Glucophage Immediate Release (GIR) China Bioequivalence Study

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: Test GIR
Drug: Reference GIR

Registration Number: NCT03393208

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: The study will assess the bioequivalence between single doses of glucophage immediate release (GIR) test tablets and GIR reference tablets under fed and fasted state in healthy subjects.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 44

Inclusion Criteria

Participants had given written informed consent before any trial-related activities
Chinese male and female participants (at least 1/4 of each gender per trial group)
Aged between 18 and 55 years, inclusive
Weighed: 50 to 80 kilogram (kg); Body mass index (BMI): 18 to 30 kg per meter square
Nonsmoker since at least 3 months
Good physical and mental health status, determined on the basis of the medical history and a physical examination
All values for biochemistry and hematology tests of blood and urine within the normal range or showied no clinically relevant deviation as judged by the Investigator
Electrocardiogram recording (12-lead ECG) without signs of clinically relevant pathology was judged by the Investigator
Vital signs (blood pressure, pulse, body temperature, and respiration) in sitting position within the normal range or showing no clinically relevant deviation was judged by the Investigator
All women of childbearing potential (WOCBP) who were not nursing, were not pregnant, and were using highly effective methods of birth control
Negative screen for alcohol and drugs of abuse (cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine) were screened at and on admission
Negative screen for hepatitis A virus (HAV) antibodies, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibodies, human immunodeficiency virus (HIV) antibodies, and Treponema pallidum (TP) antibodies

Exclusion Criteria

Participation in a clinical trial within 90 days prior to first drug administration
Blood donation (equal or more than 500 milliliter [mL]) or significant blood loss within 90 days prior to first drug administration
Any surgical or medical condition, including findings in the medical history or in the pretrial assessments, or any other significant disease, that in the opinion of the Investigator, constitutes a risk or a contraindication for the participation of the participant in the trial or that could interfere with the trial objectives, conducted or evaluated
History of surgery of the gastrointestinal tract which could influence the gastrointestinal absorption and/or motility according to the Investigator's opinion
History or presence of relevant liver diseases or hepatic dysfunction Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the Investigator considered affectted the outcome of the trial
Receipt of any prescription or nonprescription medication within 2 weeks before the first IMP administration, including multivitamins and herbal products (example, St John's Wort, or traditional Chinese medicines), except paracetamol
Renal failure or renal dysfunction (creatinine clearance < 80 mL/minute) as assessed by using the estimated measure with the Modification of Diet in Renal Disease (MDRD) equation
Known lack of participant compliance or inability to communicate or cooperate with the Investigator (example, language problem and poor mental status)
Nonacceptance of trial high-fat breakfast (example, vegetarians, vegans, and participants followed special diets)
Consumption of large quantities of methyl xanthine-containing beverages (> 5 cups of coffee/day or equivalent)
Consumption of grapefruit, cranberry or juices of these fruits, from 14 days prior to drug administration until collection of the last pharmacokinetic sample in Period 2
Any contraindication to Glucophage
Abnormal and clinically significant chest X-ray finding at screening

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
First Test GIR (Fasting), Then Reference GIR (Fasting)	Test GIR	Participants received a single oral dose of 500 milligram (mg) of test Glucophage Immediate Release (GIR) tablet Sino-American Shanghai Squibb (SASS)/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GIR (Merck Santé in Semoy (MSS)/France) on Day 8 in treatment period 2 under fasting condition. There was a wash-out period of 7 days between each treatment period.
First Reference GIR (Fed), Then Test GIR (Fed)	Test GIR	Participants received a single oral dose of 500 mg of reference GIR tablet (MSS/ France) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GIR (SASS/China) on Day 8 in treatment period 2 under fed condition. There was a wash-out period of 7 days between each treatment period.
First Reference GIR (Fed), Then Test GIR (Fed)	Reference GIR	Participants received a single oral dose of 500 mg of reference GIR tablet (MSS/ France) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GIR (SASS/China) on Day 8 in treatment period 2 under fed condition. There was a wash-out period of 7 days between each treatment period.
First Test GIR (Fed), Then Reference GIR (Fed)	Test GIR	Participants received a single oral dose of 500 mg of test GIR tablet (SASS/ China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GIR (MSS/France) on Day 8 in treatment period 2 under fed condition. There was a wash-out period of 7 days between each treatment period.
First Test GIR (Fed), Then Reference GIR (Fed)	Reference GIR	Participants received a single oral dose of 500 mg of test GIR tablet (SASS/ China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GIR (MSS/France) on Day 8 in treatment period 2 under fed condition. There was a wash-out period of 7 days between each treatment period.
First Reference GIR (Fasting), Then Test GIR (Fasting)	Test GIR	Participants received a single oral dose of 500 mg of reference GIR tablet (MSS/France) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GIR (SASS/China) on Day 8 in treatment period 2 under fasting condition. There was a wash-out period of 7 days between each treatment period.
First Test GIR (Fasting), Then Reference GIR (Fasting)	Reference GIR	Participants received a single oral dose of 500 milligram (mg) of test Glucophage Immediate Release (GIR) tablet Sino-American Shanghai Squibb (SASS)/China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GIR (Merck Santé in Semoy (MSS)/France) on Day 8 in treatment period 2 under fasting condition. There was a wash-out period of 7 days between each treatment period.
First Reference GIR (Fasting), Then Test GIR (Fasting)	Reference GIR	Participants received a single oral dose of 500 mg of reference GIR tablet (MSS/France) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GIR (SASS/China) on Day 8 in treatment period 2 under fasting condition. There was a wash-out period of 7 days between each treatment period.

Primary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	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.
Maximum Observed Plasma Concentration (Cmax) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve.

Secondary Outcome Measures

Name	Time	Method
Time to Reach Maximum Plasma Concentration of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Total Body Clearance (CL/f) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Apparent Terminal Half-Life (t1/2) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	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 λz.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	Baseline up to Day 15	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.
Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing.
Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings	Baseline up to Day 15	The laboratory measurements included hematology, blood chemistry and urinalysis. Vital sign assessment included blood pressure, pulse rate and body temperature. ECG parameters included heart rate, PR, QRS,QT, RR, QTcB and QTcF Here, we are reporting number of participants with clinically significant abnormalities in Vital signs, laboratory parameters, physical findings and ECG findings.
Elimination Rate Constant (λz) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Apparent Volume of Distribution at Steady-State After Extravascular Administration (Vss/f) of Metformin	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	Vss/F was derived from concentration versus time data for all participants.
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ λz, 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 λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUCextra) of Metformin (GIR Tablet Active Ingredient)	Pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 14 hours post-dose on Day 1; 24 and 36 hours post-dose on Day 2; 48 hours post-dose on Day 3	AUCextra% was defined as area under the curve from time tlast extrapolated to infinity as percentage of AUC 0-infinity. Here, tlast is the last sampling time at which the concentration is at or above the lower limit of quantification.