%
Hemoglobin High >18 g/dL(N=68, 72, 74, 67)	1 1.5%	1 1.4%	1 1.4%	1 1.5%
Creatinine High >=1.5*PreRX(N=68, 72, 74, 67)	2 2.9%	1 1.4%	1 1.4%	4 5.9%
AST 3*ULN (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
ALT 3*ULN (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
ALT 5*ULN (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
AST or ALT >3*ULN (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
AST or ALT >5*ULN (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
Total bilirubin >1.5*ULN (N=68, 72, 74, 67)	2 2.9%	0 0%	1 1.4%	0 0%
Total bilirubin >2*ULN (N=68, 72, 74, 67)	1 1.5%	0 0%	0 0%	0 0%
ALP >1.5*ULN (N=68, 72, 74, 67)	1 1.5%	3 4.2%	1 1.4%	1 1.5%
ALP >3*ULN (N=68, 72, 74, 67)	1 1.5%	0 0%	0 0%	0 0%
Glucose >350 mg/dL (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
Creatinine Kinase > 5X ULN (N=68, 72, 74, 67)	0 0%	3 4.2%	0 0%	0 0%
Calcium <7.5 mg/dL (N=68, 72, 74, 67)	1 1.5%	2 2.8%	0 0%	0 0%
Calcium (mg/dL) >=1 vs ULN and >=0.5 vs baseline	1 1.5%	0 0%	0 0%	0 0%
Potassium >= 6 meq/L (N=68, 72, 74, 67)	0 0%	0 0%	2 2.7%	1 1.5%
Magnesium <1 meq/L (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
Sodium <130 meq/L (N=68, 72, 74, 67)	1 1.5%	1 1.4%	0 0%	0 0%
Sodium >150 meq/L (N=68, 72, 74, 67)	0 0%	0 0%	1 1.4%	0 0%
Sodium < 120 meq/L	1 1.5%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	24 Weeks plus 30 days; Day 1 of double blind treatment to last patient, last visit.
Arm/Group Title	Dapagliflozin 1mg		Dapagliflozin 2.5 mg		Dapagliflozin 5 mg		Placebo
Arm/Group Description	1 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.		2.5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.		5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.		Placebo tablets matching either 1 mg, 2.5 mg, or 5 mg dapagliflozin tablets were taken orally once daily (with morning meal) for 24 weeks during the Double Blind Treatment Period.
All Cause Mortality
	Dapagliflozin 1mg		Dapagliflozin 2.5 mg		Dapagliflozin 5 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dapagliflozin 1mg		Dapagliflozin 2.5 mg		Dapagliflozin 5 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/72 (2.8%)		2/74 (2.7%)		0/68 (0%)		0/68 (0%)
Infections and infestations
Pneumonia	0/72 (0%)		1/74 (1.4%)		0/68 (0%)		0/68 (0%)
Tuberculosis	1/72 (1.4%)		0/74 (0%)		0/68 (0%)		0/68 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	0/72 (0%)		1/74 (1.4%)		0/68 (0%)		0/68 (0%)
Nervous system disorders
Convulsion	1/72 (1.4%)		0/74 (0%)		0/68 (0%)		0/68 (0%)
Other (Not Including Serious) Adverse Events
	Dapagliflozin 1mg		Dapagliflozin 2.5 mg		Dapagliflozin 5 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/72 (19.4%)		14/74 (18.9%)		7/68 (10.3%)		18/68 (26.5%)
Infections and infestations
Pharyngitis	1/72 (1.4%)		4/74 (5.4%)		2/68 (2.9%)		3/68 (4.4%)
Nasopharyngitis	5/72 (6.9%)		1/74 (1.4%)		2/68 (2.9%)		3/68 (4.4%)
Metabolism and nutrition disorders
Hypercholesterolaemia	0/72 (0%)		0/74 (0%)		1/68 (1.5%)		4/68 (5.9%)
Hypertriglyceridaemia	2/72 (2.8%)		1/74 (1.4%)		1/68 (1.5%)		4/68 (5.9%)
Nervous system disorders
Headache	5/72 (6.9%)		4/74 (5.4%)		2/68 (2.9%)		5/68 (7.4%)
Dizziness	3/72 (4.2%)		5/74 (6.8%)		0/68 (0%)		2/68 (2.9%)

Limitations/Caveats

[Not Specified]

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.