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Due to changes in EMA guidelines on modified release dosage forms (Feb 2013; EMA/CHMP/EWP/280/96). The Part B formulation would not meet the new guidelines.
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This is a an open-label, randomized, single dose, four-way crossover, multi-stage study enrolling 20 healthy adult male and female subjects per part. This study consists of two separate parts (Part A and B) with each part comprising four treatment periods. Each subject will participate in all four treatment periods per part; Subjects may not enrol in both Parts A and B.
This study is being conducted to compare the pharmacokinetics (PK) of two extended release fixed dose combinations (FDC) oral formulations of metformin and glimepiride at two doses, 500mg/1mg and 1000mg/2mg, with each FDC formulation to be administered orally as a single dose and compared with the commercially available formulations of metformin extended release (XR) (GLUCOPHAGE ™ Sustained Release [SR]) and glimepiride immediate release (IR) (AMARYL ™).
Part A of study will evaluate the bioavailability of a formulation comprising a film coated tablet containing release controlling polymers; and Part B will evaluate the bioavailability of a formulation comprising a tablet coated with release controlling polymers.
In each part there will be 4 treatment periods. During each period, subjects will be randomized sequentially to receive a single dose of a reference treatment of 500 mg metformin XR / 1 mg glimepiride IR; and a reference treatment of 1000 mg metformin XR / 2 mg glimepiride IR; and an FDC tablet containing 500 mg metformin XR and 1 mg glimepiride XR; and an FDC tablet containing 1000 mg metformin XR and 2 mg glimepiride XR.Serial PK sampling for up to 36 hours and safety assessments will be performed. Each period will be separated by a washout period of at least 5 days and a follow-up visit will occur 14 days after the last dose of study drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A and B:Arm 1: 500 mg metformin XR / 1 mg glimepiride IR | Active Comparator | In Part A and Part B of the study, subjects will receive single dose oral tablets of 500 mg metformin XR and 1 mg glimepiride IR on Day 1 of the respective period per randomized sequence |
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| Part A and B:Arm 2: 1000 mg metformin XR / 2 mg glimepiride IR | Active Comparator | In Part A and Part B of the study, subjects will receive single dose oral tablets of 1000 mg metformin XR and 2 mg glimepiride IR on Day 1 of the respective period per randomized sequence |
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| Part A:Arm 3: 500 mg metformin XR and 1 mg glimepiride XR | Experimental | In Part A of the study subjects will receive single oral dose of 500 mg metformin XR and 1 mg glimepiride XR (FDC1) film coated tablet containing release controlling polymers on Day 1 of the respective period per randomized sequence |
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| Part A:Arm 4: 1000 mg metformin XR and 2 mg glimepiride XR | Experimental | In Part A of the study subjects will receive single oral dose of 1000 mg metformin XR and 2 mg glimepiride XR (FDC1) film coated tablet containing release controlling polymers on Day 1 of the respective period per randomized sequence |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Metformin, 500 mg extended release tablet | Drug | In Part A and Part B of the study, Metformin 500 mg XR tablet will be administered with 240 millilitre (mL) water ; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of metformin | The PK parameter: maximum concentration (Cmax) will be determines from the plasma concentration-time data. To select the dose of metformin and glimepiride that achieves the best PK profile Cmax will be measured | At regular timepoints on Day 1 (0.5, 1, 1.5, ,2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose) and once at Day 2 (36 hours post dose) of each of the 4 treatment periods in Part A and Part B |
| AUC(0-t) and AUC(0-inf) for metformin and glimepiride | The PK parameters: Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable AUC(0-t) concentration; and area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time AUC(0-∞) will be determines from the plasma concentration-time data. To select the dose of metformin and glimepiride that achieves the best PK profile AUC(0-t) and AUC(0-∞) will be measured | At regular timepoints on Day 1 (0.5, 1, 1.5, ,2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose) and once at Day 2 (36 hours post dose) of each of the 4 treatment periods in Part A and Part B |
| Measure | Description | Time Frame |
|---|---|---|
| Tmax and t1/2 of of metformin and glimepiride | The PK parameters: Time of occurrence of Cmax (tmax); and terminal phase half-life (t½) will be determines from the plasma concentration-time data. To select the dose of metformin and glimepiride that achieves the best PK profile tmax and t1/2 will be measured , as data permit | At regular timepoints on Day 1 (0.5, 1, 1.5, ,2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose) and once at Day 2 (36 hours post dose) of each of the 4 treatment periods in Part A and Part B |
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Inclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Randwick | New South Wales | 2031 | Australia |
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| Label | URL |
|---|---|
| Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research. | View source |
| Results for study 116806 can be found on the GSK Clinical Study Register. | View source |
| ID | Type | URL | Comment |
|---|---|---|---|
| 116806 | Clinical Study Report | View IPD |
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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| Part B:Arm 5: 500 mg metformin XR and 1 mg glimepiride XR | Experimental | In Part B of the study subjects will receive single oral dose of 500 mg metformin XR and 1 mg glimepiride XR (FDC3) tablet coated with release controlling polymers on Day 1 of the respective period per randomized sequence |
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| Part B:Arm 6: 1000 mg metformin XR and 2 mg glimepiride XR | Experimental | In Part B of the study subjects will receive single oral dose of 1000 mg metformin XR and 2 mg glimepiride XR (FDC4) tablet coated with release controlling polymers on Day 1 of the respective period per randomized sequence |
|
| Metformin, 1000 mg extended release tablet | Drug | In Part A and Part B of the study, Metformin 1000 mg XR tablet will be administered with 240mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
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| Glimepiride, 1 mg immediate release tablet | Drug | In Part A and Part B of the study, Glimepiride 1 mg IR tablet will be administered with 240mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
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| Glimepiride, 2 mg immediate release tablet | Drug | In Part A and Part B of the study, Glimepiride 2 mg IR tablet will be administered with 240mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
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| Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers | Drug | In Part A of the study, 1 XR film coated tablet combination of Metformin 500 mg and Glimepiride 1 mg will be administered with 240 mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
|
| Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers | Drug | In Part A of the study, 1 XR film coated tablet combination of Metformin 1000 mg and Glimepiride 2 mg will be administered with 240 mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
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| Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers | Drug | In Part B of the study, 1 XR tablet combination of Metformin 500 mg and Glimepiride 1 mg will be administered with 240 mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
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| Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers | Drug | In Part B of the study, 1 XR tablet combination of Metformin 1000 mg and Glimepiride 2 mg will be administered with 240 mL water; 125 mL of LUCOZADE was administered every 30 mins for 4 hours after dosing. |
|
| Percentage AUCex for metformin and glimepiride; and AUC(0-∞), AUC (0-t) for metformin and glimepiride in relevant treatments | Percentage of AUC(0-∞) obtained by extrapolation (%AUCex), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-∞)) and area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC (0-t))will be determined from the plasma concentration-time data | At regular timepoints on Day 1 (0.5, 1, 1.5, ,2, 2.5, 3, 4, 6, 8, 10, 12, 16, 24 hours post dose) and once at Day 2 (36 hours post dose) of each of the 4 treatment periods in Part A and Part B |
| Number of subjects with adverse events (AE)s | Comparison of adverse events (as determined by vital signs and electrocardiogram measurements and clinical lab results) after administration of two metformin and glimepiride fixed dose combinations in comparison to reference treatment (to determine the safety and tolerability) in Part A and Part B of the study | Participants will be followed and monitored for the duration of their hospital stay (24 hours per treatment period). The longest duration of participation in the study will be approximately 13 weeks |
For additional information about this study please refer to the GSK Clinical Study Register |
| 116806 | Annotated Case Report Form | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116806 | Study Protocol | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116806 | Dataset Specification | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116806 | Informed Consent Form | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116806 | Individual Participant Data Set | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| 116806 | Statistical Analysis Plan | View IPD | For additional information about this study please refer to the GSK Clinical Study Register |
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| C057619 | glimepiride |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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