Bexagliflozin Efficacy and Safety Trial (BEST)

• ClinicalTrials.gov Identifier: NCT02558296
• Recruitment Status: Completed
• First Posted: September 23, 2015
• Results First Posted: July 7, 2021
• Last Update Posted: July 14, 2021
• Sponsor: Theracos
• Information provided by (Responsible Party): Theracos

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Type 2 Diabetes Mellitus
• Interventions: Drug: Bexagliflozin; Drug: Placebo
• Enrollment: 1700

Participant Flow

Recruitment Details	A total of 1700 patients were recruited from 10 countries: Canada, Czech Republic, Demark, Republic of Korea, Mexico, the Netherlands, Poland, Russian Federation, Taiwan, and the United States.
Pre-assignment Details	Subjects ≥ 40 years old with inadequately controlled T2DM with HbA1c between 7.5% (7.0% since protocol version 8) and 11% on stable medications and elevated risk for CV adverse events were enrolled. All subjects must belong to 1 of 3 CV risk groups to be eligible. All eligible subjects took placebo during 13 ± 2 days run-in period.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Period Title: Completed the Study Through Week 24
Started	1133	567
Completed	1089	542
Not Completed	44	25
Reason Not Completed
Adverse Event	9	3
Death	7	7
Lost to Follow-up	8	1
Physician Decision	1	0
Protocol Violation	1	1
Withdrawal by Subject	17	13
The subject was randomized, but did not take any investigational product	1	0
Period Title: Completed the Study
Started [1]	1133	567
Completed	987	482
Not Completed	146	85
Reason Not Completed
Adverse Event	14	5
Death	39	25
Lost to Follow-up	31	23
Physician Decision	6	0
Protocol Violation	2	1
Withdrawal by Subject	53	31
The subject was randomized, but did not take any investigational product	1	0
[1] The number of participants started is equal to ITT population

Baseline Characteristics

Arm/Group Title		Bexagliflozin Tablets, 20 mg	Placebo Tablets	Total
Arm/Group Description		Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator	Total of all reporting groups
Overall Number of Baseline Participants		1133	567	1700
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	562 49.6%	276 48.7%	838 49.3%
	>=65 years	571 50.4%	291 51.3%	862 50.7%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	1133 participants	567 participants	1700 participants
		64.4 (7.94)	64.6 (8.01)	64.4 (7.96)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	Female	341 30.1%	177 31.2%	518 30.5%
	Male	792 69.9%	390 68.8%	1182 69.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	Hispanic or Latino	166 14.7%	93 16.4%	259 15.2%
	Not Hispanic or Latino	967 85.3%	474 83.6%	1441 84.8%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	American Indian or Alaska Native	98 8.6%	54 9.5%	152 8.9%
	Asian	108 9.5%	55 9.7%	163 9.6%
	Native Hawaiian or Other Pacific Islander	2 0.2%	0 0.0%	2 0.1%
	Black or African American	46 4.1%	28 4.9%	74 4.4%
	White	879 77.6%	430 75.8%	1309 77.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	1133 participants	567 participants	1700 participants
Canada		67	24	91
Netherlands		36	18	54
South Korea		48	26	74
United States		397	205	602
Czechia		118	52	170
Taiwan		46	20	66
Denmark		17	10	27
Poland		196	97	293
Mexico		121	62	183
Russia		87	53	140
Cardiovascular Risk Groups [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	Group 1: History of atherosclerotic vascular disease	703 62.0%	362 63.8%	1065 62.6%
	Group 2: History of heart failure	166 14.7%	80 14.1%	246 14.5%
	Group 3: Age >= 55 years with > 2 risk factors	264 23.3%	125 22.0%	389 22.9%
		[1] Measure Description: 1: History of atherosclerotic vascular disease with > 1 of the following: i) MI/ischemic stroke > 3 months but < 5 years prior to screening ii) Documented history of coronary, carotid or peripheral arterial revascularization (CABG must have occurred > 5 years prior to screening) 2: History of heart failure 3: Age >= 55 with > 2 of the following: i) Diabetes duration of > 10 years ii) Uncontrolled hypertension defined as SBP > 140 mmHg despite > 3 anti-hypertensive medications iii) current smoker iv) Urine albumin: creatinine ratio > 30 mg/g v) eGFR 45-60 mL/min/1.73 m2 vi) HDL < 1 mmol/L
Body Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	1133 participants	567 participants	1700 participants
		94.59 (21.87)	92.62 (19.999)	93.94 (20.745)
Body Mass Index; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	1133 participants	567 participants	1700 participants
		32.80 (6.068)	32.24 (5.751)	32.62 (5.968)
Body Mass Index Categories; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	BMI < 25 kg/m^2	86 7.6%	45 7.9%	131 7.7%
	BMI >= 25 kg/m^2	1047 92.4%	522 92.1%	1569 92.3%
Systolic Blood Pressure; Mean (Standard Deviation); Unit of measure: mmHg
	Number Analyzed	1133 participants	567 participants	1700 participants
		134.2 (16.24)	133.7 (16.18)	134.0 (16.21)
Systolic Blood Pressure Groups; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	< 140 mmHg	685 60.5%	352 62.1%	1037 61.0%
	>= 140 mmHg	448 39.5%	215 37.9%	663 39.0%
Diastolic Blood Pressure; Mean (Standard Deviation); Unit of measure: mmHg
	Number Analyzed	1133 participants	567 participants	1700 participants
		77.1 (9.94)	76.8 (10.16)	77.0 (10.01)
eGFR at Screening; Mean (Standard Deviation); Unit of measure: mL/min/1.73 m^2
	Number Analyzed	1133 participants	567 participants	1700 participants
		77.93 (19.475)	77.76 (19.653)	77.88 (19.529)
eGFR group; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	< 60 mL/min/1.73 m^2	225 19.9%	109 19.2%	334 19.6%
	>= 60 mL/min/1.73 m^2	908 80.1%	458 80.8%	1366 80.4%
HbA1c; Mean (Standard Deviation); Unit of measure: % of HbA1c
	Number Analyzed	1133 participants	567 participants	1700 participants
		8.32 (0.897)	8.33 (0.944)	8.32 (0.913)
HbA1c group; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	<= 8.5%	716 63.2%	362 63.8%	1078 63.4%
	> 8.5%	417 36.8%	205 36.2%	622 36.6%
Duration of Diabetes from Diagnosis to the date of informed consent; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	1133 participants	567 participants	1700 participants
		14.87 (8.635)	15.23 (9.253)	14.99 (8.845)
Insulin Use at Baseline; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	Yes	610 53.8%	292 51.5%	902 53.1%
	No	523 46.2%	275 48.5%	798 46.9%
Use of Anti-Diabetic Treatment at Baseline; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1133 participants	567 participants	1700 participants
	Yes	1125 99.3%	564 99.5%	1689 99.4%
	No	8 0.7%	3 0.5%	11 0.6%
NT-proBNP; Mean (Standard Deviation); Unit of measure: pmol/L
	Number Analyzed	1133 participants	567 participants	1700 participants
		391.9 (760.75)	264.0 (427.15)	346.1 (661.93)
Left Ventricular Ejection Fraction; Mean (Standard Deviation); Unit of measure: % of Left Ventricular Ejection Fraction
	Number Analyzed	1133 participants	567 participants	1700 participants
		49.2 (14.13)	50.8 (12.95)	49.8 (13.74)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 24
Description	The primary efficacy objective of this trial is to evaluate the placebo-adjusted change in HbA1c from baseline after 24 weeks of treatment with 20 mg bexagliflozin tablets in type 2 diabetic subjects with increased risk of cardiovascular adverse events.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Number of subjects with a value at baseline and at Week 24.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	1046	531
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage of glycated hemoglobin
	-0.85; (-0.90 to -0.80)	-0.37; (-0.44 to -0.30)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the primary endpoint was that the mean change in HbA1c from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 24 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.39
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline in HbA1c at Week 24 for Subjects Who Have Been Prescribed Insulin
Description	To evaluate the effect of 20 mg bexagliflozin on the change in HbA1c from baseline to week 24 in randomized subjects who have been prescribed insulin to control their diabetes
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Number of subjects with a value at baseline and at week 24.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	561	273
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percentage of HbA1c
	-0.84; (-0.92 to -0.77)	-0.32; (-0.43 to -0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the secondary endpoint was that the mean change in HbA1c from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 24 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories, history of heart failure, treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.65 to -0.40
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change in Body Weight From Baseline to Week 48
Description	To evaluate the effect of 20 mg bexagliflozin on the change in body weight from baseline to week 48 in randomized subjects with a BMI ≥ 25 kg/m2 compared to placebo
Time Frame	48 weeks

Outcome Measure Data

Analysis Population Description

Number of subjects with a value at baseline and at Week 48 is included.

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	922	456
Least Squares Mean (95% Confidence Interval); Unit of Measure: kg
	-3.03; (-3.27 to -2.80)	-0.38; (-0.72 to -0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the secondary endpoint was that the mean change in body weight from baseline to Week 48 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in body weight from baseline to Week 48 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is presented based on one-sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline HbA1c and eGFR, history of heart failure, insulin use (Y/N), treatment, visit and baseline body weight as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.65
	Confidence Interval	(2-Sided) 95%; -3.07 to -2.24
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change in Systolic Blood Pressure From Baseline to Week 24 in Subjects Hypertensive at Baseline
Description	To evaluate the effect of 20 mg bexagliflozin on the change in systolic blood pressure (SBP) from baseline to week 24 in subjects with baseline systolic blood pressure ≥ 140 mmHg compared to placebo
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

Number of subjects with a value at baseline and at week 24

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	417	204
Least Squares Mean (95% Confidence Interval); Unit of Measure: mm Hg
	-9.83; (-11.28 to -8.38)	-6.87; (-8.95 to -4.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the secondary endpoint was that the mean change in systolic blood pressure from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in systolic blood pressure from baseline to Week 24 was less than the mean change in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	0.0112
	Comments	P-value is presented based on one-sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline HbA1c, GFR categories, BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline SBP as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.96
	Confidence Interval	(2-Sided) 95%; -5.51 to -0.42
	Estimation Comments	[Not Specified]

5. Other Pre-specified Outcome

Title	Change in HbA1c From Baseline Over Time
Description	To assess the effect of 20 mg bexagliflozin treatment on the change in HbA1c from baseline versus placebo over time up to 168 weeks
Time Frame	Baseline (week 0) and weeks 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168

Outcome Measure Data

Analysis Population Description

Number of subjects with a value at baseline and at the specified visit.

Arm/Group Title		Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:		Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed		1133	567
Least Squares Mean (95% Confidence Interval); Unit of Measure: Percentage of HbA1c
Week 6	Number Analyzed	1111 participants	553 participants
		-0.69; (-0.72 to -0.65)	-0.24; (-0.28 to -0.19)
Week 12	Number Analyzed	1075 participants	544 participants
		-0.89; (-0.94 to -0.85)	-0.34; (-0.39 to -0.28)
Week 24	Number Analyzed	1046 participants	531 participants
		-0.84; (-0.89 to -0.79)	-0.37; (-0.45 to -0.30)
Week 36	Number Analyzed	1017 participants	511 participants
		-0.86; (-0.92 to -0.81)	-0.39; (-0.47 to -0.32)
Week 48	Number Analyzed	992 participants	496 participants
		-0.84; (-0.90 to -0.79)	-0.38; (-0.46 to -0.30)
Week 72	Number Analyzed	965 participants	469 participants
		-0.76; (-0.83 to -0.70)	-0.34; (-0.44 to -0.25)
Week 96	Number Analyzed	874 participants	426 participants
		-0.68; (-0.75 to -0.62)	-0.29; (-0.39 to -0.20)
Week 120	Number Analyzed	768 participants	364 participants
		-0.65; (-0.73 to -0.58)	-0.22; (-0.33 to -0.11)
Week 144	Number Analyzed	445 participants	196 participants
		-0.62; (-0.71 to -0.53)	-0.23; (-0.37 to -0.10)
Week 168	Number Analyzed	218 participants	99 participants
		-0.56; (-0.67 to -0.45)	-0.29; (-0.46 to -0.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 6 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Superiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 6 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95%; -0.50 to -0.39
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 12 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 12 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -0.63 to -0.49
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 24 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.38
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 36 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 36 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.38
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 48 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 48 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.37
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 72 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 72 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.31
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 96 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 96 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.27
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 120 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 120 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.30
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 144 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 144 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.23
	Estimation Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in HbA1c from baseline to Week 168 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline HbA1c from baseline to Week 168 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	0.0045
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories and BMI, history of heart failure, insulin use (Y/N), treatment, visit and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.47 to -0.07
	Estimation Comments	[Not Specified]

6. Other Pre-specified Outcome

Title	Change in Fasting Plasma Glucose Over Time
Description	To evaluate the effect of bexagliflozin treatment on the change in fasting plasma glucose (FPG) versus placebo over time up to 168 weeks
Time Frame	Baseline (week 0) and weeks 6, 12, 24, 36, 48, 72, 96, 120, 144 and 168

Outcome Measure Data

Analysis Population Description

Number of subjects with a value at baseline and at the specified visit.

Arm/Group Title		Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:		Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed		1133	567
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmol/L
Week 6	Number Analyzed	1107 participants	552 participants
		-1.28; (-1.40 to -1.16)	0.07; (-0.10 to 0.24)
Week 12	Number Analyzed	1078 participants	545 participants
		-1.33; (-1.46 to -1.21)	0.06; (-0.12 to 0.23)
Week 24	Number Analyzed	1045 participants	530 participants
		-1.43; (-1.56 to -1.30)	-0.05; (-0.23 to 0.13)
Week 36	Number Analyzed	1016 participants	513 participants
		-1.21; (-1.36 to -1.06)	-0.06; (-0.27 to 0.15)
Week 48	Number Analyzed	996 participants	494 participants
		-1.36; (-1.50 to -1.21)	-0.12; (-0.33 to 0.08)
Week 72	Number Analyzed	966 participants	469 participants
		-1.14; (-1.30 to -0.98)	-0.15; (-0.38 to 0.07)
Week 96	Number Analyzed	873 participants	425 participants
		-1.16; (-1.32 to -0.99)	0.04; (-0.20 to 0.29)
Week 120	Number Analyzed	765 participants	365 participants
		-0.90; (-1.09 to -0.71)	0.25; (-0.02 to 0.53)
Week 144	Number Analyzed	445 participants	195 participants
		-1.03; (-1.24 to -0.81)	-0.40; (-0.72 to -0.08)
Week 168	Number Analyzed	218 participants	101 participants
		-1.06; (-1.39 to -0.73)	-0.55; (-1.04 to -0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 6 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 6 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.35
	Confidence Interval	(2-Sided) 95%; -1.55 to -1.15
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 12 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 12 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -1.61 to -1.18
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 24 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 24 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -1.61 to -1.16
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 36 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 36 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95%; -1.41 to -0.89
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 48 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 48 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95%; -1.48 to -0.98
	Estimation Comments	[Not Specified]

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 72 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 72 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.99
	Confidence Interval	(2-Sided) 95%; -1.27 to -0.72
	Estimation Comments	[Not Specified]

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 96 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 96 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.20
	Confidence Interval	(2-Sided) 95%; -1.50 to -0.90
	Estimation Comments	[Not Specified]

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 120 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 120 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.15
	Confidence Interval	(2-Sided) 95%; -1.49 to -0.82
	Estimation Comments	[Not Specified]

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 144 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 144 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	0.0008
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.24
	Estimation Comments	[Not Specified]

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	The null hypothesis for the exploratory endpoint was that the mean change in FPG from baseline to Week 168 in the bexagliflozin arm would be equal to or greater than the mean change in the placebo arm.
	Type of Statistical Test	Non-Inferiority
	Comments	Rejection of the null hypothesis would imply that the mean change in baseline FPG from baseline to Week 168 was less than that in the placebo arm by a value that could not be attributed to chance alone.
Statistical Test of Hypothesis	P-Value	0.0462
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Mixed-effects repeated measures
	Comments	Region, baseline eGFR categories & BMI, history of HF, insulin use, treatment, visit, hypoglycemic use and baseline FPG as fixed effect covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -1.09 to 0.08
	Estimation Comments	[Not Specified]

7. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring an Intensification of Hypoglycemic Agent and Time to First Intensification
Description	To measure the proportion of subjects requiring an intensification of hypoglycemic agent in the bexagliflozin arm versus placebo during 24 week period
Time Frame	24 week

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	1133	567
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of participants
	0.06; (0.05 to 0.08)	0.18; (0.15 to 0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.30
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.41
	Estimation Comments	Odds ratio is calculated as the odds ratio of bexagliflozin over placebo.

8. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring an Intensification of Hypoglycemic Agent and Time to First Intensification
Description	To measure the proportion of subjects requiring an intensification of hypoglycemic agent in the bexagliflozin arm versus placebo during the entire study period
Time Frame	Duration of study (168 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	1133	567
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of participants
	0.06; (0.05 to 0.08)	0.18; (0.15 to 0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.35 to 0.49
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for time to first event in the bexagliflozin arm vs. placebo arm during entire study.

9. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring a Relaxation of Hypoglycemic Agent
Description	To measure the proportion of subjects requiring a relaxation of hypoglycemic agent in the bexagliflozin arm versus placebo during 24 week period
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	1133	567
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of participants
	0.09; (0.08 to 0.11)	0.05; (0.03 to 0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.04
	Confidence Interval	(2-Sided) 95%; 1.33 to 3.11
	Estimation Comments	Odds ratio is calculated as the ratio of bexagliflozin over placebo.

10. Other Pre-specified Outcome

Title	Proportion of Subjects Requiring a Relaxation of Hypoglycemic Agent
Description	To measure the proportion of subjects requiring a relaxation of hypoglycemic agent in the bexagliflozin arm versus placebo during the entire study
Time Frame	Duration of study (168 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bexagliflozin Tablets, 20 mg	Placebo Tablets
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
Overall Number of Participants Analyzed	1133	567
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of participants
	0.09; (0.08 to 0.11)	0.05; (0.03 to 0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablets, 20 mg, Placebo Tablets
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95%; 1.40 to 2.38
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for time to first event in the bexagliflozin arm vs. placebo arm during the entire study.

11. Other Pre-specified Outcome

Title	Proportion of Participants With Incidence of Hospitalization for Heart Failure
Description	To measure the incidence of hospitalization for heart failure among all subjects and among subjects who have a history of heart failure at baseline
Time Frame	Duration of study (168 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Subjects: Bexagliflozin Tablets, 20 mg	All Subjects: Placebo Tablets	Subjects With HF History: Bexagliflozin Tablets, 20 mg	Subjects With HF History: Placebo
Arm/Group Description:	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet This group includes all subjects who have received bexagliflozin in the study.	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator This group includes all subjects who have received placebo in the study.	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet This group includes subjects who reported a history of heart failure and randomized to the bexagliflozin arm.	Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator This group includes subjects who reported a history of heart failure and randomized to the placebo arm.
Overall Number of Participants Analyzed	1133	567	302	151
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Proportion of participants
	0.01; (0.01 to 0.02)	0.02; (0.01 to 0.03)	0.05; (0.03 to 0.08)	0.09; (0.05 to 0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Subjects: Bexagliflozin Tablets, 20 mg, All Subjects: Placebo Tablets
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0803
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.33 to 1.20
	Estimation Comments	Odds ratio is calculated as the odds ratio of bexagliflozin over placebo.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Subjects With HF History: Bexagliflozin Tablets, 20 mg, Subjects With HF History: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0272
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Logistic
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.22 to 1.01
	Estimation Comments	Odds ratio is calculated as the odds ratio of bexagliflozin over placebo.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	All Subjects: Bexagliflozin Tablets, 20 mg, All Subjects: Placebo Tablets
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0757
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.34 to 1.18
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for treatment comparison vs. placebo.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Subjects With HF History: Bexagliflozin Tablets, 20 mg, Subjects With HF History: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0273
	Comments	P-value is based on one sided statistical tests using a 0.025 level of significance.
	Method	Regression, Cox
	Comments	Region, baseline eGFR categories & BMI, history of heart failure, insulin use (Y/N), treatment and baseline HbA1c as fixed effect covariate.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; 0.23 to 1.01
	Estimation Comments	Hazard ratio and p-value were estimated using Cox regression model for treatment comparison vs. placebo.

Adverse Events

Time Frame	Adverse event data were collected from the first dose to the last day of follow up (4 weeks after the End of Treatment visit, an average of 127 weeks)
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Bexagliflozin Tablets, 20 mg		Placebo Tablets
Arm/Group Description	Each subject will receive bexagliflozin 20 mg once daily for the duration of the study. Bexagliflozin: 20 mg, tablet		Each subject will receive placebo (inactive tablet) once daily for the duration of the study. Placebo: 20 mg tablet to match active comparator
All-Cause Mortality
	Bexagliflozin Tablets, 20 mg		Placebo Tablets
	Affected / at Risk (%)		Affected / at Risk (%)
Total	39/1132 (3.45%)		26/567 (4.59%)
Serious Adverse Events
	Bexagliflozin Tablets, 20 mg		Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	373/1132 (32.95%)		208/567 (36.68%)
Blood and lymphatic system disorders
Anaemia † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Thrombocytopenia † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Haemorrhagic anaemia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Iron deficiency anaemia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cardiac disorders
Angina unstable † 1	31/1132 (2.74%)	39	19/567 (3.35%)	22
Acute myocardial infarction † 1	31/1132 (2.74%)	33	14/567 (2.47%)	15
Cardiac failure congestive † 1	18/1132 (1.59%)	21	15/567 (2.65%)	21
Cardiac failure † 1	21/1132 (1.86%)	27	7/567 (1.23%)	9
Angina pectoris † 1	16/1132 (1.41%)	20	11/567 (1.94%)	12
Coronary artery disease † 1	21/1132 (1.86%)	21	6/567 (1.06%)	6
Atrial fibrillation † 1	15/1132 (1.33%)	21	9/567 (1.59%)	17
Myocardial infarction † 1	11/1132 (0.97%)	11	13/567 (2.29%)	13
Cardiac arrest † 1	12/1132 (1.06%)	12	2/567 (0.35%)	2
Cardiac failure chronic † 1	5/1132 (0.44%)	6	4/567 (0.71%)	4
Myocardial ischaemia † 1	8/1132 (0.71%)	8	1/567 (0.18%)	1
Ventricular tachycardia † 1	3/1132 (0.27%)	3	6/567 (1.06%)	7
Coronary artery occlusion † 1	3/1132 (0.27%)	3	3/567 (0.53%)	3
Atrial flutter † 1	3/1132 (0.27%)	3	2/567 (0.35%)	4
Coronary artery stenosis † 1	3/1132 (0.27%)	3	2/567 (0.35%)	2
Arrhythmia † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Cardiac disorder † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Cardio-respiratory arrest † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Cardiopulmonary arrest † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Sinus node dysfunction † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Acute coronary syndrome † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Aortic valve stenosis † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Bradycardia † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Congestive cardiomyopathy † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Tachycardia † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Ventricular arrhythmia † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Anginal equivalent † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Aortic valve disease † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Aortic valve incompetence † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Atrioventricular block † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cardiac asthma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cardiac failure acute † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Cardiogenic shock † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cardiomyopathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cardiorenal syndrome † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Heart valve incompetence † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Intracardiac thrombus † 1	1/1132 (0.09%)	3	0/567 (0.00%)	0
Ischaemic cardiomyopathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Left ventricular failure † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Mitral valve incompetence † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Pericardial effusion † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Sinus tachycardia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Ventricular fibrillation † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Congenital, familial and genetic disorders
Hydrocele † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Atrial septal defect † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Phimosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Ear and labyrinth disorders
Vertigo † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Vertigo positional † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Eye disorders
Cataract † 1	3/1132 (0.27%)	4	1/567 (0.18%)	1
Corneal lesion † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Glaucoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Keratopathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Lens dislocation † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Retinal vein thrombosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Gastrointestinal disorders
Gastrointestinal haemorrhage † 1	2/1132 (0.18%)	2	4/567 (0.71%)	4
Diarrhoea † 1	4/1132 (0.35%)	4	0/567 (0.00%)	0
Colitis † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Diverticulum † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Gastric ulcer † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Gastrooesophageal reflux disease † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Small intestinal obstruction † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Umbilical hernia † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Upper gastrointestinal haemorrhage † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Large intestine polyp † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Abdominal pain † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Abdominal pain upper † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Anal fistula † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Barret's oesophagus † 1	1/1132 (0.09%)	2	0/567 (0.00%)	0
Colitis ischaemic † 1	0/1132 (0.00%)	0	1/567 (0.18%)	2
Crohn's disease † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Duodenal ulcer haemorrhage † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Enterocutaneous fistula † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Fecal incontinence † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Gastric polyps † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Gastrointestinal polyp haemorrhage † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Hiatus hernia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Incarcerated inguinal hernia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Inguinal hernia † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Intra-abdominal haematoma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Mesenteric vein thrombosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pancreatitis acute † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Rectal perforation † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Rectal polyp † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Subileus † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
General disorders
Non-cardiac chest pain † 1	6/1132 (0.53%)	7	5/567 (0.88%)	5
Chest pain † 1	6/1132 (0.53%)	7	3/567 (0.53%)	3
Necrosis † 1	3/1132 (0.27%)	3	1/567 (0.18%)	1
Death † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Device malfunction † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Oedema peripheral † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Adverse drug reaction † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Asthenia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Chest discomfort † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Complication associated with device † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Impaired healing † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Medical device complication † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Sudden cardiac death † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hepatobiliary disorders
Cholecystitis † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Cholangitis † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Cholecystitis acute † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Cholelithiasis † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Bile duct stone † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cholangitis acute † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hepatic cirrhosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Infections and infestations
Pneumonia † 1	11/1132 (0.97%)	11	10/567 (1.76%)	10
Cellulitis † 1	9/1132 (0.80%)	11	2/567 (0.35%)	2
Osteomyelitis † 1	10/1132 (0.88%)	13	1/567 (0.18%)	1
Sepsis † 1	9/1132 (0.80%)	9	1/567 (0.18%)	1
Urinary tract infection † 1	6/1132 (0.53%)	6	3/567 (0.53%)	3
Gangrene † 1	4/1132 (0.35%)	5	3/567 (0.53%)	4
Diverticulitis † 1	3/1132 (0.27%)	3	3/567 (0.53%)	3
Appendicitis † 1	2/1132 (0.18%)	2	2/567 (0.35%)	2
Localised infection † 1	4/1132 (0.35%)	4	0/567 (0.00%)	0
Pyelonephritis † 1	3/1132 (0.27%)	3	1/567 (0.18%)	1
Endocarditis † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Influenza † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Septic shock † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Urosepsis † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Abdominal abscess † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Bacteraemia † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Erysipelas † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Gastroenteritis † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Gastroenteritis viral † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Wound infection † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Abdominal wall abscess † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Abscess limb † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Atypical pneumonia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Biliary tract infection † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Bronchitis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Bursitis infective † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Chronic sinusitis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Device related infection † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Diabetic foot infection † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Ear infection † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Emphysematous cholecystitis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Enterococcal bacteraemia † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Gas gangrene † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Gastroenteritis salmonella † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Hepatitis B † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Infected skin ulcer † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Medical device site joint infection † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Myelitis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Oesophageal candidiasis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Peritonitis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pneumonia legionella † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pneumonia streptococcal † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Postoperative wound infection † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Pyelonephritis acute † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Scrotal abscess † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Skin infection † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Subcutaneous abscess † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Viral infection † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Injury, poisoning and procedural complications
Contusion † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Femur fracture † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Hip fracture † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Patella fracture † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Concussion † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Foot fracture † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Joint injury † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Rib fracture † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Spinal fracture † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Anastomotic ulcer † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Compression fracture † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Craniocerebral injury † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Fall † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Fibula fracture † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Humerus fracture † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Laceration † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Ligament rupture † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Limb injury † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Lower limb fracture † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Meniscus injury † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pneumoconiosis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Post procedural complication † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Post procedural haemorrhage † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Procedural pain † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pulmonary contusion † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Seroma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Subdural haematoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Subdural haemorrhage † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Vascular pseudoaneurysm † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Investigations
Troponin increased † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Blood creatinine increased † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Metabolism and nutrition disorders
Hypoglycaemia † 1	14/1132 (1.24%)	15	8/567 (1.41%)	10
Dehydration † 1	1/1132 (0.09%)	1	3/567 (0.53%)	3
Hyperkalaemia † 1	3/1132 (0.27%)	3	1/567 (0.18%)	1
Diabetic ketoacidosis † 1	0/1132 (0.00%)	0	3/567 (0.53%)	4
Gout † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Diabetes mellitus inadequate control † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Hyperglycaemia † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Hypokalaemia † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Metabolic acidosis † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Diabetic complication † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Latent autoimmune diabetes in adults † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Obesity † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis † 1	15/1132 (1.33%)	17	4/567 (0.71%)	4
Musculoskeletal chest pain † 1	2/1132 (0.18%)	2	2/567 (0.35%)	2
Arthritis † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Intervertebral disc protrusion † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Spinal column stenosis † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Lumbar spinal stenosis † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Musculoskeletal pain † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Arthralgia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Arthropathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Bursitis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cervical spinal stenosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Dupuytren's contracture † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Immunoglobulin G4 related sclerosing disease † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Intervertebral disc disorder † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Joint instability † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Muscle spasms † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Neuropathic arthropathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Osteochondrosis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Scoliosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Spinal osteoarthritis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Tenosynovitis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Pancreatic carcinoma † 1	0/1132 (0.00%)	0	3/567 (0.53%)	3
Prostate cancer † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Transitional cell carcinoma † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Invasive ductal breast carcinoma † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Lipoma † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Lung adenocarcinoma † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Lung neoplasm malignant † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Malignant melanoma † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Adenocarcinoma gastric † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Adenocarcinoma of colon † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Adenocarcinoma pancreas † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Adrenal adenoma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
B-cell lymphoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Biliary cancer metastatic † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Carcinoid tumour of the appendix † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cervix carcinoma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Colon cancer † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Colon cancer recurrent † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Colorectal adenocarcinoma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Endometrial adenocarcinoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Gastric adenoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hepatic neoplasm † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Hepatocellular carcinoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Invasive papillary breast carcinoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Malignant neoplasm of ampulla of Vater † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Metastatic renal cell carcinoma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Myelodysplastic syndrome † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Myeloproliferative disorder † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Non-small cell lung cancer † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Ovarian cancer † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Papillary cystadenoma lymphomatosum † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Pituitary tumour benign † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Polycythaemia vera † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Renal cancer † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Renal cancer metastatic † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Renal cell carcinoma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Squamous cell carcinoma of lung † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Uterine leiomyoma † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Nervous system disorders
Cerebrovascular accident † 1	15/1132 (1.33%)	15	7/567 (1.23%)	7
Ischaemic stroke † 1	10/1132 (0.88%)	11	4/567 (0.71%)	4
Transient ischaemic attack † 1	6/1132 (0.53%)	7	5/567 (0.88%)	6
Carotid artery stenosis † 1	7/1132 (0.62%)	9	3/567 (0.53%)	3
Syncope † 1	4/1132 (0.35%)	4	4/567 (0.71%)	4
Subarachnoid haemorrhage † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Carpal tunnel syndrome † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Cerebral infarction † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Dizziness † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Presyncope † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Sciatica † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Aphasia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Brain stem infarction † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Central nervous system haemorrhage † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Cerebral artery stenosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cerebral artery thrombosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cervical myelopathy † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Cervical radiculopathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Encephalopathy † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Epilepsy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Haemorrhage intracranial † 1	1/1132 (0.09%)	2	0/567 (0.00%)	0
Headache † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hemiparesis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hypoaesthesia † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Miller Fisher syndrome † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Myasthenia gravis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Neurological symptom † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Normal pressure hydrocephalus † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Paraesthesia † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Parkinson's disease † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Polyneuropathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Radiculopathy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Thalamic infarction † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Psychiatric disorders
Bipolar I disorder † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Delirium † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Suicidal ideation † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Suicide attempt † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Renal and urinary disorders
Acute kidney injury † 1	9/1132 (0.80%)	10	4/567 (0.71%)	4
Nephrolithiasis † 1	3/1132 (0.27%)	4	2/567 (0.35%)	2
Calculus ureteric † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Calculus urinary † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Chronic kidney disease † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Haematuria † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Obstructive uropathy † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Renal colic † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Urinary retention † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia † 1	3/1132 (0.27%)	3	1/567 (0.18%)	1
Erectile dysfunction † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Cervix disorder † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Oedema genital † 1	1/1132 (0.09%)	2	0/567 (0.00%)	0
Prostatism † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Prostatitis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Uterine prolapse † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	10/1132 (0.88%)	11	3/567 (0.53%)	6
Respiratory failure † 1	9/1132 (0.80%)	10	3/567 (0.53%)	4
Acute respiratory failure † 1	6/1132 (0.53%)	6	1/567 (0.18%)	1
Pleural effusion † 1	4/1132 (0.35%)	4	0/567 (0.00%)	0
Acute pulmonary edema † 1	2/1132 (0.18%)	2	0/567 (0.00%)	0
Pulmonary oedema † 1	0/1132 (0.00%)	0	2/567 (0.35%)	2
Aspiration † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Asthma † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Dyspnoea † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Epistaxis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Haemothorax † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hypoxia † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Lung disorder † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Nasal polyps † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pleurisy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Pneumothorax † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Respiratory distress † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Sleep apnoea syndrome † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Vocal cord polyp † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Skin and subcutaneous tissue disorders
Skin ulcer † 1	2/1132 (0.18%)	2	3/567 (0.53%)	6
Diabetic foot † 1	3/1132 (0.27%)	3	1/567 (0.18%)	1
Dermatitis contact † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Excessive granulation tissue † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Surgical and medical procedures
Cardiac pacemaker battery replacement † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Cardiac pacemaker replacement † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Implantable defibrillator insertion † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Prophylaxis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Vitrectomy † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Vascular disorders
Peripheral ischaemia † 1	11/1132 (0.97%)	12	7/567 (1.23%)	8
Peripheral arterial occlusive disease † 1	8/1132 (0.71%)	11	6/567 (1.06%)	8
Hypotension † 1	5/1132 (0.44%)	5	1/567 (0.18%)	1
Hypertension † 1	2/1132 (0.18%)	2	2/567 (0.35%)	2
Orthostatic hypotension † 1	3/1132 (0.27%)	3	1/567 (0.18%)	1
Arteriosclerosis † 1	2/1132 (0.18%)	2	1/567 (0.18%)	1
Femoral artery occlusion † 1	3/1132 (0.27%)	3	0/567 (0.00%)	0
Hypertensive crisis † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Intermittent claudication † 1	1/1132 (0.09%)	3	2/567 (0.35%)	2
Peripheral vascular disorder † 1	1/1132 (0.09%)	1	2/567 (0.35%)	2
Deep vein thrombosis † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Peripheral artery stenosis † 1	2/1132 (0.18%)	3	0/567 (0.00%)	0
Peripheral artery thrombosis † 1	1/1132 (0.09%)	1	1/567 (0.18%)	1
Aortic stenosis † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Hypertensive emergency † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Iliac artery occlusion † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Leriche syndrome † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Lymphoedema † 1	0/1132 (0.00%)	0	1/567 (0.18%)	2
Necrosis ischaemic † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Subclavian vein thrombosis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
Varicose vein † 1	1/1132 (0.09%)	1	0/567 (0.00%)	0
Venous thrombosis † 1	0/1132 (0.00%)	0	1/567 (0.18%)	1
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Bexagliflozin Tablets, 20 mg		Placebo Tablets
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	739/1132 (65.28%)		386/567 (68.08%)
Gastrointestinal disorders
Diarrhoea † 1	72/1132 (6.36%)	90	31/567 (5.47%)	40
Nausea † 1	54/1132 (4.77%)	64	37/567 (6.53%)	45
Infections and infestations
Bronchitis † 1	52/1132 (4.59%)	65	34/567 (6.00%)	40
Nasopharyngitis † 1	96/1132 (8.48%)	115	39/567 (6.88%)	46
Upper respiratory tract infection † 1	112/1132 (9.89%)	147	53/567 (9.35%)	82
Urinary tract infection † 1	128/1132 (11.31%)	190	60/567 (10.58%)	96
Metabolism and nutrition disorders
Diabetes mellitus inadequate control † 1	49/1132 (4.33%)	53	29/567 (5.11%)	37
Hyperglycaemia † 1	68/1132 (6.01%)	181	41/567 (7.23%)	80
Hypoglycaemia † 1	475/1132 (41.96%)	3743	246/567 (43.39%)	1857
Musculoskeletal and connective tissue disorders
Arthralgia † 1	49/1132 (4.33%)	56	30/567 (5.29%)	37
Back pain † 1	66/1132 (5.83%)	72	33/567 (5.82%)	36
Vascular disorders
Hypertension † 1	45/1132 (3.98%)	46	36/567 (6.35%)	38
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Albert Collinson
• Organization: Theracos Sub, LLC
• Phone: (508) 630-2129
• EMail: acollinson@theracos.com

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT02558296
• Other Study ID Numbers: THR-1442-C-476
• First Submitted: September 22, 2015
• First Posted: September 23, 2015
• Results First Submitted: May 4, 2021
• Results First Posted: July 7, 2021
• Last Update Posted: July 14, 2021