GXR RM (Glucophage® Extended Release Reduced Mass) 500 Milligram (mg) Korea Bioequivalence (BE) Study

Study Overview
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Brief Summary
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The purpose of this study was to assess bioequivalence (BE) of newly developed Glucophage® XR (GXR) reduced mass (RM) tablet (metformin hydrochloride 500 milligrams (mg) test tablet) and marketed Glucophage ® XR tablet (metformin hydrochloride 500 mg reference tablet) following single oral dose administration under fasted and fed conditions by comparing pharmacokinetics, safety and tolerability between test and reference in healthy participants.

Official Title
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A Randomized Phase I, Open-Label, Active-Controlled Study Assessing The BE Between Single Doses of 500 mg GXR RM Tablets and 500 mg GXR Tablets Under Fasted and Fed State in Two 2-Way Crossover Groups of Healthy Participants

Conditions
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Healthy

Intervention / Treatment
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* Drug: Glucophage® XR RM Test
* Drug: Glucophage® XR Reference


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All values for hematology and biochemistry tests of blood and urinalysis (especially Estimated Glomerular Filtration Rate [eGFR] greater than [>] 80 milliliters per minute per 1.73 square meter [80 ml/min/1.73 m^2] and normal Creatinine) within the normal range or showing no clinically relevant deviation as judged by the Investigator Are not having congenital or chronic diseases, nor pathological symptoms based on the screening Have no history of gastrointestinal resection that may affect drug absorption Have no history of psychiatric disorder within 5 years prior to screening Vital signs (body temperature [tympanic], blood pressure [BP], and pulse rate in sitting position) within the normal range or showing no clinically relevant deviation as judged by the Investigator Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in particular QTc (Bazett) less than or equal to [<=] 450 millisecond (ms) Non-smoker (that is [i.e.] zero cigarettes, pipes, cigars or others) at least three months before study entry Negative screen for Hepatitis B surface antigen (HBsAg) and Hepatitis B Virus antibody (anti-HBc), Hepatitis C Virus antibody (anti-HCV) and Human Immunodeficiency Virus antibodies (anti-HIV 1 and 2) and Rapid Plasma Reagin Antibody (RPR Ab) Have a body weight within the range 55 to 95 kilograms (kg) and a Body Mass Index (BMI) within the range 18.5 to 29.9 kilograms per square meter (kg/m^2) (inclusive) Other protocol defined inclusion criteria could apply Exclusion Criteria: Participants determined ineligible to participate in this study at the discretion of the Principal Investigator (or delegated investigators) Hypersensitivity to venous puncture Known hypersensitivity to ingredients of Study Interventions or Biguanides, or having other clinically relevant hypersensitivities Type I diabetes mellitus, lactic acidosis, acute or chronic metabolic acidosis including diabetic ketoacidosis, with or without coma; diabetic pre-coma, pre-diabetes Participants with renal impairment (eGFR < 80 ml/min/1.73m^2) - calculations according to Modification of Diet in Renal Disease (MDRD) formula). Participants presenting with acute conditions with the potential to alter renal function such as dehydration, severe infection, cardiovascular collapse (shock), acute myocardial infraction, and septicemia Participants with acute and unstable heart failure Participants with severe infection or severe traumatic general disorder Participants who are scheduled to undergo surgical procedures Participants with malnutrition, inanition, pituitary dysfunction or adrenal function failure Participants with hepatic dysfunction, acute or chronic disease which may cause tissue hypoxia such as respiratory failure, acute myocardial infarction, shock and gastrointestinal (GI) disorder such as excessive alcohol intake, hydration, diarrhea, vomiting etc. Participants undergoing intravascular administration of iodinated contrast materials in radio diagnostic examinations (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (CT) scans with intravascular contrast materials etc.) Participants who took drugs that significantly induce (e.g., barbiturate) or inhibit drug metabolism enzymes, and those drugs that may alter metformin pharmacokinetic (pK), most importantly organic cation transporter 1/2 [OCT1/2] inhibitors and inducers, within 30 days prior to screening Use of a concomitant drug. However, any medications that are considered necessary for participant's welfare and will not interfere with the trial medication may be given at the discretion of the investigator Use of any medication that may affect the outcome of the study within 10 days prior to screening and during study conduct Participation in another bioequivalence or other clinical studies where the last administration of previous study medication was within 6 months, before the first drug administration in this study Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 19 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Reference GXR (Fasting), Then Test GXR RM (Fasting)<br>Participants received a single oral dose of 500 milligram (mg) of reference GXR (Glucophage® Extended Release) tablet on Day 1 in treatment period 1 followed by single oral dose of 500 mg test GXR RM (Reduced Mass) tablet on Day 8 in treatment period 2 under fasting conditions. There was a washout period of 7 days between two treatment period. | Drug: Glucophage® XR RM Test<br>* Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;Drug: Glucophage® XR Reference<br>* Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;|
| Experimental: First Test GXR RM (Fasting), Then Reference GXR (Fasting)<br>Participants received a single oral dose of 500 milligrams (mg) of test GXR RM tablet on Day 1 in treatment period 1 followed by single oral dose of 500 mg of reference GXR tablet on Day 8 in treatment period 2 under fasting conditions. There was a washout period of 7 days between two treatment period. | Drug: Glucophage® XR RM Test<br>* Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;Drug: Glucophage® XR Reference<br>* Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;|
| Experimental: First Reference GXR (Fed), Then Test GXR RM (Fed)<br>Participants received a single oral dose of 500 milligrams (mg) of reference GXR tablet on Day 1 in treatment period 1 followed by single oral dose of 500 mg of test GXR RM tablet on Day 8 in treatment period 2 under fed conditions. There was a washout period of 7 days between two treatment period. | Drug: Glucophage® XR RM Test<br>* Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;Drug: Glucophage® XR Reference<br>* Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;|
| Experimental: First Test GXR RM (Fed), Then Reference GXR (Fed)<br>Participants received a single oral dose of 500 milligrams (mg) of test GXR RM tablet on Day 1 in treatment period 1 followed by single oral dose of 500 mg of reference GXR tablet on Day 8 in treatment period 2 under fed conditions. There was a washout period of 7 days between two treatment period. | Drug: Glucophage® XR RM Test<br>* Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;Drug: Glucophage® XR Reference<br>* Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.<br>* Other names: Metformin hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of Metformin | Area under the plasma concentration vs time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule. | Part 1 (fasted): Pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours post dose. Part 2 (fed): Pre-dose 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours post dose | 
| Maximum Observed Plasma Concentration (Cmax) of Metformin | Cmax was obtained directly from the concentration versus time curve. | Part 1 (fasted): Pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours post dose. Part 2 (fed): Pre-dose 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs. | From Day 1 up to 3 weeks | 
| Number of Participants Taking Concomitant Medications | Concomitant medications included medications administered from the first administration of study interventions to the end of observation. | From Day 1 up to 3 weeks | 
| Number of Participants With Clinically Significant Change From Baseline in Laboratory Values | The laboratory measurements included hematology, blood chemistry, urinalysis and Blood Sugar Test (BST). Number of participants with clinically significant changes from baseline in laboratory values were reported. Clinically Significance was decided by investigator. | From Day1 (baseline) up to 3 weeks | 
| Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings | The 12-lead ECG recordings were obtained after 5 minutes of rest in a semi-supine position. ECG recordings included rhythm, ventricular rate, PR interval, QRS duration, QT and QTc intervals. Number of participants with clinically significant changes from baseline in 12-lead ECG findings were reported. Clinically significance was decided by investigator. | From Day 1 (baseline) up to 3 weeks | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital sign assessment included blood pressure, pulse rate, body temperature and respiration rate. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinically significance was decided by investigator. | From Day 1 (baseline) up to 3 weeks | 
| Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings | Physical examination included assessments of the skin, lungs, cardiovascular system, abdomen (liver and spleen), and the symptoms reported by the participant. Number of participants with clinically significant changes from baseline in vital signs were reported. Clinically significance was decided by investigator. | From Day 1 (baseline) up to 3 weeks | 
| Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | AUC0-inf was calculated by combining AUC0-t and AUC extra. AUC extra represents an extrapolated value obtained by Clast/ lambda z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and lambda z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase. | Part 1 (fasted): Pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours post dose. Part 2 (fed): Pre-dose 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours post dose | 
| Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-tlast) to Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | The ratio of AUClast to AUCinf were reported. | Part 1 (fasted): Pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours post dose. Part 2 (fed): Pre-dose 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours post dose | 
| Apparent Terminal Half-Life (t1/2) of Metformin | Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by lambda z. | Part 1 (fasted): Pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours post dose. Part 2 (fed): Pre-dose 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours post dose | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. | Part 1 (fasted): Pre-dose and 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 24 and 32 hours post dose. Part 2 (fed): Pre-dose 1, 2, 3, 4, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 24 and 32 hours post dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Glucophage Extended Release, Bioequivalence Study