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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.
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:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group 1: Bexagliflozin alone | Active Comparator |
| |
| Group 1: Metformin alone | Active Comparator |
| |
| Group 1: Bexagliflozin + Metformin | Active Comparator |
| |
| Group 2: Bexagliflozin alone | Active Comparator |
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| Group 2: Glimepiride alone | Active Comparator |
| |
| Group 2: Bexagliflozin + Glimepiride | Active Comparator |
| |
| Group 3: Bexagliflozin alone | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bexagliflozin | Drug | Bexagliflozin tablets, 20 mg |
|
| 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. |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Mason Freeman, M.D. | Massachusetts General Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Research Site | Evansville | Indiana | 47710 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | Group 1: Bexagliflozin + Metformin | Bexagliflozin tablets 20 mg alone, Metformin tablets 1000 mg alone, or Bexagliflozin 20 mg + Metformin 1000 mg |
| FG001 | Group 2: Bexagliflozin + Glimepiride | Bexagliflozin tablets 20 mg alone, Glimepiride tablets 2 mg alone, or Bexagliflozin 20 mg + Glimepiride 2 mg |
| FG002 | Group 3: Bexagliflozin + Sitagliptin | Bexagliflozin tablets 20 mg alone, Sitagliptin 100 mg alone, or Bexagliflozin 20 mg + Sitagliptin 100 mg |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Group 1: Bexagliflozin + Metformin | Bexagliflozin tablets 20 mg alone, Metformin tablets 1000 mg alone, or Bexagliflozin 20 mg + Metformin 1000 mg |
| BG001 | Group 2: Bexagliflozin + Glimepiride |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | The study was designed to evaluate the potential bexagliflozin drug interactions. Study participants were dosed with bexagliflozin alone, other drug alone or both drugs sequentially. The pharmacokinetic parameters were calculated based on the specific analyte using samples collected after dosing of the drug. Therefore, not all samples were analyzed for all outcome measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Up to 72 hours |
|
Adverse event collection began on the first clinical admission day (Day 0) and continued through D17. The subjects were actively monitored for serious adverse events for at least 14 days after discharge from the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Group 1: Bexagliflozin Alone | Bexagliflozin: Bexagliflozin tablets, 20 mg | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Program Director | Translational Medicine Group | 617-726-4236 | yhalvorsen@ccib.mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 1, 2016 | Feb 12, 2020 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 7, 2017 | Jun 28, 2021 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C000705992 | bexagliflozin |
| D008687 | Metformin |
| C057619 | glimepiride |
| D000068900 | Sitagliptin Phosphate |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
| D014230 |
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| Group 3: Sitagliptin alone | Active Comparator |
|
| Group 3: Bexagliflozin + Sitagliptin | Active Comparator |
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| Metformin | Drug | 1000 mg metformin |
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| Glimepiride | Drug | 4 mg glimepiride |
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| Sitagliptin | Drug | 100 mg sitagliptin |
|
| Up to 72 hours |
| up to 0-72 hr |
Bexagliflozin tablets 20 mg alone, Glimepiride tablets 2 mg alone, or Bexagliflozin 20 mg + Glimepiride 2 mg
| BG002 | Group 3: Bexagliflozin + Sitagliptin | Bexagliflozin tablets 20 mg alone, Sitagliptin 100 mg alone, or Bexagliflozin 20 mg + Sitagliptin 100 mg |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | kg |
|
| Height | Mean | Standard Deviation | cm |
|
Bexagliflozin: Bexagliflozin tablets, 20 mg |
| OG001 | Group 1: Metformin Alone | Metformin: Metformin tablets, 1000 mg |
| OG002 | Group 1: Bexagliflozin + Metformin | Bexagliflozin: Bexagliflozin tablets, 20 mg Metformin: Metformin tablets, 1000 mg |
| OG003 | Group 2: Bexagliflozin Alone | Bexagliflozin: Bexagliflozin tablets, 20 mg |
| OG004 | Group 2: Glimepiride Alone | Glimepiride: Glimepiride tablets, 2 mg |
| OG005 | Group 2: Bexagliflozin + Glimepiride | Bexagliflozin: Bexagliflozin tablets, 20 mg Glimepiride: Glimepiride tablets, 2 mg |
| OG006 | Group 3: Bexagliflozin Alone | Bexagliflozin: Bexagliflozin tablets, 20 mg |
| OG007 | Group 3: Sitagliptin Alone | Sitagliptin: Sitagliptin tablets, 100 mg |
| OG008 | Group 3: Bexagliflozin + Sitagliptin | Bexagliflozin: Bexagliflozin tablets, 20 mg Sitagliptin: Sitagliptin tablets, 100 mg |
|
|
|
| Primary | 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. | The study was designed to evaluate the potential bexagliflozin drug interactions. Study participants were dosed with bexagliflozin alone, other drug alone or both drugs sequentially. The pharmacokinetic parameters were calculated based on the specific analyte using samples collected after dosing of the drug. Therefore, not all samples were analyzed for all outcome measurements. | Posted | Median | Full Range | hours | Up to 72 hours |
|
|
|
| Primary | 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. | The study was designed to evaluate the potential bexagliflozin drug interactions. Study participants were dosed with bexagliflozin alone, other drug alone or both drugs sequentially. The pharmacokinetic parameters were calculated based on the specific analyte using samples collected after dosing of the drug. Therefore, not all samples were analyzed for all outcome measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Up to 72 hours |
|
|
|
| Primary | 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. | The study was designed to evaluate the potential bexagliflozin drug interactions. Study participants were dosed with bexagliflozin alone, other drug alone or both drugs sequentially. The pharmacokinetic parameters were calculated based on the specific analyte using samples collected after dosing of the drug. Therefore, not all samples were analyzed for all outcome measurements. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Up to 72 hours |
|
|
|
|
| Secondary | 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. | Only subjects with data in the specific category is analyzed | Posted | Mean | Standard Deviation | g | up to 0-72 hr |
|
|
|
| 18 |
| 0 |
| 18 |
| 3 |
| 18 |
| EG001 | Group 1: Metformin Alone | Metformin: Metformin tablets, 1000 mg | 0 | 18 | 0 | 18 | 11 | 18 |
| EG002 | Group 1: Bexagliflozin + Metformin | Bexagliflozin: Bexagliflozin tablets, 20 mg Metformin: Metformin tablets, 1000 mg | 0 | 18 | 0 | 18 | 13 | 18 |
| EG003 | Group 2: Bexagliflozin Alone | Bexagliflozin: Bexagliflozin tablets, 20 mg | 0 | 18 | 0 | 18 | 6 | 18 |
| EG004 | Group 2: Glimepiride Alone | Glimepiride: Glimepiride tablets, 2 mg | 0 | 18 | 0 | 18 | 2 | 18 |
| EG005 | Group 2: Bexagliflozin + Glimepiride | Bexagliflozin: Bexagliflozin tablets, 20 mg Glimepiride: Glimepiride tablets, 2 mg | 0 | 18 | 0 | 18 | 4 | 18 |
| EG006 | Group 3: Bexagliflozin Alone | Bexagliflozin: Bexagliflozin tablets, 20 mg | 0 | 18 | 0 | 18 | 3 | 18 |
| EG007 | Group 3: Sitagliptin Alone | Sitagliptin: Sitagliptin tablets, 100 mg | 0 | 18 | 0 | 18 | 1 | 18 |
| EG008 | Group 3: Bexagliflozin + Sitagliptin | Bexagliflozin: Bexagliflozin tablets, 20 mg Sitagliptin: Sitagliptin tablets, 100 mg | 0 | 18 | 0 | 18 | 2 | 18 |
| Nausea | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Dyspepsia | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Tenderness | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Vessel puncture site haemorrhage | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Puncture site pain | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Puncture site swelling | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Xerosis | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Catheter site induration | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Catheter site pain | General disorders | MedDRA 20.0 | Systematic Assessment |
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| Gun shot wound | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
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| Hypoglycemia | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
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| Paresthesia | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
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| Dysmenorrhea | Reproductive system and breast disorders | MedDRA 20.0 | Systematic Assessment |
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| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Swelling of face | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
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| Urticaria | Skin and subcutaneous tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
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| Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |
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| Metformin PK parameters |
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| Glimepiride PK parameters |
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| Sitagliptin PK parameters |
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| Metformin PK parameters |
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| Glimepiride PK parameters |
|
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| Sitagliptin PK parameters |
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| Metformin PK parameters |
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| Glimepiride PK parameters |
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| Sitagliptin PK parameters |
|
|
Geometric LS Mean was used as PK parameters |
| Ratio of Geometric LSM |
| 103.24 |
| 2-Sided |
| 90 |
| 94.59 |
| 112.68 |
Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subject as a random effect |
| Equivalence |
The acceptance range for bioequivalence is 80.0 - 125.00% |
| Geometric LS Mean was used as PK parameters | Ratio of Geometric LSM | 94.46 | 2-Sided | 90 | 80.34 | 111.06 | Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subject as a random effect | Equivalence | The acceptance range for bioequivalence is 80.0 - 125.00% |
| Geometric LS Mean was used as PK parameters | [Ratio of Geometric LSM] | 127.19 | 2-Sided | 90 | 110.33 | 146.62 | Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subject as a random effect | Equivalence | The acceptance range for bioequivalence is 80.0 - 125.00%. |
| Geometric LS Mean was used as PK parameters | [Ratio of Geometric LSM] | 113.09 | 2-Sided | 90 | 107.61 | 118.86 | Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subject as a random effect | Equivalence | The acceptance range for bioequivalence is 80.0 - 125.00% |
| Geometric LS Mean was used as PK parameters | [Ratio of Geometric LSM] | 103.16 | 2-Sided | 90 | 99.30 | 107.17 | Equivalence | The acceptance range for bioequivalence is 80.0 - 125.00% | Confidence interval from ANOVA with treatment, period, and sequence as fixed effects, and subject as a random effect |
|
| 12 - 24 hours |
|
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| 24 - 36 hours |
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| 36 - 48 hours |
|
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| 48 - 60 hours |
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| 60 - 72 hours |
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|