Healthy
Conditions
Keywords
Diabetes Mellitus, Glucophage Immediate Release (GIR), Bioequivalence Study
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.
Interventions
DRUGTest GIR
Participants received 500 milligrams (mg) test GIR in fasting or fed state on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).
DRUGReference GIR
Participants received 500 mg reference GIR in fasting or fed state 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
* 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
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 (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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| First Test GIR (Fasting), Then Reference GIR (Fasting) 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. | 13 |
| First Reference GIR (Fasting), Then Test GIR (Fasting) 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. | 13 |
| First Test GIR (Fed), Then Reference GIR (Fed) 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. | 9 |
| First Reference GIR (Fed), Then Test GIR (Fed) 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. | 9 |
| Total | 44 |
Baseline characteristics
| Characteristic | First Test GIR (Fasting), Then Reference GIR (Fasting) | Total | First Reference GIR (Fed), Then Test GIR (Fed) | First Test GIR (Fed), Then Reference GIR (Fed) | First Reference GIR (Fasting), Then Test GIR (Fasting) |
|---|---|---|---|---|---|
| Age, Continuous | 32.8 years STANDARD_DEVIATION 7.97 | 31.7 years STANDARD_DEVIATION 7.65 | 32.2 years STANDARD_DEVIATION 7.03 | 29.8 years STANDARD_DEVIATION 9.01 | 31.5 years STANDARD_DEVIATION 7.39 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 13 Participants | 44 Participants | 9 Participants | 9 Participants | 13 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 | 3 Participants | 14 Participants | 4 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 30 Participants | 5 Participants | 6 Participants | 9 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 / 26 | 0 / 26 | 0 / 18 | 0 / 18 |
| other Total, other adverse events | 2 / 26 | 2 / 26 | 2 / 18 | 3 / 18 |
| serious Total, serious adverse events | 0 / 26 | 0 / 26 | 0 / 18 | 0 / 18 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin (GIR Tablet Active Ingredient)
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.
Time frame: 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
Population: The Pharmacokinetic (PK) Analysis Set included all participants who completed the study with adequate study drug compliance, without any relevant protocol violations with respect to factors likely to affect comparability of PK results, and with sufficient evaluable data to determine primary endpoints (AUC0-t and Cmax ) for both treatments.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin (GIR Tablet Active Ingredient) | 6260 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 22.4 |
| Treatment B Reference GIR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin (GIR Tablet Active Ingredient) | 6280 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 16.3 |
| Treatment A: Test GIR (Fed) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin (GIR Tablet Active Ingredient) | 4950 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 25.6 |
| Treatment B: Reference GIR (Fed) | Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC 0-t) of Metformin (GIR Tablet Active Ingredient) | 5020 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 23.3 |
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fasting state90% CI: [92.84, 107.2]
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fed state90% CI: [91.25, 106.69]
Primary
Maximum Observed Plasma Concentration (Cmax) of Metformin (GIR Tablet Active Ingredient)
Pharmacokinetic (PK) parameter Cmax was obtained directly from the concentration versus time curve.
Time frame: 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
Population: The Pharmacokinetic analysis set.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Maximum Observed Plasma Concentration (Cmax) of Metformin (GIR Tablet Active Ingredient) | 1110 ng/mL | Geometric Coefficient of Variation 30.1 |
| Treatment B Reference GIR (Fasting) | Maximum Observed Plasma Concentration (Cmax) of Metformin (GIR Tablet Active Ingredient) | 1110 ng/mL | Geometric Coefficient of Variation 22.7 |
| Treatment A: Test GIR (Fed) | Maximum Observed Plasma Concentration (Cmax) of Metformin (GIR Tablet Active Ingredient) | 711 ng/mL | Geometric Coefficient of Variation 22.4 |
| Treatment B: Reference GIR (Fed) | Maximum Observed Plasma Concentration (Cmax) of Metformin (GIR Tablet Active Ingredient) | 700 ng/mL | Geometric Coefficient of Variation 18.6 |
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fasting state90% CI: [92.69, 106.77]
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fed state90% CI: [93.72, 109.92]
Secondary
Apparent Terminal Half-Life (t1/2) of Metformin (GIR Tablet Active Ingredient)
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.
Time frame: 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
Population: The Pharmacokinetic analysis set. Here Number of particpants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Apparent Terminal Half-Life (t1/2) of Metformin (GIR Tablet Active Ingredient) | 4.38 hours | Geometric Coefficient of Variation 40.5 |
| Treatment B Reference GIR (Fasting) | Apparent Terminal Half-Life (t1/2) of Metformin (GIR Tablet Active Ingredient) | 4.90 hours | Geometric Coefficient of Variation 47.4 |
| Treatment A: Test GIR (Fed) | Apparent Terminal Half-Life (t1/2) of Metformin (GIR Tablet Active Ingredient) | 4.23 hours | Geometric Coefficient of Variation 45.6 |
| Treatment B: Reference GIR (Fed) | Apparent Terminal Half-Life (t1/2) of Metformin (GIR Tablet Active Ingredient) | 4.16 hours | Geometric Coefficient of Variation 67.3 |
Secondary
Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin (GIR Tablet Active Ingredient)
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, 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
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 |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin (GIR Tablet Active Ingredient) | 485 liter | Geometric Coefficient of Variation 46.6 |
| Treatment B Reference GIR (Fasting) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin (GIR Tablet Active Ingredient) | 551 liter | Geometric Coefficient of Variation 52.5 |
| Treatment A: Test GIR (Fed) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin (GIR Tablet Active Ingredient) | 602 liter | Geometric Coefficient of Variation 34.3 |
| Treatment B: Reference GIR (Fed) | Apparent Volume of Distribution at After Extravascular Administration (Vz/f) of Metformin (GIR Tablet Active Ingredient) | 581 liter | Geometric Coefficient of Variation 73.1 |
Secondary
Apparent Volume of Distribution at Steady-State After Extravascular Administration (Vss/f) of Metformin
Vss/F was derived from concentration versus time data for all participants.
Time frame: 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
Population: As AUCextra was \>20% of AUC0-inf, Vss/f derived from λz was regarded as unreliable estimate of the extent of exposure and not calculated.
Secondary
Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Metformin (GIR Tablet Active Ingredient)
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.
Time frame: 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
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 |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Metformin (GIR Tablet Active Ingredient) | 6520 ng*h/mL | Geometric Coefficient of Variation 20.2 |
| Treatment B Reference GIR (Fasting) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Metformin (GIR Tablet Active Ingredient) | 6410 ng*h/mL | Geometric Coefficient of Variation 16 |
| Treatment A: Test GIR (Fed) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Metformin (GIR Tablet Active Ingredient) | 5070 ng*h/mL | Geometric Coefficient of Variation 25 |
| Treatment B: Reference GIR (Fed) | Area Under the Plasma Concentration-Time Curve From Time 0 to Infinity (AUCinf) of Metformin (GIR Tablet Active Ingredient) | 5160 ng*h/mL | Geometric Coefficient of Variation 21.2 |
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fasting state90% CI: [94.33, 108.69]
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fed state90% CI: [91.61, 105.21]
Secondary
Area Under the Plasma Concentration-Time Curve From Time Tlast Extrapolated to Infinity (AUCextra) of Metformin (GIR Tablet Active Ingredient)
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, 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
Population: As AUCextra was \>20% of AUC0-inf, parameters derived from λz including AUCextra% were regarded as unreliable estimate of the extent of exposure and not calculated.
Secondary
Elimination Rate Constant (λz) of Metformin (GIR Tablet Active Ingredient)
λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: 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
Population: As AUCextra was \>20% of AUC0-inf, parameters derived from λz were regarded as unreliable estimate of the extent of exposure and not calculated.
Secondary
Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings
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.
Time frame: Baseline up to Day 15
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug. Here number of particpants were analyzed who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Vital Signs | 0 Participants |
| Treatment A: Test GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Laboratory Parameters | 0 Participants |
| Treatment A: Test GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Physical Examination | 0 Participants |
| Treatment A: Test GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | 12-Lead Electrocardiogram (ECG) | 0 Participants |
| Treatment B Reference GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Laboratory Parameters | 0 Participants |
| Treatment B Reference GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Physical Examination | 0 Participants |
| Treatment B Reference GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | 12-Lead Electrocardiogram (ECG) | 0 Participants |
| Treatment B Reference GIR (Fasting) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Vital Signs | 0 Participants |
| Treatment A: Test GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Physical Examination | 0 Participants |
| Treatment A: Test GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Laboratory Parameters | 0 Participants |
| Treatment A: Test GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | 12-Lead Electrocardiogram (ECG) | 0 Participants |
| Treatment A: Test GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Vital Signs | 0 Participants |
| Treatment B: Reference GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | 12-Lead Electrocardiogram (ECG) | 0 Participants |
| Treatment B: Reference GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Laboratory Parameters | 0 Participants |
| Treatment B: Reference GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Vital Signs | 0 Participants |
| Treatment B: Reference GIR (Fed) | Number of Participants With Clinically Significant Abnormalities in Vital Signs, Laboratory Parameters, Physical Examination Findings and 12-lead Electrocardiogram (ECG) Findings | Physical Examination | 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: Baseline up to 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) |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 2 Participants |
| Treatment A: Test GIR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 0 Participants |
| Treatment B Reference GIR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 0 Participants |
| Treatment B Reference GIR (Fasting) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 2 Participants |
| Treatment A: Test GIR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 2 Participants |
| Treatment A: Test GIR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 0 Participants |
| Treatment B: Reference GIR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Any TEAE | 3 Participants |
| Treatment B: Reference GIR (Fed) | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAE | 0 Participants |
Secondary
Time to Reach Maximum Plasma Concentration of Metformin (GIR Tablet Active Ingredient)
Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.
Time frame: 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
Population: The Pharmacokinetic analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment A: Test GIR (Fasting) | Time to Reach Maximum Plasma Concentration of Metformin (GIR Tablet Active Ingredient) | 2.00 hours |
| Treatment B Reference GIR (Fasting) | Time to Reach Maximum Plasma Concentration of Metformin (GIR Tablet Active Ingredient) | 2.00 hours |
| Treatment A: Test GIR (Fed) | Time to Reach Maximum Plasma Concentration of Metformin (GIR Tablet Active Ingredient) | 2.75 hours |
| Treatment B: Reference GIR (Fed) | Time to Reach Maximum Plasma Concentration of Metformin (GIR Tablet Active Ingredient) | 2.75 hours |
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fasting state90% CI: [-0.25, 0.25]
Comparison: Statistical Comparison of Treatment A Versus Treatment B in Fed state90% CI: [-0.25, 0.5]
Secondary
Total Body Clearance (CL/f) of Metformin (GIR Tablet Active Ingredient)
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, 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
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 |
|---|---|---|---|
| Treatment A: Test GIR (Fasting) | Total Body Clearance (CL/f) of Metformin (GIR Tablet Active Ingredient) | 76.7 liter per hour | Geometric Coefficient of Variation 20.2 |
| Treatment B Reference GIR (Fasting) | Total Body Clearance (CL/f) of Metformin (GIR Tablet Active Ingredient) | 78.0 liter per hour | Geometric Coefficient of Variation 16 |
| Treatment A: Test GIR (Fed) | Total Body Clearance (CL/f) of Metformin (GIR Tablet Active Ingredient) | 98.6 liter per hour | Geometric Coefficient of Variation 25 |
| Treatment B: Reference GIR (Fed) | Total Body Clearance (CL/f) of Metformin (GIR Tablet Active Ingredient) | 96.8 liter per hour | Geometric Coefficient of Variation 21.2 |