Back to resultsCrossover Study to Evaluate the Comparative Bioavailability of Two Fixed Dose Combination Tablet Formulations of Extended Release Metformin and Extended Release Glimepiride in Health Volunteers
Primary Purpose
Diabetes Mellitus, Type 2
Status
Terminated
Phase
Phase 1
Locations
Australia
Study Type
Interventional
Intervention
Metformin, 500 mg extended release tablet
Metformin, 1000 mg extended release tablet
Glimepiride, 1 mg immediate release tablet
Glimepiride, 2 mg immediate release tablet
Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers
Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers
Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers
Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus, Type 2 focused on measuring healthy volunteers, Diabetes mellitus, glimepiride, pharmacokinetics, metformin
Eligibility Criteria
Inclusion Criteria:
- Healthy male or female subjects between 18 and 65 years of age inclusive with body weight >= 50 kg and body mass index (BMI) within the range 19 to 32 kilogram/meter squared
- Alanine aminotransferase (ALT) alkaline phosphatase and bilirubin <or=1.5x upper limit of normal (ULN).
- Normal ECG measurements. Average QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 millisecond or QTcF <480 msec in subjects with Bundle Branch Block based on an average from three electrocardiograms (ECGs) obtained over a brief recording period.
- Female subjects of non-child bearing potential. Females of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy until 14 days post-last dose of metformin/glimepiride.
- Capable of giving written informed consent
Exclusion Criteria:
- The subject has a positive: drug/alcohol screen, Hepatitis, HIV screen
- Abuse of alcohol
- Current or chronic history of liver disease, or known hepatic or biliary abnormalities
- Exposure to more than four new investigational chemical entities within 12 months prior to the first dosing day
- Participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)
- Sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
- Donation of more than 500 mL blood within a 56 day period
- Pregnant or lactating females
- Unwillingness or inability to follow the procedures outlined in the protocol
- Subject is mentally or legally incapacitated
- Subject having positive urinary cotinine levels indicative of use of tobacco or nicotine-containing products within 6 months prior to screening.
- Unable to refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose
- Subjects having asthma or are positive carbon monoxide (CO) on admission to the Unit
- Unable to refrain from the use of prescription or non-prescription drugs within 7 days prior to first dose of study medication, unless approved by the Investigator and GSK Medical Monitor.
Sites / Locations
- GSK Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Active Comparator
Active Comparator
Experimental
Experimental
Experimental
Experimental
Arm Label
Part A and B:Arm 1: 500 mg metformin XR / 1 mg glimepiride IR
Part A and B:Arm 2: 1000 mg metformin XR / 2 mg glimepiride IR
Part A:Arm 3: 500 mg metformin XR and 1 mg glimepiride XR
Part A:Arm 4: 1000 mg metformin XR and 2 mg glimepiride XR
Part B:Arm 5: 500 mg metformin XR and 1 mg glimepiride XR
Part B:Arm 6: 1000 mg metformin XR and 2 mg glimepiride XR
Arm Description
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
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
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
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
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
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
Outcomes
Primary Outcome Measures
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
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
Secondary Outcome Measures
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
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
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
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01725672
Brief Title
Crossover Study to Evaluate the Comparative Bioavailability of Two Fixed Dose Combination Tablet Formulations of Extended Release Metformin and Extended Release Glimepiride in Health Volunteers
Official Title
An Open-Label, Randomized, Single Dose, Four-way Crossover, Multi-stage Study to Determine the Comparative Bioavailability of Two Fixed Dose Combination Tablet Formulations, 500 mg or 1000 mg Extended Release Metformin and 1 mg or 2 mg Extended Release Glimepiride, in Healthy Adult Male and Female Subjects in the Fed State
Study Type
Interventional
2. Study Status
Record Verification Date
June 2017
Overall Recruitment Status
Terminated
Why Stopped
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.
Study Start Date
September 27, 2012 (Actual)
Primary Completion Date
August 21, 2013 (Actual)
Study Completion Date
August 21, 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2
Keywords
healthy volunteers, Diabetes mellitus, glimepiride, pharmacokinetics, metformin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part A and B:Arm 1: 500 mg metformin XR / 1 mg glimepiride IR
Arm Type
Active Comparator
Arm Description
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
Arm Title
Part A and B:Arm 2: 1000 mg metformin XR / 2 mg glimepiride IR
Arm Type
Active Comparator
Arm Description
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
Arm Title
Part A:Arm 3: 500 mg metformin XR and 1 mg glimepiride XR
Arm Type
Experimental
Arm Description
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
Arm Title
Part A:Arm 4: 1000 mg metformin XR and 2 mg glimepiride XR
Arm Type
Experimental
Arm Description
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
Arm Title
Part B:Arm 5: 500 mg metformin XR and 1 mg glimepiride XR
Arm Type
Experimental
Arm Description
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
Arm Title
Part B:Arm 6: 1000 mg metformin XR and 2 mg glimepiride XR
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Metformin, 500 mg extended release tablet
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin, 1000 mg extended release tablet
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Glimepiride, 1 mg immediate release tablet
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Glimepiride, 2 mg immediate release tablet
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers
Intervention Description
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.
Primary Outcome Measure Information:
Title
Cmax of metformin
Description
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
Time Frame
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
Title
AUC(0-t) and AUC(0-inf) for metformin and glimepiride
Description
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
Time Frame
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
Secondary Outcome Measure Information:
Title
Tmax and t1/2 of of metformin and glimepiride
Description
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
Time Frame
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
Title
Percentage AUCex for metformin and glimepiride; and AUC(0-∞), AUC (0-t) for metformin and glimepiride in relevant treatments
Description
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
Time Frame
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
Title
Number of subjects with adverse events (AE)s
Description
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
Time Frame
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria:
Healthy male or female subjects between 18 and 65 years of age inclusive with body weight >= 50 kg and body mass index (BMI) within the range 19 to 32 kilogram/meter squared
Alanine aminotransferase (ALT) alkaline phosphatase and bilirubin <or=1.5x upper limit of normal (ULN).
Normal ECG measurements. Average QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 millisecond or QTcF <480 msec in subjects with Bundle Branch Block based on an average from three electrocardiograms (ECGs) obtained over a brief recording period.
Female subjects of non-child bearing potential. Females of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy until 14 days post-last dose of metformin/glimepiride.
Capable of giving written informed consent
Exclusion Criteria:
The subject has a positive: drug/alcohol screen, Hepatitis, HIV screen
Abuse of alcohol
Current or chronic history of liver disease, or known hepatic or biliary abnormalities
Exposure to more than four new investigational chemical entities within 12 months prior to the first dosing day
Participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)
Sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
Donation of more than 500 mL blood within a 56 day period
Pregnant or lactating females
Unwillingness or inability to follow the procedures outlined in the protocol
Subject is mentally or legally incapacitated
Subject having positive urinary cotinine levels indicative of use of tobacco or nicotine-containing products within 6 months prior to screening.
Unable to refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose
Subjects having asthma or are positive carbon monoxide (CO) on admission to the Unit
Unable to refrain from the use of prescription or non-prescription drugs within 7 days prior to first dose of study medication, unless approved by the Investigator and GSK Medical Monitor.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Randwick
State/Province
New South Wales
ZIP/Postal Code
2031
Country
Australia
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Links:
URL
https://www.clinicalstudydatarequest.com
Description
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.
Available IPD and Supporting Information:
Available IPD/Information Type
Clinical Study Report
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Annotated Case Report Form
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Study Protocol
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Dataset Specification
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Informed Consent Form
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Statistical Analysis Plan
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
116806
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Learn more about this trial
Crossover Study to Evaluate the Comparative Bioavailability of Two Fixed Dose Combination Tablet Formulations of Extended Release Metformin and Extended Release Glimepiride in Health Volunteers
We'll reach out to this number within 24 hrs