Bioequivalence Study of Two Strengths of Two Different Metformin Tablets Administered to Healthy Male and Female Subjects

Bioequivalence of Two Strengths (1000 mg and 500 mg) of Two Different Metformin Tablets Administered to Healthy Male and Female Subjects in an Open, Randomised, Single-dose, Two-period Crossover, Phase I Trial

Investigation of bioequivalence of BMS Glucophage® tablets and Merck Glucophage® tablets in the strengths of 1000 mg (part I) and 500 mg (part II)

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Merck Glucophage® high dose; Drug: BMS Glucophage® high dose; Drug: Merck Glucophage® low dose; Drug: BMS Glucophage® low dose

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy males and females according to the following criteria: a complete medical history, including the physical examination, vital signs (Blood Pressure (BP), Pulse Rate (PR)), 12-lead electrocardiogram (ECG) and clinical laboratory tests
• Age ≥ 18 and Age ≤ 55 years
• BMI ≥ 18.5 and ≤ 29.9 kg/m2 (Body Mass Index)
• Signed and dated written informed consent prior to admission to the study in accordance with Good clinical practice (GCP) and the local legislation

Exclusion Criteria:

• Any finding of the medical examination deviating from normal and of clinical relevance. Repeated measurement of a systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg
• Any evidence of a clinically relevant concomitant disease
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Surgery of the gastrointestinal tract (except appendectomy)
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
• Intake of drugs within one month or less than 10 half-lives of the respective drug prior to first study drug administration except if a relevant interaction can be ruled out
• Participation in another trial with an investigational drug within two months prior to first study drug administration
• Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day)
• Inability to refrain from smoking on trial days
• Alcohol abuse (average consumption of more than 20 g/day in females and 30 g/day in males)
• Drug abuse
• Blood donation (more than 100 mL within four weeks prior to the start of study)
• Any laboratory value outside the reference range that is of clinical relevance
• Inability to comply with dietary regimen of trial site
• A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
• A history of additional risk factors for Torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)

For female subjects:

• Positive pregnancy test, pregnancy or planning to become pregnant during the study or within 1 month after study completion
• No adequate contraception during the study and until 1 month after study completion, i.e. not any of the following: implants, injectables, combined oral contraceptives, IUD (intrauterine device), sexual abstinence for at least 1 month prior to enrolment, vasectomised partner (vasectomy performed at least 1 year prior to enrolment), or surgical sterilisation (including hysterectomy). Females, who do not have a vasectomised partner, are not sexually abstinent or surgically sterile will be asked to use an additional barrier method (e.g. condom, diaphragm with spermicide)
• Lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Glucophage® high dose; Part I: Treatment A + B	Drug: Merck Glucophage® high dose; Part I: Treatment A; Drug: BMS Glucophage® high dose; Part I: Treatment B
Experimental: Glucophage® low dose; Part II: Treatment C+ D	Drug: Merck Glucophage® low dose; Part II: Treatment C; Drug: BMS Glucophage® low dose; Part II: Treatment D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
AUC0-infinity (area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity)	up to 48 h after drug administration
Cmax (maximum measured concentration of metformin in plasma)	up to 48 hours after drug administration

Secondary Outcome Measures

Outcome Measure	Time Frame
AUC0-tz (area under the concentration-time curve of metformin in plasma over the time interval from 0 to the time of the last quantifiable data point)	up to 48 h after drug administration
AUCt1-t2 (Area under the concentration time curve of metformin in plasma over the time interval t1 to t2)	up to 48 h after drug administration
tmax (time from dosing to the maximum concentration of metformin in plasma)	up to 48 h after drug administration
λz (terminal rate constant in plasma)	up to 48 h after drug administration
t1/2 (terminal half-life of metformin in plasma)	up to 48 h after drug administration
MRTpo (mean residence time of metformin in the body after po administration)	up to 48 h after drug administration
CL/F (apparent clearance of metformin in the plasma after extravascular administration)	up to 48 h after drug administration
Vz/F (apparent volume of distribution during the terminal phase λz following an extravascular dose)	up to 48 h after drug administration
Number of patients with clinically relevant differences in physical examination	Baseline, day 1 prior, within 2-10 days following the last study drug administration
Number of patients with clinically relevant differences in vital signs (BP (Blood pressure), PR (Pulse rate))	Baseline, day 1 prior, within 2-10 days following the last study drug administration
Number of patients with clinically relevant differences in 12-lead ECG (electrocardiogram)	Baseline, day 1 prior, within 2-10 days following the last study drug administration
Number of patients with clinically relevant differences in clinical laboratory tests	Baseline, day 1 prior, within 2-10 days following the last study drug administration
Number of patients with adverse events	within 2- 10 after last study drug administration
Assessment of tolerability by investigator on a 4 point scale	within 2- 10 after last study drug administration

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): April 1, 2009
• Study Completion: December 6, 2022

Study Registration Dates

• First Submitted: July 7, 2014
• First Submitted That Met QC Criteria: July 7, 2014
• First Posted (Estimate): July 8, 2014

Study Record Updates

• Last Update Posted (Estimate): July 8, 2014
• Last Update Submitted That Met QC Criteria: July 7, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 1218.57

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No