Bioequivalence Study of 500 mg and 1000 mg Glucophage (Metformin) Tablets in Healthy Subjects

Bioequivalence Study of 500 mg and 1000 mg Glucophage (Metformin) Tablets Manufactured by Bristol-Myers Squibb Relative to 500 mg and 1000 mg Diabex (Metformin) Tablets Marketed in Australia by Alphapharm Administered to Healthy Subjects in the Fed State

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01068730

Enrollment

Registered

2010-02-15

Start date

2010-02-28

Completion date

2010-04-30

Last updated

2015-05-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Type 2 Diabetes Mellitus

Brief summary

To demonstrate the bioequivalence of 500 mg and 1000 mg Glucophage tablets manufactured by BMS relative to the respective strengths of 500 mg and 1000 mg Diabex tablets marketed in Australia by Alphapharm in the fed state

Interventions

DRUGmetformin (Diabex)

Tablets, Oral, 500 mg, Once daily, single dose

DRUGmetformin (Glucophage™)

Tablets, Oral, 500 mg, Once Daily, single dose

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

Inclusion criteria

* Men and women ages 18 to 55 inclusive * Healthy subjects as determined by no clinically significant deviation from normal in medical history, physical examination, electrocardiograms (ECGs), and clinical laboratory determinations * Body Mass Index (BMI) of 18 to 32 kg/m², inclusive. BMI = weight (kg)/ \[height (m)\]²

Exclusion criteria

* Any significant acute or chronic medical illness * Current or recent (within 3 months) gastrointestinal disease * Any major surgery within 4 weeks of study drug administration * History of allergy or intolerance to metformin or other similar acting agents * Prior exposure to metformin within 3 months of study drug administration * Estimated creatinine clearance (Clcr) of \< 80ml/min using the Cockcroft Gault formula

Design outcomes

Primary

Measure	Time frame	Description
Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.
Metformin PK Parameter Observed Maximum Plasma Concentration (Cmax)	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.

Secondary

Measure	Time frame	Description
Participants With Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs)	AEs: from study drug administration Day 1/Period 1 till study discharge. SAEs: from date of written consent until 30 days after discontinuation of dosing or study participation. Duration of the study was approximately 45 days (including screening).	AE=any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject administered an investigational product and that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that results in death, is life-threatening, requires or prolongs inpatient hospitalization (including elective surgery), results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.
Participants With Abnormal Physical Findings	From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening).	Physical findings that were considered abnormal by the investigator.
Participants With Abnormal Vital Sign Findings Reported as an AE	From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening).	per investigator
Participants With Electrocardiogram Abnormalities Considered Clinically Significant or Reported as an AE	From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening).	Clinically significant was determined by the investigator. ECGs were recorded after participants had been supine for at least 5 minutes.
Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Hematology	From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening).	Clinically significant was determined by the investigator.
Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Serum Chemistry	From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening).	Clinically significant was determined by the investigator.
Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Urinalysis	From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening).	Clinically significant was determined by the investigator.

Other

Measure	Time frame	Description
Metformin Pharmacokinetic (PK) Parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax)	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Tmax is the time taken to reach the maximum observed plasma concentration.
Metformin Pharmacokinetic (PK) Parameter Terminal Half-life (T 1/2)	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. T 1/2 is the time required for the concentration of the drug to reach half of its original value in plasma
Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC[0-t])	Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing	PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC\[0-t\] is the area under the plasma concentration-time curve from time zero to time of last measurable concentration.

Countries

United States

Participant flow

Recruitment details

A total of 28 participants who met all of the inclusion and none of the exclusion criteria were planned and enrolled in the study from a single site in the United States.

Pre-assignment details

Participants were screened for eligibility within 21 days before Day 1 of period 1. On Day -1 of each period, the participants were admitted to the clinical facility and confined for 4 days. All the 28 participants were randomly assigned to 1 of 4 treatment sequences (ADBC, BACD, CBDA, or DCAB). The washout between each dose was at least 7 days.

Participants by arm

Arm	Count
All Enrolled and Treated Participants Participants who were randomly assigned to 1 of 4 treatment sequences (ADBC, BACD, CBDA, or DCAB). Treatment A: single oral 500-mg Diabex (metformin) tablet administered under fed condition. Treatment B: single oral 500-mg Glucophage tablet administered under fed condition. Treatment C: single oral 1000-mg Diabex tablet administered under fed condition.Treatment D: single oral 1000-mg Glucophage (metformin) tablet administered under fed condition.	28
Total	28

Arm

Count

All Enrolled and Treated Participants

Participants who were randomly assigned to 1 of 4 treatment sequences (ADBC, BACD, CBDA, or DCAB). Treatment A: single oral 500-mg Diabex (metformin) tablet administered under fed condition. Treatment B: single oral 500-mg Glucophage tablet administered under fed condition. Treatment C: single oral 1000-mg Diabex tablet administered under fed condition.Treatment D: single oral 1000-mg Glucophage (metformin) tablet administered under fed condition.

Total

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Period 3	Personal reason	1	0	0	0
Period 4	Family emergency	0	1	0	0

Baseline characteristics

Characteristic	All Enrolled and Treated Participants
Age, Continuous	34.6 years STANDARD_DEVIATION 11.05
Body Mass Index	26.58 kg/m^2 STANDARD_DEVIATION 3.64
Height	169.54 Centimeter STANDARD_DEVIATION 11.44
Race/Ethnicity, Customized Black or African American	4 Participants
Race/Ethnicity, Customized Hispanic or Latino	10 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	18 Participants
Race/Ethnicity, Customized White	24 Participants
Sex: Female, Male Female	12 Participants
Sex: Female, Male Male	16 Participants
Weight	77.02 kg STANDARD_DEVIATION 15.88

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	— / —	— / —	— / —	— / —
other Total, other adverse events	5 / 27	6 / 27	6 / 28	2 / 27
serious Total, serious adverse events	0 / 27	0 / 27	0 / 28	0 / 27

Outcome results

Primary

Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. AUC (0-inf) is the area under the plasma concentration-time curve from time zero extrapolated to infinite time.

Time frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing

Population: All treated participants with evaluable PK analyses. In treatment D, AUC (0-inf) was not analysed for 1 participant who did not have a clear terminal elimination phase.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Treatment A - 500 mg Diabex	Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])	7062.76 ng*hr/mL	Geometric Coefficient of Variation 26.91
Treatment B - 500 mg Glucophage	Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])	7187.14 ng*hr/mL	Geometric Coefficient of Variation 25.95
Treatment C - 1000 mg Diabex	Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])	11577.85 ng*hr/mL	Geometric Coefficient of Variation 27.36
Treatment D - 1000 mg Glucophage	Metformin Pharmacokinetic (PK) Parameter Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC[0-inf])	11424.73 ng*hr/mL	Geometric Coefficient of Variation 29.06

Comparison: If there was no difference between the bioavailabilities of metformin from the 500-mg or 1000-mg Glucophage tablets manufactured by BMS and 500-mg or 1000-mg Diabex tablets manufactured in Australia by Alphapharm, then 20 subjects would have provided 99% power to conclude bioequivalence (BE) with respect to Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would have provided 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.95% CI: [99.07, 106.23]

Comparison: If there was no difference between the bioavailabilities of metformin from the 500-mg or 1000-mg Glucophage tablets manufactured by BMS and 500-mg or 1000-mg Diabex tablets manufactured in Australia by Alphapharm, then 20 subjects would have provided 99% power to conclude BE with respect to Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would have provided 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.95% CI: [96.16, 103.31]

Comparison: Geometric least squares means for Treatment A

Comparison: Geometric least squares means for Treatment B

Comparison: Geometric least squares means for Treatment C

Comparison: Geometric least squares means for Treatment D

Primary

Metformin PK Parameter Observed Maximum Plasma Concentration (Cmax)

PK is the process by which a drug is absorbed, distributed, metabolized, and eliminated by the body. Cmax is the maximum observed concentration of drug substance in plasma.

Time frame: Periods 1, 2, 3, & 4: pre-dosing, 15, 30, 45 mins & 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36 & 48 hrs post-dosing

Population: All treated participants with evaluable PK analyses.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Treatment A - 500 mg Diabex	Metformin PK Parameter Observed Maximum Plasma Concentration (Cmax)	1013.57 ng/mL	Geometric Coefficient of Variation 25.67
Treatment B - 500 mg Glucophage	Metformin PK Parameter Observed Maximum Plasma Concentration (Cmax)	1019.59 ng/mL	Geometric Coefficient of Variation 25.26
Treatment C - 1000 mg Diabex	Metformin PK Parameter Observed Maximum Plasma Concentration (Cmax)	1635.30 ng/mL	Geometric Coefficient of Variation 27.67
Treatment D - 1000 mg Glucophage	Metformin PK Parameter Observed Maximum Plasma Concentration (Cmax)	1593.20 ng/mL	Geometric Coefficient of Variation 26.87

Comparison: If there was no difference between the bioavailabilities of metformin from the 500-mg or 1000-mg Glucophage tablets manufactured by BMS and 500-mg or 1000-mg Diabex tablets manufactured in Australia by Alphapharm, then 20 subjects would have provided 99% power to conclude BE with respect to Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would have provided 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.95% CI: [96.36, 106.11]

Comparison: If there was no difference between the bioavailabilities of metformin from the 500-mg or 1000-mg Glucophage tablets manufactured by BMS and 500-mg or 1000-mg Diabex tablets manufactured in Australia by Alphapharm, then 20 subjects would have provided 99% power to conclude BE with respect to Cmax and AUC0-inf. If there was a 5% difference, then 20 subjects would have provided 97% and 99% power to conclude BE with respect to Cmax and AUC0-inf, respectively.95% CI: [93.94, 103.59]

Comparison: Geometric least squares means for Treatment A

Comparison: Geometric least squares means for Treatment B

Comparison: Geometric least squares means for Treatment C

Comparison: Geometric least squares means for Treatment D

Secondary

Participants With Abnormal Physical Findings

Physical findings that were considered abnormal by the investigator.

Time frame: From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening).