Study to Evaluate the Effects of a High-Fat Meal on Bexagliflozin in Healthy Subjects

• Sponsor: Theracos (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02820298
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 2
• Actual Duration (Months): 2.3
• Patients Per Site Per Month: 10.9

Study Details

Study Description

Brief Summary

The purpose of this study was to investigate the effect of a high-fat meal on the levels of bexagliflozin in the blood in healthy subjects.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Bexagliflozin	Phase 1

Detailed Description

This was a single center, Phase 1, open-label, 2 × 2 crossover study designed to assess the effects of a high-fat meal on the PK of orally administered bexagliflozin tablets in 18 healthy adults. Subjects were randomized 1:1 to receive bexagliflozin tablets with a high-fat meal on day 1 and without a meal on day 8 after an overnight fast or to receive bexagliflozin tablets without a meal on day 1 after an overnight fast and with a high-fat meal on day 8.

Subjects were admitted to the clinic on the day before dosing in each treatment period, and stayed in the clinic until 48 h post-dose.

The subjects dosed in the fed state received an oral bexagliflozin tablet, 20 mg, 30 min after starting to consume a high-fat meal following an overnight fast. The meal was to be ingested in its entirety over an approximate 25-minute period, such that it was completed at least 5 minutes prior to the scheduled time of bexagliflozin dosing for the fed state treatment. Subjects dosed in the fasting state received an oral bexagliflozin tablet, 20 mg, after an overnight fast.

Blood samples for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. Urine collection in 12 h batches was performed at pre-dose (-12 to 0 h on day 0 and day 7), and at post-dose (0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h) intervals.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Open-label, Randomized, Two-period, Two-treatment, Crossover Study to Evaluate the Effect of A High-Fat Meal on the Pharmacokinetics of Bexagliflozin in Healthy Subjects
• Actual Study Start Date: Jun 20, 2016
• Actual Primary Completion Date: Aug 29, 2016
• Actual Study Completion Date: Aug 29, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 - Bexagliflozin dosed in fed state, then in fasted state Group 1 subjects will take one dose of 20 mg of bexagliflozin with food on day 1 after an overnight fast and will take a second dose of bexagliflozin without food on day 8 after an overnight fast.	Drug: Bexagliflozin; Bexagliflozin tablet, 20 mg; Other Names: EGT0001442, EGT0001474
Experimental: Group 2 - Bexagliflozin in fasted state, then in fed state Group 2 subjects will take one dose of 20 mg bexagliflozin without food on day 1 after an overnight fast and will take a second dose of bexagliflozin with food on day 8 after an overnight fast.	Drug: Bexagliflozin; Bexagliflozin tablet, 20 mg; Other Names: EGT0001442, EGT0001474

Outcome Measures

Primary Outcome Measures

1. Cmax (Maximum Observed Plasma Concentration) [1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose]

   Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)

2. Tmax (Time of Maximum Observed Plasma Concentration) [1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose]

   Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)

3. AUC0-t (Area Under the Plasma Concentration-time Curve From Time 0 to t) [1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose]

   Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)

4. AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time 0 to ∞) [1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose]

   Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)

5. T1/2 (Apparent Terminal Elimination Half-life) [1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose]

   Whole venous blood samples of 3 mL were collected from a peripheral vein prior to dosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin; On Day 1 and Day 5 for Study 1, Day 1 and Day 6 for Study 2, Day 1 and Day 4 for Study 3. The pharmacokinetic parameters were estimated from the bexagliflozin plasma concentration data for each subject by non-compartmental analysis (NCA).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Each subject had to meet the following criteria to be eligible for the study:

1. Subjects who were between 18-65 years of age with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2.

2. Male subjects who were surgically sterile or male subjects who were not surgically sterile must have agreed to refrain from donating sperm and used appropriate birth control for a period of 30 days after discharge from the clinic.

3. Female subjects of childbearing potential who were willing to use an adequate method of contraception and to not become pregnant for the duration of the study.

4. Female subjects who were surgically sterile or postmenopausal were eligible if they tested negative on the urine pregnancy test.

5. Subjects who were non-smokers for at least 3 months prior to screening.

6. Subjects with adequate venous access at multiple sites in both arms.

7. Subjects who were willing and able to be confined to the clinical research facility as required by the Protocol.

8. Subjects who had the ability to comprehend and willingness to provide written informed consent in accordance with institutional and regulatory guidelines.

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

1. Subjects who were determined by the Investigator or sub-Investigator to be unsuitable for participating in the study based on medical conditions.

2. Female subjects who were nursing or pregnant.

3. Subjects with a clinically significant history of allergy to drugs or latex.

4. Subjects with a history of alcohol or drug dependence in the last 12 months.

5. Subjects who had 400 mL of whole blood collected within four months or 200 mL of whole blood collected within one month of the screening test.

6. Subjects who had blood component collection within 14 days prior to the screening test.

7. Subjects who had used prescription or over-the-counter drugs within 14 days prior to the first dose.

8. Subjects who had used vitamin preparations or supplements (including St. John's Wort and ginseng) within 14 days prior to the first dose.

9. Subjects who had undergone strenuous activity within 72 hours prior to Day 1 in each period.

10. Subjects who were unable (e.g., food intolerance) or unwilling to consume a high-fat breakfast within 25 minutes.

11. Subjects who had been treated with an investigational drug within 30 days or 7 half-lives of the investigational drug, whichever was longer, prior to the first dose of study drug in this trial.

12. Subjects who had previously received EGT0001474 or bexagliflozin, or any other SGLT2 inhibitors within 3 months from screening.

13. Subjects whose screening electrocardiogram (ECG) demonstrated any one of the following: heart rate >100 bpm, QRS >120 msec, QTc >470 msec (corrected by Bazett's formula), PR >220 msec (a subject with PR >220 msec would generally be excluded but exceptions may have been allowed at the discretion of the Investigator), or any rhythm that was not sinus rhythm, sinus bradycardia, or sinus arrhythmia.

14. Subjects whose sitting blood pressure was above 140/90 mmHg at screening.

15. Subjects who had a positive result of hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, urinary drug or urinary cotinine test.

16. Subjects with known human immunodeficiency virus (HIV) disease.

17. Subjects with abnormal vital signs, laboratory values, symptoms or signs that were deemed clinically significant by the Investigator.

18. Subjects who had had a febrile illness within 5 days prior to the first dose of study medication.

19. Subjects vaccinated within 30 days prior to the first dose of medication.

20. Detectable urine glucose at screening (trace or greater).

21. Subjects with eGFR <90 mL/min/1.73 m2 or a history of kidney transplant.

22. Subjects with digestion problems, including gastroesophageal reflux disease, irritable bowel syndrome, gastroparesis, and any other disorder deemed by the Investigator to be clinically significant.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Denver Clinical Research Unit	Lakewood	Colorado	United States	80228

Sponsors and Collaborators

• Theracos

Investigators

• Study Director: Robert Williams, M.D., Davita Clinical Research

Study Documents (Full-Text)

• Study Protocol - May 20, 2016
• Statistical Analysis Plan - Sep 13, 2016

More Information

Publications

None provided.

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT02820298
• Other Study ID Numbers: THR-1442-C-481
• First Posted: Jun 30, 2016
• Last Update Posted: Jun 10, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Bexagliflozin

Study Results

Participant Flow

Arm/Group Title	Bexagliflozin Administered in Fed Condition, Then in Fasted Condition	Bexagliflozin Administered in Fasted Condition, Then in Fed Condition
Arm/Group Description	Subjects were dosed with bexagliflozin tablet, 20 mg, with a high-fat meal on day 1 and a second dose of bexagliflozin tablet in fasted state on day 8.	Subjects were dosed with bexagliflozin tablet, 20 mg, in fasted state on day 1 and second dose of bexagliflozin tablet with a high-fat meal on day 8
Period Title: Overall Study
STARTED	13	12
COMPLETED	12	10
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	Bexagliflozin Administered in Fed Condition, Then in Fasted Condition	Bexagliflozin Administered in Fasted Condition, Then in Fed Condition	Total
Arm/Group Description	Subjects were dosed with bexagliflozin tablet, 20 mg, with a high-fat meal on day 1 and a second dose of bexagliflozin tablet in fasted state on day 8.	Subjects were dosed with bexagliflozin tablet, 20 mg, in fasted state on day 1 and second dose of bexagliflozin tablet with a high-fat meal on day 8	Total of all reporting groups
Overall Participants	13	12	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.0 (10.1)	31.8 (10.6)	31.4 (10.1)
Sex: Female, Male (Count of Participants)
Female	3 23.1%	3 25%	6 24%
Male	10 76.9%	9 75%	19 76%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 38.5%	5 41.7%	10 40%
Not Hispanic or Latino	8 61.5%	7 58.3%	15 60%
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	0 0%	1 8.3%	1 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 15.4%	1 8.3%	3 12%
White	8 61.5%	9 75%	17 68%
More than one race	1 7.7%	0 0%	1 4%
Unknown or Not Reported	2 15.4%	1 8.3%	3 12%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	75.05 (14.65)	71.58 (12.42)	73.38 (13.46)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	173.6 (9.3)	171.1 (8.8)	172.4 (9.0)

Outcome Measures

1. Primary Outcome

Title	Cmax (Maximum Observed Plasma Concentration)
Description	Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose

Outcome Measure Data

Analysis Population Description

The PK Population included all randomized subjects who received study drug and who had sufficient plasma bexagliflozin measurements to derive at least one PK parameter following dosing.

Arm/Group Title	Bexagliflozin Tablet Dosed in Fed Condition	Bexagliflozin Tablet Dosed in Fasted Condition
Arm/Group Description	Subjects were dosed with bexagliflozin tablet, 20 mg, with a high-fat meal on day 1 after an overnight fast and a second dose of bexagliflozin without a high-fat meal on day 8 after an overnight fast.	Subjects were dosed with bexagliflozin tablet, 20 mg, without a high-fat meal on day 1 after an overnight fast and a second dose of bexagliflozin with a high-fat meal on day 8 after an overnight fast.
Measure Participants	23	24
Geometric Least Squares Mean (Geometric Coefficient of Variation) [ng/mL]	176.1 (30.6)	133.7 (42.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablet Dosed in Fed Condition, Bexagliflozin Tablet Dosed in Fasted Condition
	Comments
	Type of Statistical Test	Equivalence
	Comments	The acceptance range for bioequivalence is 80.0 - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LSM
	Estimated Value	131.41
	Confidence Interval	(2-Sided) 90%; 117.03 to 147.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of Geometric LSM is the ratio of exponentiated mean difference of log-transformed PK parameter. Confidence interval from ANOVA (linear mixed-effects model) with treatment, period, and sequence as fixed effects, and subject as a random effect.

2. Primary Outcome

Title	Tmax (Time of Maximum Observed Plasma Concentration)
Description	Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Bexagliflozin Tablet Dosed in Fed Condition	Bexagliflozin Tablet Dosed in Fasted Condition
Arm/Group Description	Subjects were dosed with bexagliflozin tablet with a high-fat meal	Subjects were dosed with bexagliflozin tablet in fasted condition
Measure Participants	23	24
Median (Full Range) [hours]	5.0	3.5

3. Primary Outcome

Title	AUC0-t (Area Under the Plasma Concentration-time Curve From Time 0 to t)
Description	Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Bexagliflozin Tablet Dosed in Fed Condition	Bexagliflozin Dosed in Fasted Condition
Arm/Group Description	Subjects were dosed with bexagliflozin tablet, 20 mg, with a high-fat meal after an overnight fast.	Subjects were dosed with bexagliflozin tablet, 20 mg, in fasted condition.
Measure Participants	23	24
Geometric Least Squares Mean (Geometric Coefficient of Variation) [h*ng/mL]	1222.7 (26.8)	1074.2 (33.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablet Dosed in Fed Condition, Bexagliflozin Tablet Dosed in Fasted Condition
	Comments
	Type of Statistical Test	Equivalence
	Comments	The acceptance range for bioequivalence is 80.0 - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LSM
	Estimated Value	110.29
	Confidence Interval	(2-Sided) 90%; 103.91 to 117.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of Geometric LSM is the ratio of exponentiated mean difference of log-transformed PK parameter. Confidence interval from ANOVA (linear mixed-effects model) with treatment, period, and sequence as fixed effects, and subject as a random effect.

4. Primary Outcome

Title	AUC0-∞ (Area Under the Plasma Concentration-time Curve From Time 0 to ∞)
Description	Blood samples (2 mL) for bexagliflozin plasma concentrations were collected at 0 h (pre-dose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose (days 1-3 in treatment period 1 and days 8-10 in treatment period 2, respectively)
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Bexagliflozin Tablet Dosed in Fed Condition	Bexagliflozin Dosed in Fasted Condition
Arm/Group Description	Group 1 subjects will take one dose of bexagliflozin tablet, 20 mg, with a high-fat meal on day 1 after an overnight fast and a second dose of bexagliflozin without a high-fat meal on day 8 after an overnight fast.	Group 2 subjects will take one dose of bexagliflozin tablet, 20 mg, without a high-fat meal on day 1 after an overnight fast and a second dose of bexagliflozin with a high-fat meal on day 8 after an overnight fast.
Measure Participants	23	24
Geometric Least Squares Mean (Geometric Coefficient of Variation) [ng*h/mL]	1258.7 (5.8)	1161.8 (5.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bexagliflozin Tablet Dosed in Fed Condition, Bexagliflozin Tablet Dosed in Fasted Condition
	Comments
	Type of Statistical Test	Equivalence
	Comments	The acceptance range for bioequivalence is 80.0 - 125.00%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LSM
	Estimated Value	108.34
	Confidence Interval	(2-Sided) 90%; 102.48 to 114.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Ratio of Geometric LSM is the ratio of exponentiated mean difference of log-transformed PK parameter. Confidence interval from ANOVA (linear mixed-effects model) with treatment, period, and sequence as fixed effects, and subject as a random effect.

5. Primary Outcome

Title	T1/2 (Apparent Terminal Elimination Half-life)
Description	Whole venous blood samples of 3 mL were collected from a peripheral vein prior to dosing and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h after administration of bexagliflozin; On Day 1 and Day 5 for Study 1, Day 1 and Day 6 for Study 2, Day 1 and Day 4 for Study 3. The pharmacokinetic parameters were estimated from the bexagliflozin plasma concentration data for each subject by non-compartmental analysis (NCA).
Time Frame	1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36 and 48 h post-dose

Outcome Measure Data

Analysis Population Description

PK population

Arm/Group Title	Bexagliflozin Tablet Dosed in Fed Condition	Bexagliflozin Dosed in Fasted Condition
Arm/Group Description	Group 1 subjects will take one dose of bexagliflozin tablet, 20 mg, with a high-fat meal on day 1 after an overnight fast and a second dose of bexagliflozin without a high-fat meal on day 8 after an overnight fast.	Group 2 subjects will take one dose of bexagliflozin tablet, 20 mg, without a high-fat meal on day 1 after an overnight fast and a second dose of bexagliflozin with a high-fat meal on day 8 after an overnight fast.
Measure Participants	23	24
Geometric Mean (Geometric Coefficient of Variation) [hours]	10.1 (28.2)	11.7 (38.0)

Adverse Events

Time Frame	The adverse event data were collected from Day 0 up to Day 10
Arm/Group Title	Bexagliflozin Tablet Dosed in Fed Condition		Bexagliflozin Tablet Dosed in Fasted Condition
Arm/Group Description	Subjects were dosed with bexagliflozin tablet, 20 mg, with a high-fat meal after an overnight fast		Subjects were dosed with bexagliflozin tablet, 20 mg, in fasted condition after an overnight fast
All Cause Mortality
	Bexagliflozin Tablet Dosed in Fed Condition		Bexagliflozin Tablet Dosed in Fasted Condition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Serious Adverse Events
	Bexagliflozin Tablet Dosed in Fed Condition		Bexagliflozin Tablet Dosed in Fasted Condition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Bexagliflozin Tablet Dosed in Fed Condition		Bexagliflozin Tablet Dosed in Fasted Condition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/23 (21.7%)		1/24 (4.2%)
Blood and lymphatic system disorders
Neutropenia	1/23 (4.3%)	1	0/24 (0%)	0
Cardiac disorders
Tachycardia	1/23 (4.3%)	1	0/24 (0%)	0
General disorders
Chest discomfort	1/23 (4.3%)	1	0/24 (0%)	0
Nervous system disorders
Dizziness	1/23 (4.3%)	1	1/24 (4.2%)	1
Headache	1/23 (4.3%)	1	1/24 (4.2%)	1
Parosmia	1/23 (4.3%)	1	0/24 (0%)	0
Reproductive system and breast disorders
Uterine hemorrhage	1/23 (4.3%)	1	0/24 (0%)	0
Nasal congestion	0/23 (0%)	0	1/24 (4.2%)	1

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 the results.