Interaction of Bexagliflozin With Metformin, Glimepiride and Sitagliptin

A Phase 1, Open-label, Randomized, Three-period, Crossover Study to Evaluate Pharmacokinetic Interaction Between Bexagliflozin Tablets and Metformin, Glimepiride, or Sitagliptin in Healthy Subjects

The purpose of this study is to examine the drug-drug interaction in your body when given the study drug, bexagliflozin, with three commonly used ant-diabetic medications, metformin, glimepiride or sitagliptin. The study will also evaluate how safe the study drug is and how well the study drug is tolerated when taken with metformin, glimepiride or sitagliptin.

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sitagliptin; Drug: Bexagliflozin; Drug: Metformin; Drug: Glimepiride

Detailed Description

A total of 54 healthy subjects were enrolled and assigned to one of three groups of eighteen. Each group participated in one of three open-label, randomized, three treatment period, crossover studies:

• Group 1: Bexagliflozin/metformin drug-drug interaction (DDI)
• Group 2: Bexagliflozin/glimepiride DDI
• Group 3: Bexagliflozin/sitagliptin DDI For each Group, every subject received a single dose of bexagliflozin tablet, 20 mg, alone, a single dose of an oral hypoglycemic agent (OHA) (1000 mg metformin, 2 mg glimepiride, or 100 mg sitagliptin) alone, and the combination of both (bexagliflozin tablet and OHA) alternately in a crossover fashion, with three treatment periods separated by a washout period of at least 7 days. Within each Group, subjects were randomized to one of six treatment sequences in an equal ratio.

To prevent hypoglycemia, subjects assigned to Group 2 (bexagliflozin/glimepiride DDI) received approximately 300 mL of a solution containing 50 g of glucose with study medication at the time of dosing, as well as approximately 75 mL of a solution containing 12.5 g of glucose every 15 minutes for 4 hours post-dose.

For each treatment period in Group 1 (bexagliflozin/metformin DDI) and Group 2 (bexagliflozin/glimepiride DDI), subjects were admitted to the clinic on the day before dosing and stayed in the clinic until 48 h post-dose. For Group 3 (bexagliflozin/sitagliptin DDI), subjects stayed in the clinic until 72 h post-dose.

For all Groups, blood samples for PK analysis were collected in each period prior to dosing (pre-dose) and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose. For Group 3, PK blood samples were also collected at 60 and 72 h post-dose. Plasma concentrations of bexagliflozin and OHAs were determined by validated liquid chromatography tandem mass spectrometry (LC MS/MS) assays.

Urine samples for PD analysis were collected in 12 h intervals. For all Groups, urine samples were collected pre-dose (-12 to 0 h) and post-dose at 0 to 12 h, 12 to 24 h, 24 to 36 h, and 36 to 48 h. For Group 3, additional samples at 48 to 60 h and 60 to 72 h post-dose were collected.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Evansville, Indiana, United States, 47710
      • Clinical Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 3 months prior to screening
3. Subjects who are willing and able to be confined to the clinical research facility as required by the protocol

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. Female subjects who are pregnant or breastfeeding
5. Subjects who are not willing to use an adequate form of birth control during the study and for 30 days after discharge from clinic
6. Subjects who have taken an investigational drug in the past 30 days or 7 half-lives of the investigational drug, whichever is longer
7. Subjects who had previously received anti-diabetic medication, including metformin, sitagliptin, glimepiride or drugs of the same class (i.e. biguanides, DPP-4 inhibitors or sulfonylureas), or SGLT2 inhibitors, in the past 3 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group 1: Bexagliflozin alone	Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg
Active Comparator: Group 1: Metformin alone	Drug: Metformin; 1000 mg metformin
Active Comparator: Group 1: Bexagliflozin + Metformin	Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg; Drug: Metformin; 1000 mg metformin
Active Comparator: Group 2: Bexagliflozin alone	Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg
Active Comparator: Group 2: Glimepiride alone	Drug: Glimepiride; 4 mg glimepiride
Active Comparator: Group 2: Bexagliflozin + Glimepiride	Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg; Drug: Glimepiride; 4 mg glimepiride
Active Comparator: Group 3: Bexagliflozin alone	Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg
Active Comparator: Group 3: Sitagliptin alone	Drug: Sitagliptin; 100 mg sitagliptin
Active Comparator: Group 3: Bexagliflozin + Sitagliptin	Drug: Sitagliptin; 100 mg sitagliptin; Drug: Bexagliflozin; Bexagliflozin tablets, 20 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax (Maximum Observed Plasma Concentration)	Whole venous blood samples of 5 mL were be collected from a peripheral vein in each period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose for Group 1 and 2. Pharmacokinetic (PK) blood samples were collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose for Group 3. Plasma was obtained from centrifugation, frozen and analyzed. Cmax was obtained directly from experimental observations.	Up to 72 hours
Tmax (Time of Maximum Observed Plasma Concentration)	Whole venous blood samples of 5 mL were collected from a peripheral vein in each period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose for Group 1 and 2. PK blood samples were collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose for Group 3. Plasma was obtained from centrifugation, frozen and analyzed. Tmax was obtained directly from experimental observations.	Up to 72 hours
T1/2 (Apparent Terminal Elimination Half-life)	Whole venous blood samples of 5 mL were collected from a peripheral vein in each period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose for Group 1 and 2. PK blood samples were collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose for Group 3. Plasma was obtained from centrifugation, frozen and analyzed. T1/2 was obtained directly from experimental observations.	Up to 72 hours
AUC0-inf (Area Under the Plasma Concentration-time Curve From Time 0 to Infinity)	Whole venous blood samples of 5 mL were collected from a peripheral vein in each period at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, and 48 h post-dose for Group 1 and 2. PK blood samples were collected at pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 36, 48, 60 and 72 h post-dose for Group 3. Plasma was obtained from centrifugation, frozen and analyzed. AUC0-inf was estimated for each subject.	Up to 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Urinary Glucose Excretion up to 0-72 hr	Pre-dose urine samples were collected from -12 to 0 h for baseline measurement. Subjects was instructed to empty their bladder prior to dosing. Post-dose urine was collected in 4 batches for Groups 1 and 2 at 0 to 12 h, 12 to 24 h, 24 o 36 h, and 36 to 48 h collections. Post-dose urine was collected in batches for Group 3 at 0 to 12 h, 12 to 24 h, 24 to 36 h, 36 to 48 h, 48 to 60 h and 60 to 72 h.	up to 0-72 hr

Collaborators and Investigators

• Sponsor: Theracos
• Investigators: Study Chair: Mason Freeman, M.D., Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: November 1, 2016
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: November 2, 2016
• First Submitted That Met QC Criteria: November 2, 2016
• First Posted (Estimate): November 4, 2016

Study Record Updates

• Last Update Posted (Actual): July 22, 2021
• Last Update Submitted That Met QC Criteria: July 1, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Sitagliptin Phosphate; Glimepiride; Bexagliflozin
• Other Study ID Numbers: THR-1442-C-453

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No