Healthy
Conditions
Brief summary
The purpose of this study is to assess bioequivalence between metformin hydrochloride (Glucophage® XR) manufactured in PT Merck Tbk, Indonesia (test drug) and metformin hydrochloride (Glucophage® XR) manufactured in Merck Santé, France (comparator drug) following single oral dose administration under fasting condition.
Interventions
DRUGGlucophage XR (Test drug)
Participants received single oral dose of Glucophage® XR tablet manufactured by PT Merck Tbk, Jakarta, Indonesia (Test Drug) under fasted conditions.
DRUGGlucophage XR (Comparator drug)
Participants received single oral dose of Glucophage® XR tablet manufactured by Merck Santé, Semoy, France (Comparator Drug) under fasted conditions.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Participants has provided written informed consent prior to the conduct of any study-related activities * Body mass index of 18 to 25 kilogram per square meter (kg/m\^2) * Good physical and mental health status, determined on the basis of medical history and physical examination * Vital signs (blood pressure, pulse rate, respiratory rate and body temperature) in sitting position within the normal range or showing no clinically relevant deviation per the Investigator's opinion * All values for laboratory assessments (hematology, clinical chemistry and urinalysis) within the normal range or showing no clinically relevant deviation per the Investigator's opinion * No clinically significant abnormality on 12-lead electrocardiogram (ECG) recording as judged by the Investigator; corrected QT interval (QTc) (Bazett) should be less than equals to (\<=) 450 milliseconds (ms) * Non-smoker or smoker less than 10 cigarettes per day * Women of childbearing potential (WOCBP) who are not nursing, are not pregnant, and are using highly effective methods of birth control. Female participants may also be enrolled if they are postmenopausal or surgically sterilized/ hysterectomized at least 6 months prior to study participation * WOCBP must have a negative urine pregnancy test at Screening and on each admission (Day 1 of each dosing period) * Negative screen for alcohol and drugs abuse (opiate class, barbiturates, cocaine and metabolites, amphetamines, cannabinoids and benzodiazepines) at Screening and on each Study Check-In (Day -1 of each dosing period) * Negative screen for Hepatitis B surface antigen (HBsAg), Hepatitis C Virus (HCV) antibodies and/or Human Immunodeficiency Virus (HIV) antibodies.
Exclusion criteria
* Participation in a clinical trial/study within 90 days prior to Screening * Blood donation (equal or more than 300 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 prestudy 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 malignant diseases, except in-situ basal cell skin tumors treated with curative intent * History of surgery of the gastrointestinal tract which could influence the gastrointestinal absorption and/or motility per the Investigator's opinion * History or presence of relevant liver diseases or hepatic dysfunction (laboratory result for liver function test greater than equals to (\>=) 1.5 upper limit of normal (ULN) * History or presence of renal failure or renal dysfunction based on clinical symptoms and finding (serum creatinine concentration \>1.4 milligram per milliliter (mg/mL) * 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 14 days before the first drug administration, except for hormonal contraceptives in female, and including multivitamins and herbal products (e.g. St John's Wort) * Consumption of large quantities of methylxanthine-containing beverages (\> 5 cups of coffee/day or equivalent) * Consumption of grapefruit, orange, cranberry or juices of these three fruits, 24 hours prior to drug administration * Known lack of participant compliance or inability to communicate or cooperate with the Investigator (e.g., language problem, poor mental status)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Metformin | Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 | The maximum plasma concentration of Metformin. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin | Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 | Area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 | AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0-inf). |
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 | Time of the maximum drug concentration. |
| Terminal Elimination Half-life in Plasma (t½) of Metformin | Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1 | Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Up to Day 51 | An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. Number of participants with TEAEs included participants with both non serious and serious TEAEs. |
Countries
Indonesia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants who received Glucophage® XR 750 mg Tablet manufactured by PT Merck Tbk, Jakarta, Indonesia or Glucophage® XR 750 mg Tablet manufactured by Merck Santé, Semoy, France on Day 1 in either first treatment period or second treatment period. | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 | Withdrawal by Subject | 1 | 1 |
| Treatment Period 2 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 33.5 Years STANDARD_DEVIATION 10.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 48 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 46 |
| other Total, other adverse events | 5 / 47 | 9 / 46 |
| serious Total, serious adverse events | 0 / 47 | 0 / 46 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin
Area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration.
Time frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Population: PK analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, with adequate study medication compliance, and who have valid primary endpoints for both treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR (Test) | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin | 7387 Nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2535.7 |
| Glucophage XR (Comparator) | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Measurable Concentration (AUC0-t) of Metformin | 6977 Nanogram*hour per milliliter (ng*h/mL) | Standard Deviation 2512 |
90% CI: [98.99, 115.19]
Primary
Maximum Observed Plasma Concentration (Cmax) of Metformin
The maximum plasma concentration of Metformin.
Time frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Population: Pharmacokinetic (PK) analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, with adequate study medication compliance, and who have valid primary endpoints for both treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR (Test) | Maximum Observed Plasma Concentration (Cmax) of Metformin | 1109 Nano-gram per milliliter (ng/mL) | Standard Deviation 318.4 |
| Glucophage XR (Comparator) | Maximum Observed Plasma Concentration (Cmax) of Metformin | 1087 Nano-gram per milliliter (ng/mL) | Standard Deviation 336.3 |
90% CI: [95.18, 112.37]
Secondary
Area Under Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin
AUC (0-inf) is defined as the area under the plasma concentration versus time curve (AUC) from time zero (predose) to extrapolated infinite time (0-inf).
Time frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Population: PK analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, with adequate study medication compliance, and who have valid primary endpoints for both treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR (Test) | Area Under Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | 7678 ng*h/mL | Standard Deviation 2559.5 |
| Glucophage XR (Comparator) | Area Under Plasma Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | 7250 ng*h/mL | Standard Deviation 2523.6 |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) was defined as any untoward medical occurrence in a participant which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. 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. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug. Number of participants with TEAEs included participants with both non serious and serious TEAEs.
Time frame: Up to Day 51
Population: The safety analysis set included all participants who have received at least one dose of the investigational product and have had one subsequent safety assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Glucophage XR (Test) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Treatment Emergent Adverse Events (TEAEs) | 5 Participants |
| Glucophage XR (Test) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
| Glucophage XR (Comparator) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Treatment Emergent Adverse Events (TEAEs) | 9 Participants |
| Glucophage XR (Comparator) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs | Serious TEAEs | 0 Participants |
Secondary
Terminal Elimination Half-life in Plasma (t½) of Metformin
Elimination Half Life (t1/2) was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half.
Time frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Population: PK analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, with adequate study medication compliance, and who have valid primary endpoints for both treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glucophage XR (Test) | Terminal Elimination Half-life in Plasma (t½) of Metformin | 5.82 Hours | Standard Deviation 2.875 |
| Glucophage XR (Comparator) | Terminal Elimination Half-life in Plasma (t½) of Metformin | 6.03 Hours | Standard Deviation 3.292 |
Secondary
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin
Time of the maximum drug concentration.
Time frame: Pre-dose, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16, 24, and 32 hours post-dose on Day 1
Population: PK analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results, with adequate study medication compliance, and who have valid primary endpoints for both treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Glucophage XR (Test) | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | 3.50 Hours |
| Glucophage XR (Comparator) | Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | 3.00 Hours |