Healthy
Conditions
Keywords
Diabetes Mellitus, Glucophage Extended Release (GXR), Bioequivalence Study
Brief summary
The study will assess the bioequivalence between single doses of GXR manufactured in Merck Nantong China (test drug) and GXR manufactured in Merck Darmstadt Germany (reference drug) under fed and fasted state in healthy participants.
Interventions
DRUGTest GXR
Participants received a single oral dose of 500 mg of test GXR tablet (Merck Nantong/China) under fasting or fed conditions on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).
DRUGReference GXR
Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt/France) under fasting or fed conditions on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Overtly healthy as determined by medical evaluation, including medical history and a physical examination * Have a body weight within 50 to 90 kilogram (kg) and Body mass index (BMI) within the range 18 to 30 kg per meter square (kg/m\^2) (inclusive) * Chinese male and female (at least 1/4 of each gender per study group) * A male participant must agree to use and to have their female partners use a highly effective contraception (that is, methods with a failure rate of less than 1 percent per year) for a period of at least 1 month before and after dosing * A female is eligible if she is not pregnant (that is, after a confirmed menstrual period and a negative serum pregnancy test), not breastfeeding, and at least one of the following conditions applies * Is not a woman of childbearing potential (WOCBP) OR * Is a WOCBP who agrees to use a highly effective contraceptive method (that is, has a failure rate of less than 1 percent per year) for a period of at least 1 month before and after dosing * Can give signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol * Non-smoker (0 cigarettes, pipes, cigars, or others) since at least 3 months * All values for biochemistry and hematology tests of blood and urine within the normal range or showing no clinically relevant deviation as judged by the Investigator * Electrocardiogram recording (12 lead ECG) without signs of clinically relevant pathology as judged by the Investigator. * Pulse, body temperature, and respiration in sitting position within the normal range or showing no clinically relevant deviation as judged by the Investigator. Blood pressure in sitting position within normal range: greater than or equals to (\>=) 90 millimeter of mercury (mmHg) and less than or equal to (=\<) 139 mmHg for systolic blood pressure; \>= 60 mmHg and =\< 90 mmHg for diastolic blood pressure * Negative screen for alcohol and drugs of abuse (cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine) at screening 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 pre-study 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 study or that could interfere with the study objectives, conduct or evaluation * 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 considers may affect the outcome of the study * Receipt of any prescription or non-prescription medication within 2 weeks before the first Investigational medicinal product (IMP) administration, including multivitamins and herbal products (that is St John's Wort, or traditional Chinese medicines), except for the permitted medications * Renal failure or renal dysfunction (creatinine clearance \[Ccr\] \< 80 mL/minute) as assessed by using the estimated measure with the Cockcroft-Gault equation. * Known lack of participant compliance or inability to communicate or cooperate with the Investigator (example, language problem, poor mental status) * Non-acceptance of study high-fat breakfast (example, vegetarians, vegans and participants who follow special diets) * Consumption of large quantities of methylxanthine-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 Pharmacokinetics sample in Period 2 * Any contraindication to Glucophage * Abnormal and clinically significant chest X-ray finding at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | Area under the plasma concentration versus 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 | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | AUC0-inf was calculated by combining AUC0-t and AUCextra. 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. |
| Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUCextra) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | 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. |
| Elimination Rate Constant (Lambda z) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Total Body Clearance (CL/f) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing. |
| Time to Reach Maximum Plasma Concentration of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve. |
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Time from informed consent up to end of study (Day 15) | Vital sign assessment included blood pressure, pulse rate, body temperature and respiration (frequency per minute). Number of participants with clinically significant abnormalities in vital signs were reported. Clinically significance was decided by investigator. |
| Number of Participants With Clinically Significant Abnormalities in Laboratory Values | Time from informed consent up to end of study (Day 15) | The laboratory measurements included hematology, blood chemistry and urinalysis. Number of participants with clinically significant abnormalities in laboratory values were reported. Clinically Significance was decided by investigator. |
| Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings | Time from informed consent up to end of study (Day 15) | Physical examination included assessments of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, abdomen, musculoskeletal, and neurological systems. Number of participants with clinically significant abnormalities in physical examination findings were reported. clinically significance was decided by investigator. |
| Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings | Time from informed consent up to end of study (Day 15) | 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 abnormalities in 12-lead ECG findings were reported. Clinically significance was decided by investigator. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Time from informed consent up to end of study (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 Terminal Half-Life (t1/2) of Metformin | Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10 | 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. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| First Test GXR (Fasting), Then Reference GXR (Fasting) Participants received a single oral dose of 500 milligrams (mg) of test GXR tablet (Merck Nantong, China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt, Germany) on Day 8 in treatment period 2 under fasting conditions. There was a wash-out period of 7 days between each treatment period. | 19 |
| First Reference GXR (Fasting), Then Test GXR (Fasting) Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt, Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong, China) on Day 8 in treatment period 2 under fasting conditions. There was a wash-out period of 7 days between each treatment period. | 18 |
| First Test GXR (Fed), Then Reference GXR (Fed) Participants received a single oral dose of 500 mg of test GXR tablet (Merck Nantong, China) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg reference GXR (Merck Darmstadt, Germany) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period. | 8 |
| First Reference GXR (Fed), Then Test GXR (Fed) Participants received a single oral dose of 500 mg of reference GXR tablet (Merck Darmstadt, Germany) on Day 1 in treatment period 1 followed by a single oral dose of 500 mg test GXR (Merck Nantong, China) on Day 8 in treatment period 2 under fed conditions. There was a wash-out period of 7 days between each treatment period. | 8 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 (Day 1-Day 3) | Enrolled, but never treated | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | First Test GXR (Fasting), Then Reference GXR (Fasting) | Total | First Reference GXR (Fed), Then Test GXR (Fed) | First Test GXR (Fed), Then Reference GXR (Fed) | First Reference GXR (Fasting), Then Test GXR (Fasting) |
|---|---|---|---|---|---|
| Age, Continuous | 31.5 years STANDARD_DEVIATION 8 | 33.0 years STANDARD_DEVIATION 8.55 | 35.8 years STANDARD_DEVIATION 11.15 | 32.6 years STANDARD_DEVIATION 7.13 | 33.5 years STANDARD_DEVIATION 8.79 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 19 Participants | 53 Participants | 8 Participants | 8 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 6 Participants | 19 Participants | 3 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 13 Participants | 34 Participants | 5 Participants | 5 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 37 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 10 / 37 | 11 / 37 | 3 / 16 | 4 / 16 |
| serious Total, serious adverse events | 0 / 37 | 0 / 37 | 0 / 16 | 0 / 16 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin
Area under the plasma concentration versus 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.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The Pharmacokinetic (PK) Analysis Set included all participants who completed the study with adequate study drug compliance, without any relevant protocol violations or events with respect to factors likely to affect comparability of PK results, and with sufficient evaluable data to determine primary outcome measures for both treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test GXR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin | 3740 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 31.5 |
| Reference GXR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin | 3780 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 26.2 |
| Test GXR (Fed) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin | 5500 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 17.1 |
| Reference GXR (Fed) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin | 5540 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 18.7 |
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fasting conditions.90% CI: [92.2, 105.64]
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fed conditions.90% CI: [93.15, 106.05]
Primary
Maximum Observed Plasma Concentration (Cmax) of Metformin
Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The PK Analysis Set included all participants who completed the study with adequate study drug compliance, without any relevant protocol violations or events with respect to factors likely to affect comparability of PK results, and with sufficient evaluable data to determine primary outcome measures for both treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test GXR (Fasting) | Maximum Observed Plasma Concentration (Cmax) of Metformin | 572 ng/mL | Geometric Coefficient of Variation 32.7 |
| Reference GXR (Fasting) | Maximum Observed Plasma Concentration (Cmax) of Metformin | 578 ng/mL | Geometric Coefficient of Variation 34.2 |
| Test GXR (Fed) | Maximum Observed Plasma Concentration (Cmax) of Metformin | 519 ng/mL | Geometric Coefficient of Variation 17.1 |
| Reference GXR (Fed) | Maximum Observed Plasma Concentration (Cmax) of Metformin | 536 ng/mL | Geometric Coefficient of Variation 16.4 |
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fasting conditions.90% CI: [91.08, 107.44]
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fed conditions.90% CI: [89.87, 104.46]
Secondary
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.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The Pharmacokinetic analysis set. Here Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test GXR (Fasting) | Apparent Terminal Half-Life (t1/2) of Metformin | 5.80 hours | Geometric Coefficient of Variation 63.7 |
| Reference GXR (Fasting) | Apparent Terminal Half-Life (t1/2) of Metformin | 5.56 hours | Geometric Coefficient of Variation 58.4 |
| Test GXR (Fed) | Apparent Terminal Half-Life (t1/2) of Metformin | 5.34 hours | Geometric Coefficient of Variation 65.1 |
| Reference GXR (Fed) | Apparent Terminal Half-Life (t1/2) of Metformin | 5.37 hours | Geometric Coefficient of Variation 99.8 |
Secondary
Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin
Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The Pharmacokinetic analysis set. Here Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test GXR (Fasting) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin | 1070 liter | Geometric Coefficient of Variation 75.6 |
| Reference GXR (Fasting) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin | 1010 liter | Geometric Coefficient of Variation 61.1 |
| Test GXR (Fed) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin | 684 liter | Geometric Coefficient of Variation 65.8 |
| Reference GXR (Fed) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin | 674 liter | Geometric Coefficient of Variation 93.7 |
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin
AUC0-inf was calculated by combining AUC0-t and AUCextra. 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.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The Pharmacokinetic analysis set. Here Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test GXR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin | 3890 ng*h/mL | Geometric Coefficient of Variation 29.4 |
| Reference GXR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin | 3980 ng*h/mL | Geometric Coefficient of Variation 25 |
| Test GXR (Fed) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin | 5630 ng*h/mL | Geometric Coefficient of Variation 17.2 |
| Reference GXR (Fed) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUC0-inf) of Metformin | 5750 ng*h/mL | Geometric Coefficient of Variation 19.2 |
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fasting conditions.90% CI: [91.38, 104.86]
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fed conditions.90% CI: [92.37, 104.14]
Secondary
Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUCextra) of Metformin
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.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: As AUCextra was \>20% of AUC0-inf, parameters derived from lambda z including AUCextra% were regarded as unreliable estimate of the extent of exposure and not calculated as it was pre-specified to not report these data in this condition.
Secondary
Elimination Rate Constant (Lambda z) of Metformin
Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: As AUCextra was \>20% of AUC0-inf, parameters derived from lambda z were regarded as unreliable estimate of the extent of exposure and not calculated as it was pre-specified to not report these data in this condition.
Secondary
Number of Participants With Clinically Significant Abnormalities 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 abnormalities in 12-lead ECG findings were reported. Clinically significance was decided by investigator.
Time frame: Time from informed consent up to end of study (Day 15)
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| Reference GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| Test GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
| Reference GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormalities in Laboratory Values
The laboratory measurements included hematology, blood chemistry and urinalysis. Number of participants with clinically significant abnormalities in laboratory values were reported. Clinically Significance was decided by investigator.
Time frame: Time from informed consent up to end of study (Day 15)
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Laboratory Values | 0 Participants |
| Reference GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Laboratory Values | 0 Participants |
| Test GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in Laboratory Values | 0 Participants |
| Reference GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in Laboratory Values | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings
Physical examination included assessments of the general appearance, skin and mucosa, superficial lymph nodes, head and neck, chest, abdomen, musculoskeletal, and neurological systems. Number of participants with clinically significant abnormalities in physical examination findings were reported. clinically significance was decided by investigator.
Time frame: Time from informed consent up to end of study (Day 15)
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings | 0 Participants |
| Reference GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings | 0 Participants |
| Test GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings | 0 Participants |
| Reference GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in Physical Examination Findings | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormalities in Vital Signs
Vital sign assessment included blood pressure, pulse rate, body temperature and respiration (frequency per minute). Number of participants with clinically significant abnormalities in vital signs were reported. Clinically significance was decided by investigator.
Time frame: Time from informed consent up to end of study (Day 15)
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Reference GXR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Test GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| Reference GXR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
Secondary
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.
Time frame: Time from informed consent up to end of study (Day 15)
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Test GXR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 10 Participants |
| Test GXR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Reference GXR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 11 Participants |
| Reference GXR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Test GXR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Test GXR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 3 Participants |
| Reference GXR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | TEAEs | 4 Participants |
| Reference GXR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
Secondary
Time to Reach Maximum Plasma Concentration of Metformin
Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The PK Analysis Set included all participants who completed the study with adequate study drug compliance, without any relevant protocol violations or events with respect to factors likely to affect comparability of PK results, and with sufficient evaluable data to determine primary outcome measures for both treatments.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Test GXR (Fasting) | Time to Reach Maximum Plasma Concentration of Metformin | 3.00 hours |
| Reference GXR (Fasting) | Time to Reach Maximum Plasma Concentration of Metformin | 4.00 hours |
| Test GXR (Fed) | Time to Reach Maximum Plasma Concentration of Metformin | 6.00 hours |
| Reference GXR (Fed) | Time to Reach Maximum Plasma Concentration of Metformin | 6.00 hours |
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fasting conditions.90% CI: [-0.5, 0]
Comparison: Statistical Comparison of Test GXR Versus Reference GXR under Fed conditions.90% CI: [-0.5, 0.5]
Secondary
Total Body Clearance (CL/f) of Metformin
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14 post-dose on Day 1 and Day 8; 24, 30, 36 hours post-dose on Day 2 and 9; 48 hours post-dose on Day 3 and 10
Population: The Pharmacokinetic analysis set. Here Number of participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Test GXR (Fasting) | Total Body Clearance (CL/f) of Metformin | 128 liter per hour | Geometric Coefficient of Variation 29.4 |
| Reference GXR (Fasting) | Total Body Clearance (CL/f) of Metformin | 126 liter per hour | Geometric Coefficient of Variation 25 |
| Test GXR (Fed) | Total Body Clearance (CL/f) of Metformin | 88.9 liter per hour | Geometric Coefficient of Variation 17.2 |
| Reference GXR (Fed) | Total Body Clearance (CL/f) of Metformin | 87.0 liter per hour | Geometric Coefficient of Variation 19.2 |