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

GlaxoSmithKline (GSK)

Status and phase: Terminated; Phase 1

Conditions: Diabetes Mellitus, Type 2

Treatments: Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers; Drug: Metformin, 500 mg extended release tablet; 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: Glimepiride, 2 mg immediate release tablet; Drug: Metformin, 1000 mg extended release tablet; Drug: Glimepiride, 1 mg immediate release tablet; Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers

Study type: Interventional

Funder types: Industry

Identifiers

NCT01725672

116806

Details and patient eligibility

About

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.

Enrollment: 20 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

---

20 participants in 6 patient groups

Part A and B:Arm 1: 500 mg metformin XR / 1 mg glimepiride IR

Active Comparator group

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

Treatment:

Drug: Metformin, 500 mg extended release tablet

Drug: Glimepiride, 1 mg immediate release tablet

Part A and B:Arm 2: 1000 mg metformin XR / 2 mg glimepiride IR

Active Comparator group

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

Treatment:

Drug: Glimepiride, 2 mg immediate release tablet

Drug: Metformin, 1000 mg extended release tablet

Part A:Arm 3: 500 mg metformin XR and 1 mg glimepiride XR

Experimental group

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

Treatment:

Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release film coated tablet containing release controlling polymers

Part A:Arm 4: 1000 mg metformin XR and 2 mg glimepiride XR

Experimental group

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

Treatment:

Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release film coated tablet containing release controlling polymers

Part B:Arm 5: 500 mg metformin XR and 1 mg glimepiride XR

Experimental group

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

Treatment:

Drug: Metformin, 500 mg and Glimepiride, 1 mg extended release tablet coated with release controlling polymers

Part B:Arm 6: 1000 mg metformin XR and 2 mg glimepiride XR

Experimental group

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

Treatment:

Drug: Metformin, 1000 mg and Glimepiride, 2 mg extended release tablet coated with release controlling polymers