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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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A | Other | 500 mg metformin (Diabex): Single oral dose of 500 mg metformin (Diabex) tablet administered in the fed condition |
|
| Treatment B | Other | 500 mg metformin (Glucophage™): Single oral dose of 500 mg metformin (Glucophage™) tablet administered in the fed condition |
|
| Treatment C | Other | 1000 mg metformin (Diabex): Single oral dose of 1000 mg metformin (Diabex) tablet administered in the fed condition |
|
| Treatment D | Other | 1000 mg metformin (Glucophage™): A Single oral dose of 1000 mg metformin (Glucophage™) tablet administered in the fed condition |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| metformin (Diabex) | Drug | Tablets, Oral, 500 mg, Once daily, single dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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 |
| 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. | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Participants With Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Metformin Pharmacokinetic (PK) Parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | 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. | 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 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Bristol-Myers Squibb | Bristol-Myers Squibb | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| PPD Development, LP | Austin | Texas | 78744 | United States |
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.
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment Sequence ADBC | Treatment A (period 1): single oral 500-mg Diabex (metformin) tablet administered under fed condition. Treatment D (period 2): single oral 1000-mg Glucophage (metformin) tablet administered under fed condition. Treatment B (period 3): single oral 500-mg Glucophage tablet administered under fed condition. Treatment C (period 4): single oral 1000-mg Diabex tablet administered under fed condition. |
| FG001 | Treatment Sequence BACD | Treatment B (period 1): single oral 500-mg Glucophage tablet administered under fed condition. Treatment A (period 2): single oral 500-mg Diabex tablet administered under fed condition. Treatment C (period 3): single oral 1000-mg Diabex tablet administered under fed condition. Treatment D (period 4): single oral 1000-mg Glucophage tablet administered under fed condition. |
| FG002 | Treatment Sequence CBDA | Treatment C (period 1): single oral 1000-mg Diabex tablet administered under fed condition. Treatment B (period 2): single oral 500-mg Glucophage tablet administered under fed condition. Treatment D (period 3): single oral 1000-mg Glucophage tablet administered under fed condition. Treatment A (period 4): single oral 500-mg Diabex tablet administered under fed condition. |
| FG003 | Treatment Sequence DCAB | Treatment D (period 1): single oral 1000-mg Glucophage tablet administered under fed condition. Treatment C (period 2): single oral 1000-mg Diabex tablet administered under fed condition. Treatment A (period 3): single oral 500-mg Diabex tablet administered under fed condition. Treatment B (period 4): single oral 500-mg Glucophage tablet administered under fed condition. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
| |||||||||||||
| Period 2 |
| |||||||||||||
| Period 3 |
| |||||||||||||
| Period 4 |
|
Not provided
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | 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 |
|
From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment C - 1000 mg Diabex | 1000 mg metformin (Diabex): Single Oral dose of 1000 mg Diabex tablet administered in the fed condition |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ocular hyperaemia | Eye disorders | MedDRA 12.1 | Systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Boaz Hirschberg | AstraZeneca Pharmaceuticals | ClinicalTrialTransparency@astrazeneca.com |
Not provided
| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D008687 | Metformin |
| ID | Term |
|---|---|
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D009930 | Organic Chemicals |
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| metformin (Glucophage™) | Drug | Tablets, Oral, 500 mg, Once Daily, single dose |
|
|
| metformin (Glucophage™) | Drug | Tablets, Oral, 1000 mg, Once daily, single dose |
|
|
| metformin (Diabex) | Drug | Tablets, Oral, 1000 mg, Once daily, single dose |
|
|
| 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). |
| Participants With Electrocardiogram Abnormalities Considered Clinically Significant or Reported as an AE | Clinically significant was determined by the investigator. ECGs were recorded after participants had been supine for at least 5 minutes. | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
| Participants With Abnormal Physical Findings | Physical findings that were considered abnormal by the investigator. | From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening). |
| Participants With Abnormal Vital Sign Findings Reported as an AE | per investigator | From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening). |
| Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Hematology | Clinically significant was determined by the investigator. | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
| Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Serum Chemistry | Clinically significant was determined by the investigator. | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
| Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Urinalysis | Clinically significant was determined by the investigator. | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
| Metformin Pharmacokinetic (PK) Parameter Terminal Half-life (T 1/2) | 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 | 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 |
| 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]) | 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. | 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 |
| COMPLETED |
|
| NOT COMPLETED |
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| COMPLETED |
|
| NOT COMPLETED |
|
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| Race/Ethnicity, Customized | Number | Participants |
|
| Height | Mean | Standard Deviation | Centimeter |
|
| Weight | Mean | Standard Deviation | kg |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| OG001 | Treatment B - 500 mg Glucophage | 500 mg metformin (Glucophage™): Single Oral dose of 500 mg Glucophage tablet administered in the fed condition |
| OG002 | Treatment C - 1000 mg Diabex | 1000 mg metformin (Diabex): Single Oral dose of 1000 mg Diabex tablet administered in the fed condition |
| OG003 | Treatment D - 1000 mg Glucophage | 1000 mg metformin (Glucophage™): Single Oral dose of 1000 mg Glucophage tablet administered in the fed condition |
|
|
|
| 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. | All treated participants with evaluable PK analyses. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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 |
|
|
|
|
| Secondary | Participants With Adverse Events (AEs), Discontinuations Due to AEs, Deaths, and Serious AEs (SAEs) | 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. | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | 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). |
|
|
|
| Secondary | Participants With Electrocardiogram Abnormalities Considered Clinically Significant or Reported as an AE | Clinically significant was determined by the investigator. ECGs were recorded after participants had been supine for at least 5 minutes. | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
|
|
|
| Secondary | Participants With Abnormal Physical Findings | Physical findings that were considered abnormal by the investigator. | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening). |
|
|
|
| Secondary | Participants With Abnormal Vital Sign Findings Reported as an AE | per investigator | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | From Day 1/Period 1 to study discharge or premature discontinuation. Duration of study was approximately 45 days (including screening). |
|
|
|
| Other Pre-specified | Metformin Pharmacokinetic (PK) Parameter Time to Achieve the Observed Maximum Plasma Concentration (Tmax) | 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. | All treated participants with evaluable PK analyses. | Posted | Mean | Standard Deviation | hr | 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 |
|
|
|
| Other Pre-specified | Metformin Pharmacokinetic (PK) Parameter Terminal Half-life (T 1/2) | 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 | All treated participants with evaluable PK analyses. In treatment D, T 1/2 was not analysed for 1 participant who did not have a clear terminal elimination phase. | Posted | Mean | Standard Deviation | hr | 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 |
|
|
|
| Secondary | Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Hematology | Clinically significant was determined by the investigator. | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
|
|
|
| Secondary | Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Serum Chemistry | Clinically significant was determined by the investigator. | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
|
|
|
| Secondary | Participants With Clinical Laboratory Findings Considered Clinically Significant or Reported as an AE: Urinalysis | Clinically significant was determined by the investigator. | All treated participants not discontinuing prior to the end of the study. | Posted | Number | Participants | From study drug administration Day 1/Period 1 till study discharge. Duration of the study was approximately 45 days (including screening). |
|
|
|
| Other Pre-specified | 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]) | 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. | All treated participants with evaluable PK analyses. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | 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 |
|
|
|
|
| 0 |
| 27 |
| 5 |
| 27 |
| EG001 | Treatment D - 1000 mg Glucophage | 1000 mg metformin (Glucophage™): Single Oral dose of 1000 mg Glucophage tablet administered in the fed condition | 0 | 27 | 6 | 27 |
| EG002 | Treatment A - 500 mg Diabex | 500 mg metformin (Diabex): Single Oral dose of 500 mg Diabex tablet administered in the fed condition | 0 | 28 | 6 | 28 |
| EG003 | Treatment B - 500 mg Glucophage | 500 mg metformin (Glucophage™): Single Oral dose of 500 mg Glucophage tablet administered in the fed condition | 0 | 27 | 2 | 27 |
| Headache | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 12.1 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 12.1 | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 12.1 | Systematic Assessment |
|
| Vascular access complication | Injury, poisoning and procedural complications | MedDRA 12.1 | Systematic Assessment |
|
| Oropharyngeal discomfort | Respiratory, thoracic and mediastinal disorders | MedDRA 12.1 | Systematic Assessment |
|
| Feeling of body temperature change | General disorders | MedDRA 12.1 | Systematic Assessment |
|
Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication
| D004700 | Endocrine System Diseases |
Bioequivalence was concluded if the 90% confidence intervals (CIs) for the test-to-reference ratios (B/A) and (D/C) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf. |
| 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. | Ratio (%) of Geometric LS Means | 98.65 | 2-Sided | 95 | 93.94 | 103.59 | Ratio=Treatment B/Treatment A. Geometric LS means values are presented in other statistical analysis entries. | Yes | Non-Inferiority or Equivalence | Bioequivalence was concluded if the 90% confidence intervals (CIs) for the test-to-reference ratios (B/A) and (D/C) of geometric means were entirely contained within 80% to 125% for both Cmax and AUC0-inf. |
| Geometric least squares means for Treatment A | Geometric Least Squares Mean (ng/mL) | 1013.6 | No | Superiority or Other |
| Geometric least squares means for Treatment B | Geometric Least Squares Mean (ng/mL) | 1024.9 | No | Superiority or Other |
| Geometric least squares means for Treatment C | Geometric Least Squares Mean (ng/mL) | 1643.8 | No | Superiority or Other |
| Geometric least squares means for Treatment D | Geometric Least Squares Mean (ng/mL) | 1621.6 | No | Superiority or Other |
| Discontinuations Due to AE |
|
| Deaths |
|
| SAEs |
|
| Ratio (%) of Geometric LS Means |
| 99.44 |
| 2-Sided |
| 95 |
| 96.08 |
| 102.92 |
Ratio=Treatment D/Treatment C. Geometric LS means values are presented in other statistical analysis entries. |
| No |
| Superiority or Other |
| Geometric least squares means for Treatment A | Geometric Least Squares Mean (ng*hr/mL) | 6907.1 | No | Superiority or Other |
| Geometric least squares means for Treatment B | Geometric Least Squares Mean (ng*hr/mL) | 7127.4 | 95 | No | Superiority or Other |
| Geometric least squares means for Treatment C | Geometric Least Squares Mean (ng*hr/mL) | 11391 | No | Superiority or Other |
| Geometric least squares means for Treatment D | [Geometric Least Squares Mean (ng*hr/mL) | 11327 | No | Superiority or Other |