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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Glucophage® XR RM Test; Drug: Glucophage® XR Reference

• Study Type: Interventional
• Enrollment (Actual): 81
• Phase: Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Daejeon, Korea, Republic of, 35015
    • Clinical Trials Center, Chungnam National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First Reference GXR (Fasting), Then Test GXR RM (Fasting); 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; Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride
Experimental: First Test GXR RM (Fasting), Then Reference GXR (Fasting); 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; Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride
Experimental: First Reference GXR (Fed), Then Test GXR RM (Fed); 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; Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride
Experimental: First Test GXR RM (Fed), Then Reference GXR (Fed); 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; Participants received a single oral dose of 500 mg of test Glucophage® XR RM tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride; Drug: Glucophage® XR Reference; Participants received a single oral dose of 500 mg of reference Glucophage® XR tablet under fasting or fed conditions.; Other Names: Metformin hydrochloride

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2020
• Primary Completion (Actual): March 11, 2022
• Study Completion (Actual): March 11, 2022

Study Registration Dates

• First Submitted: December 21, 2020
• First Submitted That Met QC Criteria: December 21, 2020
• First Posted (Actual): December 24, 2020

Study Record Updates

• Last Update Posted (Actual): December 29, 2023
• Last Update Submitted That Met QC Criteria: December 28, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Diabetes Mellitus; Bioequivalence Study; Glucophage Extended Release
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: MS200084_0028

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website https://bit.ly/IPD21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No