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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01725672




Registration number
NCT01725672
Ethics application status
Date submitted
1/11/2012
Date registered
14/11/2012
Date last updated
12/06/2017

Titles & IDs
Public 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
Scientific 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
Secondary ID [1] 0 0
116806
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes Mellitus, Type 2 0 0
Condition category
Condition code
Metabolic and Endocrine 0 0 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Metformin, 500 mg extended release tablet
Treatment: Drugs - Metformin, 1000 mg extended release tablet
Treatment: Drugs - Glimepiride, 1 mg immediate release tablet
Treatment: Drugs - Glimepiride, 2 mg immediate release tablet
Treatment: Drugs - Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers
Treatment: Drugs - Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers
Treatment: Drugs - Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers
Treatment: Drugs - Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers

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


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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
Timepoint [1] 0 0
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
Primary outcome [2] 0 0
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(0-8) 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(0-8) will be measured
Timepoint [2] 0 0
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 [1] 0 0
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
Timepoint [1] 0 0
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 [2] 0 0
Percentage AUCex for metformin and glimepiride; and AUC(0-8), AUC (0-t) for metformin and glimepiride in relevant treatments - Percentage of AUC(0-8) obtained by extrapolation (%AUCex), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-8)) 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
Timepoint [2] 0 0
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 [3] 0 0
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
Timepoint [3] 0 0
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

Eligibility
Key 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
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
GSK Investigational Site - Randwick
Recruitment postcode(s) [1] 0 0
2031 - Randwick

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT01725672
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT01725672