Safety and Efficacy of Bexagliflozin Compared to Placebo as Add-on Therapy to Metformin in Type 2 Diabetes Subjects

• ClinicalTrials.gov Identifier: NCT03259789
• Recruitment Status: Completed
• First Posted: August 24, 2017
• Results First Posted: July 7, 2021
• Last Update Posted: July 7, 2021
• Sponsor: Theracos
• Information provided by (Responsible Party): Theracos

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Type2 Diabetes Mellitus
• Interventions: Drug: Bexagliflozin tablets, 20 mg; Drug: Bexagliflozin tablets, placebo
• Enrollment: 351

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo	High Glycemic Group
Arm/Group Description	Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive Bexagliflozin tablet, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Period Title: Overall Study
Started	158	159	34
Completed	141	142	28
Not Completed	17	17	6
Reason Not Completed
Adverse Event	3	2	1
Withdrawal by Subject	9	5	1
Lost to Follow-up	5	9	4
Physician Decision	0	1	0

Baseline Characteristics

Arm/Group Title		Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo	High Glycemic Group	Total
Arm/Group Description		Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Total of all reporting groups
Overall Number of Baseline Participants		158	159	34	351
Baseline Analysis Population Description		[Not Specified]
Age, Continuous [1] [2]; Mean (Standard Deviation); Unit of measure: Years
Double-blind Group	Number Analyzed	158 participants	159 participants	0 participants	317 participants
		56.0 (10.05)	55.6 (11.18)		55.8 (10.62)
High Glycemic Group	Number Analyzed	0 participants	0 participants	34 participants	34 participants
				52.1 (8.59)	52.1 (8.59)
		[1] Measure Description: Total number of participants for Double-blind group is 317. The number of participants for High Glycemic group is 34.; [2] Measure Analysis Population Description: For the Double-blind group, the High Glycemic group is excluded. Therefore, the number of participants analyzed is 317. Conversely, for the High Glycemic group, the Double-blind group is excluded. Therefore, the number of participants analyzed is 34.
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	158 participants	159 participants	34 participants	351 participants
	Female	58 36.7%	65 40.9%	15 44.1%	138 39.3%
	Male	100 63.3%	94 59.1%	19 55.9%	213 60.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	158 participants	159 participants	34 participants	351 participants
	Hispanic or Latino	35 22.2%	32 20.1%	9 26.5%	76 21.7%
	Not Hispanic or Latino	123 77.8%	127 79.9%	25 73.5%	275 78.3%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	158 participants	159 participants	34 participants	351 participants
	American Indian or Alaska Native	1 0.6%	1 0.6%	1 2.9%	3 0.9%
	Asian	78 49.4%	79 49.7%	9 26.5%	166 47.3%
	Native Hawaiian or Other Pacific Islander	1 0.6%	0 0.0%	1 2.9%	2 0.6%
	Black or African American	26 16.5%	29 18.2%	12 35.3%	67 19.1%
	White	51 32.3%	48 30.2%	11 32.4%	110 31.3%
	More than one race	1 0.6%	2 1.3%	0 0.0%	3 0.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	158 participants	159 participants	34 participants	351 participants
		83	83	27	193
Japan	Number Analyzed	158 participants	159 participants	34 participants	351 participants
		75	76	7	158
Height [1] [2]; Mean (Standard Deviation); Unit of measure: Cm
Double-blind Group	Number Analyzed	158 participants	159 participants	0 participants	317 participants
		168.4 (9.71)	167.3 (9.55)		167.8 (9.63)
High Glycemic Group	Number Analyzed	0 participants	0 participants	34 participants	34 participants
				169.4 (9.34)	169.4 (9.34)
		[1] Measure Description: Total number of participants for Double-blind group is 317. The number of subjects for High Glycemic group is 34.; [2] Measure Analysis Population Description: For the Double-blind group, the High Glycemic group is excluded. Therefore, the number of participants analyzed is 317. Conversely, for the High Glycemic group, the Double-blind group is excluded. Therefore, the number of participants analyzed is 34.
Body Weight [1] [2]; Mean (Standard Deviation); Unit of measure: Kg
Double-blind Group	Number Analyzed	158 participants	159 participants	0 participants	317 participants
		84.58 (21.989)	84.44 (20.928)		84.51 (21.43)
High Glycemic Group	Number Analyzed	0 participants	0 participants	34 participants	34 participants
				87.28 (17.759)	87.28 (17.759)
		[1] Measure Description: Total number of participants for Double-blind group is 317. The number of participants for High Glycemic group is 34.; [2] Measure Analysis Population Description: For the Double-blind group, the High Glycemic group is excluded. Therefore, the number of participants analyzed is 317. Conversely, for the High Glycemic group, the Double-blind group is excluded. Therefore, the number of participants analyzed is 34.
BMI [1] [2]; Mean (Standard Deviation); Unit of measure: Kg/m^2
Double-blind Group	Number Analyzed	158 participants	159 participants	0 participants	317 participants
		29.67 (6.45)	29.99 (6.342)		29.83 (6.388)
High Glycemic Group	Number Analyzed	0 participants	0 participants	34 participants	34 participants
				30.37 (5.558)	30.37 (5.558)
		[1] Measure Description: Total number of participants for Double-blind group is 317. The number of participants for High Glycemic group is 34.; [2] Measure Analysis Population Description: For the Double-blind group, the High Glycemic group is excluded. Therefore, the number of participants analyzed is 317. Conversely, for the High Glycemic group, the Double-blind group is excluded. Therefore, the number of participants analyzed is 34.

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in HbA1c at Week 24 for Double-blind Group
Description	HbA1c was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population was used for the primary analysis. Subjects with a value at baseline and at week 24 were analyzed.

Arm/Group Title	Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo
Arm/Group Description:	Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	142	145
Least Squares Mean (Standard Error); Unit of Measure: percentage of HbA1c
	-1.09 (0.076)	-0.56 (0.075)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Mixed-effects repeated measures
	Comments	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -0.74 to -0.32
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Change From Baseline in HbA1c at Week 24 for High Glycemic Group
Description	The change in HbA1c from baseline at Week 24 in High Glycemic Group was calculated by subtracting the mean HbA1c at baseline from the mean HbA1c at Week 24
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

The intention-to-treat (ITT) population was used for the primary analysis. Subjects with a value at baseline and at week 24 were analyzed.

Arm/Group Title	High Glycemic Group
Arm/Group Description:	Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: percentage of HbA1c
	-2.82 (1.084)

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for Double-blind Group
Description	FPG was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.
Time Frame	Baseline, up to 24 weeks

Outcome Measure Data

Analysis Population Description

ITT population was used for the analysis. Subjects with a value at baseline and at week 24 were analyzed.

Arm/Group Title	Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo
Arm/Group Description:	Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	142	145
Least Squares Mean (Standard Error); Unit of Measure: mmol/L
	-2.51 (0.174)	-1.16 (0.173)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Mixed-effects repeated measures
	Comments	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-1.35
	Confidence Interval	(2-Sided) 95%; -1.83 to -0.86
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for High Glycemic Group
Description	The change in FPG from baseline at Week 24 for High Glycemic Group was calculated by subtracting the mean FPG at baseline from the mean FPG at Week 24
Time Frame	Baseline, up to 24 weeks

Outcome Measure Data

Analysis Population Description

ITT population was used for the analysis. Subjects with a value at baseline and at week 24 were analyzed.

Arm/Group Title	High Glycemic Group
Arm/Group Description:	Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	29
Mean (Standard Deviation); Unit of Measure: mmol/L
	-4.98 (3.437)

5. Secondary Outcome

Title	Change From Baseline in Systolic Blood Pressure (SBP) at Week 24
Description	Changes from baseline at Week 24 in SBP for the double-blind group and high glycemic group
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

The ITT population was used for the analysis. Subjects with a value at baseline and at the specific visit were analyzed.

Arm/Group Title	Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo	High Glycemic Group
Arm/Group Description:	Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	143	145	29
Least Squares Mean (Standard Error); Unit of Measure: mm Hg
	-5.03 (0.993)	2.04 (0.987)	-8.19 (14.882)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	Mixed-effects repeated measures
	Comments	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-7.07
	Confidence Interval	(2-Sided) 95%; -9.83 to -4.32
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c < 7% Over Time for Double-blind Group
Description	The proportion of subjects who achieved HbA1c < 7% at 6, 12, 18 and 24 weeks were calculated based on the number of subjects with a value at each time point for each group. The model-adjusted proportion was calculated based on a logistic analysis using Generalized Estimating Equation (GEE) logistic regression that includes country, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as a fixed effect covariate. An unstructured correlation structure will be used, or autoregressive if the model with the unstructured structure does not converge.
Time Frame	Baseline, up to 24 weeks

Outcome Measure Data

Analysis Population Description

The number of subjects in the ITT population with a value at baseline and at the specified visit was included. Model-adjusted proportion (LS proportion) and 95% confidence interval were reported for Double-blind Treatment Group.

Arm/Group Title		Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo
Arm/Group Description:		Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed		158	159
Least Squares Mean (95% Confidence Interval); Unit of Measure: Proportion of subjects
Week 6	Number Analyzed	152 participants	152 participants
		0.14; (0.09 to 0.23)	0.03; (0.01 to 0.07)
Week 12	Number Analyzed	149 participants	146 participants
		0.26; (0.18 to 0.38)	0.06; (0.03 to 0.12)
Week 18	Number Analyzed	143 participants	144 participants
		0.26; (0.18 to 0.39)	0.10; (0.06 to 0.18)
Week 24	Number Analyzed	142 participants	145 participants
		0.38; (0.26 to 0.55)	0.10; (0.06 to 0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Odds ratio at Week 6 was calculated as the odds ratio of bexagliflozin group over placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0014
	Comments	P-value is presented based on one-sided statistical tests using a 0.025 level of significance
	Method	Mixed-effects repeated measures
	Comments	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.69
	Confidence Interval	(2-Sided) 95%; 1.70 to 12.95
	Estimation Comments	The odds ratios of bexagliflozin group over the placebo group at each visit will be estimated from LS means based on the model with the corresponding p-values and their two-sided 95% CIs presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Odds ratio at Week 12 was calculated as the odds ratio of bexagliflozin group over placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
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	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.18
	Confidence Interval	(2-Sided) 95%; 1.96 to 8.92
	Estimation Comments	The odds ratios of bexagliflozin group over the placebo group at each visit will be estimated from LS means based on the model with the corresponding p-values and their two-sided 95% CIs presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Odds ratio at Week 18 was calculated as the odds ratio of bexagliflozin group over placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0030
	Comments	P-value is presented based on one-sided statistical tests using a 0.025 level of significance
	Method	Mixed-effects repeated measures
	Comments	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.57
	Confidence Interval	(2-Sided) 95%; 1.31 to 5.04
	Estimation Comments	The odds ratios of bexagliflozin group over the placebo group at each visit will be estimated from LS means based on the model with the corresponding p-values and their two-sided 95% CIs presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Odds ratio at Week 24 was calculated as the odds ratio of bexagliflozin group over placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
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	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.88
	Confidence Interval	(2-Sided) 95%; 1.99 to 7.58
	Estimation Comments	The odds ratios of bexagliflozin group over the placebo group at each visit will be estimated from LS means based on the model with the corresponding p-values and their two-sided 95% CIs presented.

7. Secondary Outcome

Title	Proportion of Subjects Achieving HbA1c < 7% Over Time for High Glycemic Group
Description	The proportion of subjects who achieved HbA1c < 7% at 6, 12, 18 and 24 weeks were calculated based on the number of subjects with a value at each time point for each group.
Time Frame	Baseline, up to 24 weeks

Outcome Measure Data

Analysis Population Description

The number of subjects in the ITT population with a value at baseline and at the specified visit was included. Proportion of subjects achieving HbA1c < 7% was reported for High Glycemic Group without a 95% confidence interval.

Arm/Group Title	High Glycemic Group
Arm/Group Description:	Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	34
Measure Type: Number; Unit of Measure: Proportion of subjects
Week 6	0
Week 12	0.065
Week 18	0.097
Week 24	0.138

8. Secondary Outcome

Title	Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for Double-blind Group
Description	Changes in body mass from baseline to week 24 was calculated based on LS means for both bexagliflozin and placebo groups.
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Subjects with a BMI >= 25 kg/m2 at baseline in the ITT population were included. The number of subjects with a value at baseline and at week 24 was analyzed. Model-adjusted mean change (LS Mean) and standard error (SE) were reported.

Arm/Group Title	Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo
Arm/Group Description:	Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	119	124
Least Squares Mean (Standard Error); Unit of Measure: kg
	-3.60 (0.348)	-1.09 (0.336)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.0001
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-2.51
	Confidence Interval	(2-Sided) 95%; -3.45 to -1.57
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for High Glycemic Group
Description	The change in body mass from baseline at week 24 for High Glycemic group was calculated by subtracting the mean body mass at baseline from the mean body mass at week 24
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Subjects with a BMI >= 25 kg/m2 at baseline in the ITT population were included. The number of subjects with a value at baseline and at week 24 was analyzed.

Arm/Group Title	High Glycemic Group
Arm/Group Description:	Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed	28
Mean (Standard Deviation); Unit of Measure: kg
	-1.40 (3.759)

10. Secondary Outcome

Title	Change From Baseline in HbA1c Over Time in Double-blind Treatment Group
Description	The change from baseline in HbA1c at 6, 12, 18 and 24 weeks was calculated based on the number of subjects with a value at each time point for each group. The model-adjusted change from baseline was calculated based on a mixed-effects repeated measures analysis that includes country, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as a fixed effect covariate.
Time Frame	Baseline, up to 24 weeks

Outcome Measure Data

Analysis Population Description

The Number Analyzed only includes the number of subjects with a value at baseline and at the specific visit. Model-adjusted mean change (LS Mean) and standard error (SE) were reported for Double-blind Treatment Group.

Arm/Group Title		Double-blind Group: Bexagliflozin 20 mg	Double-blind Group: Placebo
Arm/Group Description:		Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.	Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed		158	159
Least Squares Mean (Standard Error); Unit of Measure: percentage of HbA1c
Week 6	Number Analyzed	152 participants	152 participants
		-0.72 (0.065)	-0.16 (0.065)
Week 12	Number Analyzed	149 participants	146 participants
		-0.97 (0.073)	-0.31 (0.073)
Week 18	Number Analyzed	143 participants	144 participants
		-1.00 (0.072)	-0.51 (0.072)
Week 24	Number Analyzed	142 participants	145 participants
		-1.09 (0.076)	-0.56 (0.075)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Model-adjusted change from baseline at week 6 was calculated as the difference in LS Mean between bexagliflozin group and placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
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	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -0.74 to -0.38
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Model-adjusted change from baseline at week 12 was calculated as the difference in LS Mean between bexagliflozin group and placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
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	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-0.66
	Confidence Interval	(2-Sided) 95%; -0.86 to -0.46
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Model-adjusted change from baseline at week 18 was calculated as the difference in LS Mean between bexagliflozin group and placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
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	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.30
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Double-blind Group: Bexagliflozin 20 mg, Double-blind Group: Placebo
	Comments	Model-adjusted change from baseline at week 24 was calculated as the difference in LS Mean between bexagliflozin group and placebo group.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
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	Mixed-effects repeated measures analysis includes country, treatment, visit, treatment and baseline HbA1c value as fixed effect covariates
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -0.74 to -0.32
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Change in HbA1c Over Time Among Subjects Who Have Baseline HbA1c of > 10.5% and ≤ 12.0%
Description	The change from baseline in HbA1c at 6, 12, 18 and 24 weeks was calculated based on the number of subjects with a value at each time point in High Glycemic Group.
Time Frame	Baseline, up to 24 weeks

Outcome Measure Data

Analysis Population Description

The Number Analyzed only includes the number of subjects with a value at baseline and at the specific visit.

Arm/Group Title		High Glycemic Group
Arm/Group Description:		Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
Overall Number of Participants Analyzed		34
Mean (Standard Deviation); Unit of Measure: percentage of HbA1c
Week 6	Number Analyzed	28 participants
		-1.72 (1.027)
Week 12	Number Analyzed	31 participants
		-2.45 (1.136)
Week 18	Number Analyzed	31 participants
		-2.62 (1.055)
Week 24	Number Analyzed	29 participants
		-2.82 (1.084)

Adverse Events

Time Frame	Adverse events were collected from Week -1 (run in period: Visit 2) to Week 26 (Follow up: Visit 8).
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Double-blind Group: Bexagliflozin 20 mg		Double-blind Group: Placebo		High Glycemic Group
Arm/Group Description	Each subject will receive bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.		Each subject will receive placebo (inactive tablet) once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.		Each subject will receive Bexagliflozin, 20 mg, once daily and open-labeled metformin background medication during the entire study at a stable dose and frequency.
All-Cause Mortality
	Double-blind Group: Bexagliflozin 20 mg		Double-blind Group: Placebo		High Glycemic Group
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/158 (0.00%)		0/159 (0.00%)		0/34 (0.00%)
Serious Adverse Events
	Double-blind Group: Bexagliflozin 20 mg		Double-blind Group: Placebo		High Glycemic Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/158 (1.90%)		4/159 (2.52%)		0/34 (0.00%)
Cardiac disorders
Acute coronary syndrome † 1	1/158 (0.63%)	1	0/159 (0.00%)	0	0/34 (0.00%)	0
Atrial fibrillation † 1	0/158 (0.00%)	0	1/159 (0.63%)	1	0/34 (0.00%)	0
Acute cardiac failure † 1	1/158 (0.63%)	1	0/159 (0.00%)	0	0/34 (0.00%)	0
Gastrointestinal disorders
Constipation † 1	0/158 (0.00%)	0	1/159 (0.63%)	1	0/34 (0.00%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis † 1	1/158 (0.63%)	1	0/159 (0.00%)	0	0/34 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Asthma † 1	0/158 (0.00%)	0	1/159 (0.63%)	1	0/34 (0.00%)	0
Chronic obstructive pulmonary disease † 1	0/158 (0.00%)	0	1/159 (0.63%)	1	0/34 (0.00%)	0
Vascular disorders
Hypertension † 1	0/158 (0.00%)	0	1/159 (0.63%)	1	0/34 (0.00%)	0
1 Term from vocabulary, MedDRA 20.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Double-blind Group: Bexagliflozin 20 mg		Double-blind Group: Placebo		High Glycemic Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/158 (10.13%)		28/159 (17.61%)		7/34 (20.59%)
Infections and infestations
Nasopharyngitis † 1	9/158 (5.70%)	9	13/159 (8.18%)	13	1/34 (2.94%)	1
Investigations
Glomerular filtration rate decreased † 1	0/158 (0.00%)	0	0/159 (0.00%)	0	2/34 (5.88%)	2
Metabolism and nutrition disorders
Diabetes mellitus inadequate control † 1	3/158 (1.90%)	3	10/159 (6.29%)	10	1/34 (2.94%)	1
Polydipsia † 1	5/158 (3.16%)	6	4/159 (2.52%)	4	3/34 (8.82%)	3
Renal and urinary disorders
Polyuria † 1	5/158 (3.16%)	7	6/159 (3.77%)	6	4/34 (11.76%)	4
1 Term from vocabulary, MedDRA 20.1; † 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.

The investigator does not have the right to publish trial results.

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: NCT03259789
• Other Study ID Numbers: THR-1442-C-419
• First Submitted: August 21, 2017
• First Posted: August 24, 2017
• Results First Submitted: April 5, 2021
• Results First Posted: July 7, 2021
• Last Update Posted: July 7, 2021