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

• ClinicalTrials.gov Identifier: NCT03115112
• Recruitment Status: Completed
• First Posted: April 14, 2017
• Results First Posted: June 4, 2021
• Last Update Posted: June 22, 2021
• Sponsor: Theracos
• Information provided by (Responsible Party): Theracos

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Type 2 Diabetes Mellitus
• Interventions: Drug: Bexagliflozin; Drug: Sitagliptin; Drug: Placebo for sitagliptin; Drug: Placebo for bexagliflozin
• Enrollment: 386

Participant Flow

Recruitment Details
Pre-assignment Details

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 [1]	191	193
Completed	180	189
Not Completed	12	5
Reason Not Completed
Adverse Event	5	1
Withdrawal by Subject	4	2
Lost to Follow-up	0	1
Death	1	0
Pregnancy	1	0
Site closure	1	1
[1] One randomized subject in each group was excluded in the ITT and the safety populations due to site closure for GCP violation.

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 Number of Baseline Participants		191	193	384
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	191 participants	193 participants	384 participants
		59.3 (9.69)	59.6 (9.76)	59.4 (9.72)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	191 participants	193 participants	384 participants
	Female	71 37.2%	67 34.7%	138 35.9%
	Male	120 62.8%	126 65.3%	246 64.1%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	191 participants	193 participants	384 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%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	191 participants	193 participants	384 participants
	American Indian or Alaska Native	0 0.0%	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%	0 0.0%
	Black or African American	6 3.1%	2 1.0%	8 2.1%
	White	158 82.7%	156 80.8%	314 81.8%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	191 participants	193 participants	384 participants
Hungary		33	23	56
Czechia		16	25	41
United States		15	21	36
Japan		27	35	62
Poland		70	44	114
Spain		30	45	75
Height; Mean (Standard Deviation); Unit of measure: Cm
	Number Analyzed	191 participants	193 participants	384 participants
		167.4 (10.67)	168.3 (9.63)	167.9 (10.16)
Body Weight; Mean (Standard Deviation); Unit of measure: Kg
	Number Analyzed	191 participants	193 participants	384 participants
		90.27 (20.736)	89.44 (19.235)	89.85 (19.974)
BMI; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	191 participants	193 participants	384 participants
		32.06 (6.052)	31.39 (5.294)	31.72 (5.686)
HbA1c; Mean (Standard Deviation); Unit of measure: Percentage of glycated hemoglobin
	Number Analyzed	191 participants	193 participants	384 participants
		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
Overall Number of Participants Analyzed	180	190
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage of HbA1c
	-0.74; (-0.86 to -0.62)	-0.82; (-0.93 to -0.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments	[Not Specified]
	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.
Method of Estimation	Estimation Parameter	Difference of LS Means
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.22
	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
Overall Number of Participants Analyzed	180	190
Least Squares Mean (95% Confidence Interval); Unit of Measure: mmol/L
	-1.82; (-2.09 to -1.55)	-1.45; (-1.70 to -1.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0123
	Comments	[Not Specified]
	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
	Estimation Comments	[Not Specified]

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
Overall Number of Participants Analyzed	158	171
Least Squares Mean (95% Confidence Interval); Unit of Measure: kg
	-3.35; (-3.85 to -2.84)	-0.81; (-1.29 to -0.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	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	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
	Estimation Comments	[Not Specified]

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
Overall Number of Participants Analyzed	180	190
Least Squares Mean (95% Confidence Interval); Unit of Measure: mm Hg
	-4.23; (-6.18 to -2.28)	-1.90; (-3.75 to -0.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin, Sitagliptin
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0276
	Comments	[Not Specified]
	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
	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)
Adverse Event Reporting Description	[Not Specified]
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 (%)		Affected / at Risk (%)
Total	1/191 (0.52%)		0/193 (0.00%)
Serious Adverse Events
	Bexagliflozin		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/191 (3.66%)		4/193 (2.07%)
Blood and lymphatic system disorders
Anemia † 1	0/191 (0.00%)	0	1/193 (0.52%)	1
Cardiac disorders
Atrial fibrillation † 1	1/191 (0.52%)	1	0/193 (0.00%)	0
Cardiac failure † 1	0/191 (0.00%)	0	1/193 (0.52%)	1
Microvascular coronary artery disease † 1	1/191 (0.52%)	2	0/193 (0.00%)	0
Gastrointestinal disorders
Gallstone ileus † 1	0/191 (0.00%)	0	1/193 (0.52%)	1
Intestinal obstruction † 1	0/191 (0.00%)	0	1/193 (0.52%)	1
Infections and infestations
Anal abscess † 1	1/191 (0.52%)	1	0/193 (0.00%)	0
Gangrene † 1	1/191 (0.52%)	1	0/193 (0.00%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis † 1	2/191 (1.05%)	2	0/193 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon † 1	1/191 (0.52%)	1	0/193 (0.00%)	0
Nervous system disorders
Intracranial aneursym † 1	0/191 (0.00%)	0	1/193 (0.52%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease † 1	0/191 (0.00%)	0	1/193 (0.52%)	1
1 Term from vocabulary, MedDRA 19.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	3%
	Bexagliflozin		Sitagliptin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/191 (14.66%)		47/193 (24.35%)
Infections and infestations
Nasopharyngitis † 1	15/191 (7.85%)	15	25/193 (12.95%)	29
Influenza † 1	3/191 (1.57%)	3	10/193 (5.18%)	10
Urinary tract infection † 1	7/191 (3.66%)	9	4/193 (2.07%)	4
Metabolism and nutrition disorders
Hypoglycemia † 1	6/191 (3.14%)	12	10/193 (5.18%)	14
1 Term from vocabulary, MedDRA 19.0; † 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 has no 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: NCT03115112
• Other Study ID Numbers: THR-1442-C-423
• First Submitted: April 11, 2017
• First Posted: April 14, 2017
• Results First Submitted: May 11, 2021
• Results First Posted: June 4, 2021
• Last Update Posted: June 22, 2021