Bexagliflozin Drug/Drug Interaction Study With Digoxin

• Sponsor: Theracos (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03197324
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Actual Duration (Months): 1.8
• Patients Per Site Per Month: 11.1

Study Details

Study Description

Brief Summary

The purpose of this study is to examine the drug-drug interaction in your body when given the study drug, bexagliflozin, with the heart failure medication digoxin. The study will evaluate whether bexagliflozin effects the amount of digoxin in your blood and how safe the study drug is and how well the study drug is tolerated when taken with digoxin.

Condition or Disease	Intervention/Treatment	Phase
Type2 Diabetes Mellitus	Drug: Bexagliflozin; Drug: Digoxin	Phase 1

Detailed Description

This was a phase 1, single center, open-label, two-period, two-treatment, crossover study to evaluate the effect of bexagliflozin tablets, 20 mg, on the pharmacokinetics (PK) of digoxin, 0.5 mg after co-administration in healthy subjects. Each subject was randomized into one of 2 treatment groups and participated in 2 treatment periods as outlined below. During the duration of the study, each subject received 8 single doses of bexagliflozin and 2 single doses of digoxin. Clinical laboratory tests and safety monitoring were conducted during Periods 1 and 2.

Group 1 - Period 1, Treatment A Subjects were admitted to the clinic on Day 0. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, starting on Day 1 for 8 days, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 3. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours (h) on Day 3, 24 h (Day 4), 48 h (Day 5), 72 h (Day 6), 96 h (Day 7), and 120 h (Day 8) after administration of digoxin. Subjects were discharged on Day 8.

Group 1 - Period 2, Treatment B Subjects were admitted to the clinic on Day 18. On Day 19, subjects received a single oral dose of 0.5 mg digoxin. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 19, 24 h (Day 20), 48 h (Day 21), 72 h (Day 22), 96 h (Day 23), and 120 h (Day 24) after administration of digoxin. Subjects were discharged on Day 24.

Group 2 - Period 1, Treatment B Subjects were admitted to the clinic on Day 0. On Day 1, subjects received a single oral dose of 0.5 mg digoxin. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 1, 24 h (Day 2), 48 h (Day 3), 72 h (Day 4), 96 h (Day 5), and 120 h (Day 6) after administration of digoxin. Subjects were discharged on Day 6.

Group 2 - Period 2, Treatment A Subjects were admitted to the clinic on Day 14. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 17. Blood samples for PK were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 h on Day 17, 24 h (Day 18), 48 h (Day 19), 72 h (Day 20), 96 h (Day 21), and 120 h (Day 22) after administration of digoxin. Subjects were discharged on Day 22.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 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 Bexagliflozin on the Pharmacokinetics of Digoxin in Healthy Subjects
• Actual Study Start Date: Jul 24, 2017
• Actual Primary Completion Date: Sep 17, 2017
• Actual Study Completion Date: Sep 17, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Digoxin Alone first, then Digoxin With Bexagliflozin	Drug: Digoxin; 2 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)
Active Comparator: Digoxin with Bexagliflozin, then Digoxin alone	Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg; Other Names: EGT0001442, EGT0001474 ; Drug: Digoxin; 2 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)

Outcome Measures

Primary Outcome Measures

1. Digoxin Cmax (Maximum Observed Plasma Concentration) [Up to 120 hours]

   Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin

2. Digoxin Tmax (Time of Maximum Observed Plasma Concentration) [Up to 120 hours]

   Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin

3. Digoxin T1/2 (Apparent Terminal Elimination Half-life) [Up to 120 hours]

   Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin

4. AUC0-inf (Area Under the Plasma Concentration-time Curve From Time 0 to Infinity) [Up to 120 hours]

   Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. Subjects with body-mass index (BMI) between 18.0 kg/m2 and 32.0 kg/m2

2. Subjects who are non-smokers for at least 6 months prior to first dose

3. Subjects who are willing to use an adequate form of birth control during the study and for 30 days after discharge from clinic

Exclusion Criteria:

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

2. Subjects with a history of alcohol or drug dependence in the past 12 months

3. Subjects who have donated a significant amount of blood in the past 2 months

4. Subjects who have taken an investigational drug in the past 30 days or 7 half-lives of the investigational drug, whichever is longer

5. Subjects who had previously received digoxin or drugs of the same class, or SGLT2 inhibitors, in the past 3 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Covance CRU	Daytona Beach	Florida	United States	32117

Sponsors and Collaborators

• Theracos

Investigators

• Study Director: Mason Freeman, M.D., Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol - Jun 13, 2017
• Statistical Analysis Plan - Oct 18, 2017

More Information

Publications

None provided.

• Responsible Party: Theracos
• ClinicalTrials.gov Identifier: NCT03197324
• Other Study ID Numbers: THR-1442-C-443
• First Posted: Jun 23, 2017
• Last Update Posted: Jul 23, 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, Type 2; Bexagliflozin; Digoxin

Study Results

Participant Flow

Pre-assignment Detail	In this crossover study, the subject was to participate in 2 periods during which subjects received 2 treatments (A: Bexagliflozin co-administered with digoxin, B: Digoxin alone).

Arm/Group Title	Digoxin and Bexagliflozin Tablet, Then Digoxin Alone	Digoxin, Then Digoxin and Bexagliflozin
Arm/Group Description	Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, starting on Day 1 for 8 days, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 3. Subjects were discharged on Day 8. On Day 19, subjects received a single oral dose of 0.5 mg digoxin and were discharged on Day 22.	On Day 1, subjects received a single oral dose of 0.5 mg digoxin. Subjects were discharged on Day 6. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 17. Subjects were discharged on Day 22.
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	9
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Bexagliflozin and Digoxin, Then Digoxin Alone	Digoxin Alone, Then Bexagliflozin and Digoxin	Total
Arm/Group Description	Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, starting on Day 1 for 8 days, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 3	On Day 1, subjects received a single oral dose of 0.5 mg digoxin. Subjects received daily oral doses of a bexagliflozin tablet, 20 mg, for 8 days starting on Day 15, and a single oral dose of 0.5 mg digoxin (two 0.25 mg tablets) was co-administered with bexagliflozin on Day 17.	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.8 (8.84)	35.2 (6.37)	40.0 (8.97)
Sex: Female, Male (Count of Participants)
Female	5 50%	5 50%	10 50%
Male	5 50%	5 50%	10 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 50%	7 70%	12 60%
Not Hispanic or Latino	5 50%	3 30%	8 40%
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 10%	1 5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 40%	2 20%	6 30%
White	6 60%	7 70%	13 65%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	73.6 (11.28)	74.2 (13.67)	73.9 (12.20)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.1 (8.44)	165.6 (9.35)	166.4 (8.71)

Outcome Measures

1. Primary Outcome

Title	Digoxin Cmax (Maximum Observed Plasma Concentration)
Description	Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
Time Frame	Up to 120 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Digoxin Alone	Digoxin With Bexagliflozin
Arm/Group Description	Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)	Bexagliflozin: Bexagliflozin tablets, 20 mg Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)
Measure Participants	20	19
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	2.315 (28.8)	2.301 (40.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Digoxin Alone, Digoxin With Bexagliflozin
	Comments	Geometric LS Mean was used as PK parameters
	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	100.40
	Confidence Interval	(2-Sided) 90%; 86.49 to 116.56
	Parameter Dispersion	Type: Value:
	Estimation Comments	Digoxin group is the denominator and Digoxin with Bexagliflozin is the numerator. Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subjects as a random effect.

2. Primary Outcome

Title	Digoxin Tmax (Time of Maximum Observed Plasma Concentration)
Description	Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
Time Frame	Up to 120 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Digoxin Alone	Digoxin With Bexagliflozin
Arm/Group Description	Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)	Bexagliflozin: Bexagliflozin tablets, 20 mg Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)
Measure Participants	20	19
Median (Full Range) [hours]	1.00	1.00

3. Primary Outcome

Title	Digoxin T1/2 (Apparent Terminal Elimination Half-life)
Description	Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
Time Frame	Up to 120 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Digoxin Alone	Digoxin With Bexagliflozin
Arm/Group Description	Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)	Bexagliflozin: Bexagliflozin tablets, 20 mg Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [hours]	34.3 (15.5)	38.2 (15.7)

4. Primary Outcome

Title	AUC0-inf (Area Under the Plasma Concentration-time Curve From Time 0 to Infinity)
Description	Blood samples for pharmacokinetic parameters were drawn at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 h after administration of digoxin
Time Frame	Up to 120 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Digoxin Alone	Digoxin With Bexagliflozin
Arm/Group Description	Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)	Bexagliflozin: Bexagliflozin tablets, 20 mg Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)
Measure Participants	18	18
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	35.558 (16.6)	37.805 (27.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Digoxin Alone, Digoxin With Bexagliflozin
	Comments	Geometric LS Mean was used as PK parameters
	Type of Statistical Test	Superiority
	Comments	Compare if co-administration of digoxin with bexagliflozin had significant impact on the PK of digoxin
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Geometric LSM
	Estimated Value	106.12
	Confidence Interval	(2-Sided) 90%; 95.82 to 117.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Digoxin group is the denominator and Digoxin with Bexagliflozin is the numerator. Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subjects as a random effect.

Adverse Events

Time Frame	Adverse event data were collected from Day 0 up to Day 24 of the study
Arm/Group Title	Digoxin Alone		Digoxin With Bexagliflozin
Arm/Group Description	Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)		Bexagliflozin: Bexagliflozin tablets, 20 mg Digoxin: Two 0.25 mg Digoxin tablets (total dose 0.5 mg digoxin)
All Cause Mortality
	Digoxin Alone		Digoxin With Bexagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)
Serious Adverse Events
	Digoxin Alone		Digoxin With Bexagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/19 (0%)
Other (Not Including Serious) Adverse Events
	Digoxin Alone		Digoxin With Bexagliflozin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		5/19 (26.3%)
Cardiac disorders
Palpitations	0/20 (0%)	0	1/19 (5.3%)	1
Eye disorders
Vision blurred	1/20 (5%)	1	0/19 (0%)	0
Gastrointestinal disorders
Nausea	1/20 (5%)	1	1/19 (5.3%)	1
General disorders
Fatigue	0/20 (0%)	0	1/19 (5.3%)	1
Medical device site reaction	1/20 (5%)	1	0/19 (0%)	0
Infections and infestations
Upper respiratory tract infection	1/20 (5%)	1	1/19 (5.3%)	1
Urinary tract infection	0/20 (0%)	0	1/19 (5.3%)	1
Injury, poisoning and procedural complications
Excoriation	0/20 (0%)	0	1/19 (5.3%)	1
Metabolism and nutrition disorders
Hypoglycemia	0/20 (0%)	0	1/19 (5.3%)	1
Nervous system disorders
Dizziness	0/20 (0%)	0	1/19 (5.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI does not have the right to publish trial results.