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

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

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Merck Glucophage® high dose
* Drug: BMS Glucophage® high dose
* Drug: Merck Glucophage® low dose
* Drug: BMS Glucophage® low dose


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glucophage® high dose<br>Part I: Treatment A + B | Drug: Merck Glucophage® high dose<br>* Part I: Treatment A<br>Drug: BMS Glucophage® high dose<br>* Part I: Treatment B<br>|
| Experimental: Glucophage® low dose<br>Part II: Treatment C+ D | Drug: Merck Glucophage® low dose<br>* Part II: Treatment C<br>Drug: BMS Glucophage® low dose<br>* Part II: Treatment D<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 |