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

• Sponsor: Theracos (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03115112
• Collaborator: (none)
• Enrollment: 386
• Locations: 56
• Arms: 2
• Actual Duration (Months): 12.6
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate the effect of bexagliflozin compared to sitagliptin 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
Type 2 Diabetes Mellitus	Drug: Bexagliflozin; Drug: Sitagliptin; Drug: Placebo for sitagliptin; Drug: Placebo for bexagliflozin	Phase 3

Detailed Description

This was a phase 3, multi-center, randomized, double-blind, parallel-group study to demonstrate that bexagliflozin was non-inferior to sitagliptin as add-on therapy in subjects whose T2DM was not adequately controlled by metformin treatment alone. The primary effectiveness endpoint was the change in HbA1c from baseline at week 24.

At the time of screening, all subjects were to have taken metformin at a stable dose of ≥ 1500 mg per day for ≥ 8 weeks and have received diet and exercise counseling. A total of 374 eligible subjects were to be enrolled in the study. Subjects who successfully completed a 1-week run-in and who met all eligibility criteria were to be randomized in a 1:1 ratio to receive once daily double-blind treatment of either active bexagliflozin tablets with placebo sitagliptin tablets or placebo bexagliflozin tablets and active sitagliptin tablets. The study subjects were to continue receiving open-labeled metformin during the entire study at a stable dose and frequency. The treatment period was 24 weeks and was conducted in an outpatient setting.

Randomization was stratified by HbA1c (≤ 8.5% vs. ˃ 8.5%) values. Symptoms and blood sugars related to the occurrence of hyperglycemia, hypoglycemic events or symptoms that could indicate ketoacidosis were to be recorded. Bexagliflozin tablets, 20 mg or placebo, and sitagliptin tablets, 100 mg or placebo, were to be taken once daily at approximately the same time each day either before or after breakfast. Background metformin was to be taken at the same dose and frequency from screening throughout the entire study.

Each subject was advised to return to the clinic at weeks 6, 12, 18 and 24 for efficacy assessment and safety monitoring, including review of AEs and concomitant medication, vital signs, ECG, physical examination and blood and urine specimen collections. Subjects were to return to the clinic for a follow-up exit visit at week 26 or 2 weeks after the last dose of study drugs if subjects withdrew from the study prior to week 24.

Study Design

• Study Type: Interventional
• Actual Enrollment: 386 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Active-Controlled Study to Evaluate the Effects of Bexagliflozin Versus Sitagliptin in Subjects With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control by Metformin
• Actual Study Start Date: Oct 12, 2017
• Actual Primary Completion Date: Oct 31, 2018
• Actual Study Completion Date: Oct 31, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bexagliflozin Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study.	Drug: Bexagliflozin; tablets containing 20 mg bexagliflozin; Other Names: EGT0001442, EGT0001474 ; Drug: Placebo for sitagliptin; inactive tablets to match the appearance of sitagliptin tablets
Active Comparator: Sitagliptin Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.	Drug: Sitagliptin; tablets containing 100 mg sitagliptin; Other Names: Januvia ; Drug: Placebo for bexagliflozin; inactive tablets to match the appearance of bexagliflozin tablets

Outcome Measures

Primary Outcome Measures

1. Change in HbA1c From Baseline to Week 24 [Baseline to week 24]

   The primary efficacy objective is to demonstrate that bexagliflozin is non-inferior to sitagliptin by evaluating the treatment effect on hemoglobin A1c (HbA1c) reduction at week 24 in subjects whose type 2 diabetes mellitus (T2DM) is inadequately controlled by metformin.

Secondary Outcome Measures

1. Change in FPG From Baseline at Week 24 [Baseline to week 24]

   To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in fasting plasma glucose (FPG) at week 24

2. Change in Body Weight in Subjects With Baseline BMI ≥ 25 kg/m2 at Week 24 [Baseline to week 24]

   To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week 24

3. Change in SBP in Subjects From Baseline at Week 24 [Baseline to week 24]

   To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in systolic blood pressure (SBP) in subjects at week 24

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Each subject was required to meet the following criteria at the time of enrollment to be eligible for the study:

1. To have been male or female adults ≥ 18 years of age.

2. To have been negative on the urine pregnancy test and agreed to abstain from coitus or use contraception during the entire study if a subject was female of childbearing potential.

3. To have had a diagnosis of T2DM with HbA1c levels between 7.0% and 11% (inclusive) at the time of screening.

4. To have been treated with a stable dose of ≥ 1500 mg/day metformin only along with diet and exercise counseling for at least 8 weeks at the time of screening.

5. To have had a BMI ≤ 45 kg per m2 at the time of screening.

6. To have been taking stable doses of treatment for dyslipidemia and/or hypertension for 30 days if applicable.

7. To have been willing and able to return for all clinic visits and to complete all study-required procedures.

8. To have adhered to the investigational product administration requirements as evidenced by missing no more than 1 day of run-in medications.

Potential subjects who exhibited any of the following characteristics were to be excluded from the study:

1. Diagnosis of type 1 diabetes mellitus or maturity-onset diabetes of the young (MODY)

2. Hemoglobinopathy that affected HbA1c measurement

3. Any contraindication to the safe use of DPP-4 therapy or sitagliptin, including known hypersensitivity reaction

4. History of pancreatitis

5. Genitourinary tract infection within 6 weeks of screening or history of ≥ 3 genitourinary infections requiring treatment within 6 months from the time of screening

6. Cancer, active or in remission, for < 3 years

7. History of alcohol or illicit drug abuse in the past 2 years

8. Triglycerides > 500 mg dL-1 at Visit V1

9. Evidence of abnormal liver function tests (total bilirubin or alkaline phosphatase > 1.5 x upper limit of normal (ULN) with the exception of isolated Gilbert's syndrome); or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN

10. Estimated GFR, as calculated by the modification of diet in renal disease study equation (MDRD), < 60 mL min-1 per 1.73 m2 at the time of screening.

11. Uncontrolled hypertension (SBP > 160 mm Hg or diastolic BP > 95 mm Hg) at Visit V1

12. Life expectancy < 2 years

13. History of MI, unstable angina, stroke or hospitalization for heart failure within 3 months at the time of screening

14. History of treatment with an investigational drug within 30 days or within 7 half-lives of the investigational drug, whichever is longer

15. Previous treatment with bexagliflozin or EGT0001474 study drug

16. Currently or within 3 months of taking any SGLT2 inhibitor

17. Currently participating in another interventional trial

18. Prior renal transplantation or evidence of nephrotic syndrome (defined as a urine albumin-to-creatinine ratio (UACR) > 1500 mg g-1 at the time of screening).

19. Any condition, disease, disorder or clinically relevant abnormality that could have jeopardized the subject's appropriate participation in this study or obscure the effects of treatment

20. Female subjects who were pregnant or nursing

21. Two or more consecutive SMBG measures ≥ 250 mg dL-1 (13.9 mmol L-1) prior to randomization accompanied by clinical signs or symptoms of hyperglycemia prior to randomization, including weight loss, blurred vision, increased thirst increased urination, or fatigue

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Research Site 1357	Lincoln	California	United States	95648
2	Clinical Research Site 1358	Long Beach	California	United States	90806
3	Clinical Research Site 1361	San Dimas	California	United States	91773
4	Clinical Research Site 1031	Port Orange	Florida	United States	32127
5	Clinical Research Site 1271	Chicago	Illinois	United States	60611
6	Clinical Research Site 1359	Topeka	Kansas	United States	66606
7	Clinical Research Site 1009	Berlin	New Jersey	United States	08009
8	Clinical Research Site 1037	Trenton	New Jersey	United States	08611
9	Clinical Research Site 1008	Munroe Falls	Ohio	United States	44262
10	Clinical Research Site 1360	San Antonio	Texas	United States	78258
11	Clinical Research Site 3119	Hodonín		Czechia	695 00
12	Clinical Research Site 3123	Mladá Boleslav		Czechia	293 01
13	Clinical Research Site 3120	Olomouc		Czechia	779 00
14	Clinical Research Site 3112	Praha		Czechia	181 00
15	Clinical Research Site 3122	Prostějov		Czechia	796 01
16	Clinical Research Site 9102	Balatonfüred		Hungary
17	Clinical Research Site 9101	Balatongyörök		Hungary
18	Clinical Research Site 9106	Budapest		Hungary
19	Clinical Research Site 9107	Szeged		Hungary
20	Clinical Research Site 9105	Zalaegerszeg		Hungary
21	Clinical Research Site 9103	Zamardi		Hungary
22	Clinical Research Site 6031	Chiba		Japan	260-0804
23	Clinical Research Site 6037	Chiba		Japan	272-8516
24	Clinical Research Site 6042	Chiba		Japan	277-0825
25	Clinical Research Site 6040	Fukuoka		Japan	819-0006
26	Clinical Research Site 6035	Fukuoka		Japan	819-0168
27	Clinical Research Site 6034	Ibaraki		Japan	300-0835
28	Clinical Research Site 6039	Ibaraki		Japan	300-1207
29	Clinical Research Site 6041	Ibaraki		Japan	306-0232
30	Clinical Research Site 6032	Ibaraki		Japan	310-0826
31	Clinical Research Site 6036	Shizuoka		Japan	424-0855
32	Clinical Research Site 6038	Tochigi		Japan	323-0022
33	Clinical Research Site 6033	Ōsaka		Japan	582-0005
34	Clinical Research Site 7137	Gdańsk		Poland	80-858
35	Clinical Research Site 7144	Kraków		Poland	30-015
36	Clinical Research Site 7142	Kraków		Poland	31-209
37	Clinical Research Site 7139	Kraków		Poland	31-261
38	Clinical Research Site 7141	Kraków		Poland	31-530
39	Clinical Research Site 7120	Lublin		Poland	20-362
40	Clinical Research Site 7138	Lublin		Poland	20-538
41	Clinical Research Site 7131	Olsztyn		Poland	10-117
42	Clinical Research Site 7143	Poznań		Poland	60-819
43	Clinical Research Site 7140	Poznań		Poland	60-821
44	Clinical Research Site 7136	Poznań		Poland	61-655
45	Clinical Research Site 7107	Puławy		Poland	24-100
46	Clinical Research Site 7128	Toruń		Poland	87-100
47	Clinical Research Site 9002	Alicante		Spain	03004
48	Clinical Research Site 9016	Almería		Spain	04001
49	Clinical Research Site 9005	Alzira		Spain	46600
50	Clinical Research Site 9017	Barcelona		Spain	08023
51	Clinical Research Site 9013	Barcelona		Spain	08500
52	Clinical Research Site 9012	Madrid		Spain	28007
53	Clinical Research Site 9011	Sevilla		Spain	41009
54	Clinical Research Site 9014	Sevilla		Spain	41013
55	Clinical Research Site 9015	Sevilla		Spain
56	Clinical Research Site 9018	Valencia		Spain	46010

Sponsors and Collaborators

• Theracos

Investigators

• Study Director: J. Paul Lock, MD, Theracos Sub, LLC

Study Documents (Full-Text)

• Study Protocol - Apr 6, 2017
• Statistical Analysis Plan - Feb 28, 2018

More Information

Publications

None provided.

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT03115112
• Other Study ID Numbers: THR-1442-C-423
• First Posted: Apr 14, 2017
• Last Update Posted: Jun 22, 2021
• Last Verified: Jun 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; Sitagliptin Phosphate; Bexagliflozin

Study Results

Participant Flow

Arm/Group Title	Bexagliflozin	Sitagliptin
Arm/Group Description	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study. Bexagliflozin: 20 mg, tablet Placebo for sitagliptin: 100 mg inactive tablet to match active comparator	Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Sitagliptin: 100 mg, tablet Placebo for bexagliflozin: 20 mg inactive tablet to match active comparator
Period Title: Overall Study
STARTED	192	194
Intention-to-treat	191	193
COMPLETED	180	189
NOT COMPLETED	12	5

Baseline Characteristics

Arm/Group Title	Bexagliflozin	Sitagliptin	Total
Arm/Group Description	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study.	Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.	Total of all reporting groups
Overall Participants	191	193	384
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.3 (9.69)	59.6 (9.76)	59.4 (9.72)
Sex: Female, Male (Count of Participants)
Female	71 37.2%	67 34.7%	138 35.9%
Male	120 62.8%	126 65.3%	246 64.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 1.6%	7 3.6%	10 2.6%
Not Hispanic or Latino	188 98.4%	186 96.4%	374 97.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	27 14.1%	35 18.1%	62 16.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 3.1%	2 1%	8 2.1%
White	158 82.7%	156 80.8%	314 81.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Hungary	33 17.3%	23 11.9%	56 14.6%
Czechia	16 8.4%	25 13%	41 10.7%
United States	15 7.9%	21 10.9%	36 9.4%
Japan	27 14.1%	35 18.1%	62 16.1%
Poland	70 36.6%	44 22.8%	114 29.7%
Spain	30 15.7%	45 23.3%	75 19.5%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.4 (10.67)	168.3 (9.63)	167.9 (10.16)
Body Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	90.27 (20.736)	89.44 (19.235)	89.85 (19.974)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.06 (6.052)	31.39 (5.294)	31.72 (5.686)
HbA1c (percentage of glycated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of glycated hemoglobin]	7.94 (0.808)	8.03 (0.921)	7.99 (0.867)

Outcome Measures

1. Primary Outcome

Title	Change in HbA1c From Baseline to Week 24
Description	The primary efficacy objective is to demonstrate that bexagliflozin is non-inferior to sitagliptin by evaluating the treatment effect on hemoglobin A1c (HbA1c) reduction at week 24 in subjects whose type 2 diabetes mellitus (T2DM) is inadequately controlled by metformin.
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Subjects in the intention-to-treat population and with a value at baseline and at week 24 were included.

Arm/Group Title	Bexagliflozin	Sitagliptin
Arm/Group Description	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study. Bexagliflozin: 20 mg, tablet Placebo for sitagliptin: 100 mg inactive tablet to match active comparator	Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Sitagliptin: 100 mg, tablet Placebo for bexagliflozin: 20 mg inactive tablet to match active comparator
Measure Participants	180	190
Least Squares Mean (95% Confidence Interval) [percentage of HbA1c]	-0.74	-0.82

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin of 0.35% was determined based on a reference clinical trial that demonstrated the effectiveness of sitagliptin, 100 mg, compared to placebo on HbA1c reduction in subjects with type 2 DM. A margin of 0.35% was selected to be approximately half of sitagliptin effect and remained clinically meaningful.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Mixed-effects repeated measures analysis includes region, treatment, visit, treatment-by-visit interaction and the baseline HbA1c value as fixed effect covariates.

2. Secondary Outcome

Title	Change in FPG From Baseline at Week 24
Description	To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in fasting plasma glucose (FPG) at week 24
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Subjects in the intention-to-treat population and with values at baseline and at week 24 were included.

Arm/Group Title	Bexagliflozin	Sitagliptin
Arm/Group Description	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study. Bexagliflozin: 20 mg, tablet Placebo for sitagliptin: 100 mg inactive tablet to match active comparator	Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Sitagliptin: 100 mg, tablet Placebo for bexagliflozin: 20 mg inactive tablet to match active comparator
Measure Participants	180	190
Least Squares Mean (95% Confidence Interval) [mmol/L]	-1.82	-1.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0123
	Comments
	Method	Mixed-effects repeated measures
	Comments	Covariate includes region, treatment, visit, treatment-by-visit interaction and the baseline FPG value as a fixed effect covariate.
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.70 to -0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Body Weight in Subjects With Baseline BMI ≥ 25 kg/m2 at Week 24
Description	To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in body weight in subjects with baseline body mass index (BMI) ≥ 25 kg/m2 at week 24
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Subjects in the intention-to-treat population with a baseline body mass index >= 25 kg/m2 and had body weight values at baseline and at week 24 were included in the analysis.

Arm/Group Title	Bexagliflozin	Sitagliptin
Arm/Group Description	Subjects received a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects continued taking metformin and received placebo for sitagliptin daily for the duration of the study. Bexagliflozin: 20 mg, tablet Placebo for sitagliptin: 100 mg inactive tablet to match active comparator	Subjects received a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects continued taking metformin and received placebo for bexagliflozin for the duration of the study. Sitagliptin: 100 mg, tablet Placebo for bexagliflozin: 20 mg inactive tablet to match active comparator
Measure Participants	158	171
Least Squares Mean (95% Confidence Interval) [kg]	-3.35	-0.81

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects repeated measures
	Comments	Included region, treatment, visit, treatment-by-visit interaction and the baseline body weight value as fixed effect covariate.
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	-2.54
	Confidence Interval	(2-Sided) 95%; -3.15 to -1.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in SBP in Subjects From Baseline at Week 24
Description	To evaluate the treatment effect of bexagliflozin vs. sitagliptin on the change in systolic blood pressure (SBP) in subjects at week 24
Time Frame	Baseline to week 24

Outcome Measure Data

Analysis Population Description

Subjects in the intention-to-treat population with values at baseline and at week 24 were included.

Arm/Group Title	Bexagliflozin	Sitagliptin
Arm/Group Description	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study. Bexagliflozin: 20 mg, tablet Placebo for sitagliptin: 100 mg inactive tablet to match active comparator	Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study. Sitagliptin: 100 mg, tablet Placebo for bexagliflozin: 20 mg inactive tablet to match active comparator
Measure Participants	180	190
Least Squares Mean (95% Confidence Interval) [mm Hg]	-4.23	-1.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0276
	Comments
	Method	t-test, 1 sided
	Comments	p value was presented based on one sided statistical tests using a 0.025 level of significance
Method of Estimation	Estimation Parameter	mixed-effects repeated measures
	Estimated Value	-2.33
	Confidence Interval	(2-Sided) 95%; -4.70 to 0.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Included region, treatment, visit, treatment-by-visit interaction and the baseline body weight value as fixed effect covariate.

Adverse Events

Time Frame	Adverse event data were collected from 1 week prior to randomization (V2) until Week 26 (V8/follow up visit)
Arm/Group Title	Bexagliflozin		Sitagliptin
Arm/Group Description	Subjects will receive a bexagliflozin tablet, 20 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for sitagliptin daily for the duration of the study.		Subjects will receive a sitagliptin tablet, 100 mg, once daily for the duration of the study. Subjects will continue taking metformin and receive placebo for bexagliflozin for the duration of the study.
All Cause Mortality
	Bexagliflozin		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/191 (0.5%)		0/193 (0%)
Serious Adverse Events
	Bexagliflozin		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/191 (3.7%)		4/193 (2.1%)
Blood and lymphatic system disorders
Anemia	0/191 (0%)	0	1/193 (0.5%)	1
Cardiac disorders
Atrial fibrillation	1/191 (0.5%)	1	0/193 (0%)	0
Cardiac failure	0/191 (0%)	0	1/193 (0.5%)	1
Microvascular coronary artery disease	1/191 (0.5%)	2	0/193 (0%)	0
Gastrointestinal disorders
Gallstone ileus	0/191 (0%)	0	1/193 (0.5%)	1
Intestinal obstruction	0/191 (0%)	0	1/193 (0.5%)	1
Infections and infestations
Anal abscess	1/191 (0.5%)	1	0/193 (0%)	0
Gangrene	1/191 (0.5%)	1	0/193 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	2/191 (1%)	2	0/193 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	1/191 (0.5%)	1	0/193 (0%)	0
Nervous system disorders
Intracranial aneursym	0/191 (0%)	0	1/193 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/191 (0%)	0	1/193 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Bexagliflozin		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/191 (14.7%)		47/193 (24.4%)
Infections and infestations
Nasopharyngitis	15/191 (7.9%)	15	25/193 (13%)	29
Influenza	3/191 (1.6%)	3	10/193 (5.2%)	10
Urinary tract infection	7/191 (3.7%)	9	4/193 (2.1%)	4
Metabolism and nutrition disorders
Hypoglycemia	6/191 (3.1%)	12	10/193 (5.2%)	14

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The investigator has no right to publish trial results.