Clinical trial NCT04684420: GXR RM (Glucophage® Extended Release Reduced Mass) 500 Milligram (mg) Korea Bioequivalence (BE) Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Diabetes Mellitus
Glucophage Extended Release
Bioequivalence Study
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2020-12-24
Enrollment: 81
Sex: ALL
Minimum age (years): 19
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of Metformin
timeFrame: 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
measure: Maximum Observed Plasma Concentration (Cmax) of Metformin
timeFrame: 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 outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs
timeFrame: From Day 1 up to 3 weeks
measure: Number of Participants Taking Concomitant Medications
timeFrame: From Day 1 up to 3 weeks
measure: Number of Participants With Clinically Significant Change From Baseline in Laboratory Values
timeFrame: From Day1 (baseline) up to 3 weeks
measure: Number of Participants With Clinically Significant Change From Baseline in 12-lead Electrocardiogram (ECG) Findings
timeFrame: From Day 1 (baseline) up to 3 weeks
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: From Day 1 (baseline) up to 3 weeks
measure: Number of Participants With Clinically Significant Change From Baseline in Physical Examination Findings
timeFrame: From Day 1 (baseline) up to 3 weeks
measure: Area Under Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin
timeFrame: 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
measure: 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
timeFrame: 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
measure: Apparent Terminal Half-Life (t1/2) of Metformin
timeFrame: 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
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin
timeFrame: 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
Other outcomes:
Locations:
city: Daejeon
country: Korea, Republic of
facility: Clinical Trials Center, Chungnam National University Hospital
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: