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

Overview[ - collapse ][ - ]

Purpose 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.
ConditionDiabetes Mellitus, Type 2
InterventionDrug: Metformin, 500 mg extended release tablet
Drug: Metformin, 1000 mg extended release tablet
Drug: Glimepiride, 1 mg immediate release tablet
Drug: Glimepiride, 2 mg immediate release tablet
Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers
Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers
Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers
Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers
PhasePhase 1
SponsorGlaxoSmithKline
Responsible PartyGlaxoSmithKline
ClinicalTrials.gov IdentifierNCT01725672
First ReceivedNovember 1, 2012
Last UpdatedNovember 27, 2013
Last verifiedNovember 2013

Tracking Information[ + expand ][ + ]

First Received DateNovember 1, 2012
Last Updated DateNovember 27, 2013
Start DateSeptember 2012
Estimated Primary Completion DateDecember 2012
Current Primary Outcome Measures
  • Cmax of metformin [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] [Designated as safety issue: No]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 [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] [Designated as safety issue: No]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
Current Secondary Outcome Measures
  • Tmax and t1/2 of of metformin and glimepiride [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] [Designated as safety issue: No]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 [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] [Designated as safety issue: No]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 [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] [Designated as safety issue: No]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

Descriptive Information[ + expand ][ + ]

Brief TitleCrossover 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 TitleAn 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
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.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 1
Study DesignAllocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment
ConditionDiabetes Mellitus, Type 2
InterventionDrug: Metformin, 500 mg extended release tablet
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.
Drug: Metformin, 1000 mg extended release tablet
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.
Drug: Glimepiride, 1 mg immediate release tablet
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.
Drug: Glimepiride, 2 mg immediate release tablet
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.
Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers
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.
Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers
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.
Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers
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.
Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers
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.
Study Arm (s)
  • Active Comparator: Part A and B:Arm 1: 500 mg metformin XR / 1 mg glimepiride IR
    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
  • Active Comparator: Part A and B:Arm 2: 1000 mg metformin XR / 2 mg glimepiride IR
    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
  • Experimental: Part A:Arm 3: 500 mg metformin XR and 1 mg glimepiride XR
    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
  • Experimental: Part A:Arm 4: 1000 mg metformin XR and 2 mg glimepiride XR
    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
  • Experimental: Part B:Arm 5: 500 mg metformin XR and 1 mg glimepiride XR
    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
  • Experimental: Part B:Arm 6: 1000 mg metformin XR and 2 mg glimepiride XR
    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

Recruitment Information[ + expand ][ + ]

Recruitment StatusTerminated
Estimated Enrollment20
Estimated Completion DateDecember 2012
Estimated Primary Completion DateDecember 2012
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 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.
GenderBoth
Ages18 Years
Accepts Healthy VolunteersAccepts Healthy Volunteers
ContactsNot Provided
Location CountriesAustralia

Administrative Information[ + expand ][ + ]

NCT Number NCT01725672
Other Study ID Numbers116806
Has Data Monitoring CommitteeNot Provided
Information Provided ByGlaxoSmithKline
Study SponsorGlaxoSmithKline
CollaboratorsNot Provided
Investigators Study Director: GSK Clinical Trials GlaxoSmithKline
Verification DateNovember 2013

Locations[ + expand ][ + ]

GSK Investigational Site
Randwick, New South Wales, Australia, 2031