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

• Sponsor: Theracos (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03259789
• Collaborator: (none)
• Enrollment: 351
• Locations: 43
• Arms: 3
• Actual Duration (Months): 13.8
• Patients Per Site: 8.2
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the effect of bexagliflozin compared to placebo as an add-on therapy to metformin in lowering hemoglobin A1c (HbA1c) levels in subjects with type 2 diabetes mellitus (T2DM).

Condition or Disease	Intervention/Treatment	Phase
Type2 Diabetes Mellitus	Drug: Bexagliflozin tablets, 20 mg; Drug: Bexagliflozin tablets, placebo; Drug: Bexagliflozin tablets, 20 mg	Phase 3

Detailed Description

Approximately 300 subjects with inadequately controlled T2DM on metformin were to be recruited from the United States and Japan. Subjects were randomly assigned to receive bexagliflozin tablets, 20 mg, or bexagliflozin tablets, placebo, in a ratio of 1:1 once daily for 24 weeks. Subjects were to continue taking metformin for the duration of the study. The study also enrolled 50 subjects with extremely poorly controlled T2DM on metformin to receive open-label bexagliflozin tablets, 20 mg, for 24 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 351 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Bexagliflozin in Subjects With Type 2 Diabetes Mellitus Who Are Not Adequately Controlled by Metformin Alone
• Actual Study Start Date: Nov 28, 2017
• Actual Primary Completion Date: Jan 23, 2019
• Actual Study Completion Date: Jan 23, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bexagliflozin tablets, 20 mg; Double-Blind	Drug: Bexagliflozin tablets, 20 mg; Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study.; Other Names: EGT0001442, EGT0001474
Placebo Comparator: Bexagliflozin tablets, Placebo; Double Blind	Drug: Bexagliflozin tablets, placebo; Each subject will receive placebo (inactive tablet) once daily for the duration of the study.
Experimental: Bexagliflozin Tablets, 20 mg; High Glycemic Group	Drug: Bexagliflozin tablets, 20 mg; Each subject will receive bexagliflozin, 20 mg once daily for the duration of the study.; Other Names: EGT0001442, EGT0001474

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in HbA1c at Week 24 for Double-blind Group [Baseline to week 24]

   HbA1c was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.

2. Change From Baseline in HbA1c at Week 24 for High Glycemic Group [Baseline to week 24]

   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

Secondary Outcome Measures

1. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for Double-blind Group [Baseline, up to 24 weeks]

   FPG was obtained at baseline and at Week 24. The model-adjusted change from baseline was calculated using mixed-effects repeated measures analysis.

2. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 for High Glycemic Group [Baseline, up to 24 weeks]

   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

3. Change From Baseline in Systolic Blood Pressure (SBP) at Week 24 [Baseline to week 24]

   Changes from baseline at Week 24 in SBP for the double-blind group and high glycemic group

4. Proportion of Subjects Achieving HbA1c < 7% Over Time for Double-blind Group [Baseline, up to 24 weeks]

   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.

5. Proportion of Subjects Achieving HbA1c < 7% Over Time for High Glycemic Group [Baseline, up to 24 weeks]

   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.

6. Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for Double-blind Group [Baseline to week 24]

   Changes in body mass from baseline to week 24 was calculated based on LS means for both bexagliflozin and placebo groups.

7. Change in Body Mass From Baseline to Week 24 in Subjects With a BMI ≥ 25 kg/m2 for High Glycemic Group [Baseline to week 24]

   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

8. Change From Baseline in HbA1c Over Time in Double-blind Treatment Group [Baseline, up to 24 weeks]

   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.

9. Change in HbA1c Over Time Among Subjects Who Have Baseline HbA1c of > 10.5% and ≤ 12.0% [Baseline, up to 24 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

The subjects were required to meet the following criteria at the time of enrollment to be eligible for the study:

1. Had been age ≥ 20 years at screening. Women of childbearing potential were required to have tested negative for pregnancy and have agreed to abstinence or contraception for the duration of the study to avoid any possible pregnancy. Females who were surgically sterile (hysterectomy, oophorectomy) or postmenopausal (absence of menses greater than 12 months) were eligible if they had tested negative for pregnancy at screening.

2. 1. Had a history of T2DM with an HbA1c level of ≥ 7.5% and ≤ 10.5% at screening, or b) Had a history of T2DM with an HbA1c level of >10.5% and ≤ 12.0% at screening

3. Had been prescribed a stable dose of metformin (≥1500 mg per day in the US or ≥ 1000 mg per day in Japan) as their sole anti-diabetic medication

4. Had a body mass index (BMI) ≤ 45 kg m-2

5. Had been able to comprehend and willing to provide written informed consent in accordance with institutional and regulatory guidelines

6. Had no recent changes to their medications for hypertension or hyperlipidemia (if applicable)

7. Had the ability to regularly self-administer medication, as evidenced by consumption of all, or at worst one less than all, doses of run-in medication prior to randomization

Subjects who met any of the following criteria were to be excluded from the study:

1. Had a diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young

2. Were pregnant or breastfeeding

3. Had one or more hemoglobin alleles that affect HbA1c measurement

4. Had a history of genitourinary tract infection (e.g., UTI, GMI, vaginitis, balanitis) within 6 weeks of screening or a history of ≥ 3 genitourinary infections requiring treatment within 6 months of screening

5. Had an estimated glomerular filtration rate (eGFR), as calculated by the modification of diet in renal disease study equation (MDRD), < 60 mL min-1 per 1.73 m2

6. Had a sitting systolic blood pressure >180 mmHg or a sitting diastolic blood pressure

110 mmHg at screening

1. Had exposure to hypoglycemic agent(s) other than metformin during the 8 weeks prior to screening

2. Had a history of illicit drug use or alcohol abuse in the past 2 years

3. Had a life expectancy < 2 years

4. Had a diagnosis of New York Heart Association (NYHA) Class IV heart failure within 3 months of screening

5. Had experienced an MI, unstable angina, stroke, or hospitalization for heart failure within 3 months of screening

6. Had exposure to an investigational drug within 30 days

7. Had a previous exposure to bexagliflozin or EGT0001474

8. Had a history of SGLT2 inhibitor treatment

9. Were participating in another interventional trial

10. Were not able to comply with the study scheduled visits

11. Had any condition, disease, disorder, or clinically relevant abnormality that, in the opinion of the primary investigator, would jeopardize the subject's appropriate participation in this study or obscure the effects of treatment

12. Had an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 × ULN or total bilirubin ≥ 1.5 × ULN at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Research Site 1232	Birmingham	Alabama	United States	35205
2	Clinical Research Site 1378	Birmingham	Alabama	United States	35242
3	Clinical Research Site 1269	Foley	Alabama	United States	36535
4	Clinical Research Site 1363	Little Rock	Arkansas	United States	72209
5	Clinical Research Site 1381	Anaheim	California	United States	92805
6	Clinical Research Site 1375	North Hollywood	California	United States	91606
7	Clinical Research Site 1365	Norwalk	California	United States	90650
8	Clinical Research Site 1382	Norwalk	Connecticut	United States	06851
9	Clinical Research Site 1372	Hollywood	Florida	United States	33024
10	Clinical Research Site 1362	Palm Springs	Florida	United States	33461
11	Clinical Research Site 1373	Pembroke Pines	Florida	United States	33026
12	Clinical Research Site 1376	Nampa	Idaho	United States	83686
13	Clinical Research Site 1366	Chicago	Illinois	United States	60602
14	Clinical Research Site 1294	New Orleans	Louisiana	United States	70124
15	Clinical Research Site 1374	Saint Louis	Missouri	United States	63117
16	Clinical Research Site 1370	Las Vegas	Nevada	United States	89104
17	Clinical Research Site 1009	Berlin	New Jersey	United States	08009
18	Clinical Research Site 1037	Trenton	New Jersey	United States	08611
19	Clinical Research Site 1286	Albuquerque	New Mexico	United States	87102
20	Clinical Research Site 1275	Bronx	New York	United States	10455
21	Clinical Research Site 1368	New York	New York	United States	10036
22	Clinical Research Site 1019	Portland	Oregon	United States	97239
23	Clinical Research Site 1379	Gonzales	Texas	United States	78629
24	Clinical Research Site 1369	Houston	Texas	United States	77051
25	Clinical Research Site 1371	San Antonio	Texas	United States	78209
26	Clinical Research Site 1360	San Antonio	Texas	United States	78258
27	Clinical Research Site 6048	Nagoya	Aichi	Japan	456-0058
28	Clinical Research Site 6050	Sapporo	Hokkaido	Japan	003-0023
29	Clinical Research Site 6041	Koga	Ibaraki	Japan	306-0232
30	Clinical Research Site 6029	Atsugi	Kanagawa	Japan	243-0035
31	Clinical Research Site 6051	Kamakura	Kanagawa	Japan	547-0055
32	Clinical Research Site 6020	Yokohama	Kanagawa	Japan	221-080
33	Clinical Research Site 6055	Tokyo	Meguro	Japan	153-0053
34	Clinical Research Site 6046	Higashiosaka	Osaka	Japan	577-0803
35	Clinical Research Site 6033	Kashiwara	Osaka	Japan	582-0005
36	Clinical Research Site 6013	Toyonaka	Osaka	Japan	560-0082
37	Clinical Research Site 6052	Kawaguchi	Saitama	Japan	332-0012
38	Clinical Research Site 6053	Shimotsuke	Tochigi	Japan	329-0433
39	Clinical Research Site 6040	Fukuoka		Japan	819-0006
40	Clinical Research Site 6043	Kyoto		Japan	600-8898
41	Clinical Research Site 6015	Osaka		Japan	536-0008
42	Clinical Research Site 6045	Tokyo		Japan	108-0075
43	Clinical Research Site 6047	Tokyo		Japan	166-0003

Sponsors and Collaborators

• Theracos

Investigators

• Study Director: J, Paul Lock, M.D., Theracos

Study Documents (Full-Text)

• Study Protocol - Jul 26, 2017
• Statistical Analysis Plan - Feb 15, 2019

More Information

Publications

None provided.

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT03259789
• Other Study ID Numbers: THR-1442-C-419
• First Posted: Aug 24, 2017
• Last Update Posted: Jul 7, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Bexagliflozin

Study Results

Participant Flow

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

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 Participants	158	159	34	351
Age (years) [Mean (Standard Deviation) ]
Double-blind Group	56.0 (10.05)	55.6 (11.18)	55.8 (10.62)
High Glycemic Group	52.1 (8.59)	52.1 (8.59)
Sex: Female, Male (Count of 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) (Count of 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%
Race (NIH/OMB) (Count of 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%	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%	3 0.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	83 52.5%	83 52.2%	27 79.4%	193 55%
Japan	75 47.5%	76 47.8%	7 20.6%	158 45%
Height (cm) [Mean (Standard Deviation) ]
Double-blind Group	168.4 (9.71)	167.3 (9.55)	167.8 (9.63)
High Glycemic Group	169.4 (9.34)	169.4 (9.34)
Body Weight (kg) [Mean (Standard Deviation) ]
Double-blind Group	84.58 (21.989)	84.44 (20.928)	84.51 (21.43)
High Glycemic Group	87.28 (17.759)	87.28 (17.759)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Double-blind Group	29.67 (6.45)	29.99 (6.342)	29.83 (6.388)
High Glycemic Group	30.37 (5.558)	30.37 (5.558)

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.
Measure Participants	142	145
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	29
Mean (Standard Deviation) [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.
Measure Participants	142	145
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	29
Mean (Standard Deviation) [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.
Measure Participants	143	145	29
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	158	159
Week 6	0.14	0.03
Week 12	0.26	0.06
Week 18	0.26	0.10
Week 24	0.38	0.10

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
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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
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
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	34
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.
Measure Participants	119	124
Least Squares Mean (Standard Error) [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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	28
Mean (Standard Deviation) [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.
Measure Participants	158	159
Week 6	-0.72 (0.065)	-0.16 (0.065)
Week 12	-0.97 (0.073)	-0.31 (0.073)
Week 18	-1.00 (0.072)	-0.51 (0.072)
Week 24	-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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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
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
	Parameter Dispersion	Type: Value:
	Estimation Comments

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.
Measure Participants	34
Week 6	-1.72 (1.027)
Week 12	-2.45 (1.136)
Week 18	-2.62 (1.055)
Week 24	-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).
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/158 (0%)		0/159 (0%)		0/34 (0%)
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 (1.9%)		4/159 (2.5%)		0/34 (0%)
Cardiac disorders
Acute coronary syndrome	1/158 (0.6%)	1	0/159 (0%)	0	0/34 (0%)	0
Atrial fibrillation	0/158 (0%)	0	1/159 (0.6%)	1	0/34 (0%)	0
Acute cardiac failure	1/158 (0.6%)	1	0/159 (0%)	0	0/34 (0%)	0
Gastrointestinal disorders
Constipation	0/158 (0%)	0	1/159 (0.6%)	1	0/34 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/158 (0.6%)	1	0/159 (0%)	0	0/34 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/158 (0%)	0	1/159 (0.6%)	1	0/34 (0%)	0
Chronic obstructive pulmonary disease	0/158 (0%)	0	1/159 (0.6%)	1	0/34 (0%)	0
Vascular disorders
Hypertension	0/158 (0%)	0	1/159 (0.6%)	1	0/34 (0%)	0
Other (Not Including 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	16/158 (10.1%)		28/159 (17.6%)		7/34 (20.6%)
Infections and infestations
Nasopharyngitis	9/158 (5.7%)	9	13/159 (8.2%)	13	1/34 (2.9%)	1
Investigations
Glomerular filtration rate decreased	0/158 (0%)	0	0/159 (0%)	0	2/34 (5.9%)	2
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	3/158 (1.9%)	3	10/159 (6.3%)	10	1/34 (2.9%)	1
Polydipsia	5/158 (3.2%)	6	4/159 (2.5%)	4	3/34 (8.8%)	3
Renal and urinary disorders
Polyuria	5/158 (3.2%)	7	6/159 (3.8%)	6	4/34 (11.8%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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