Amoxicillin-Clavulanic Acid 400 mg-57 mg Chewable Tablets Under Non-Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00836901
• Collaborator: (none)
• Enrollment: 52
• Location: 1
• Arms: 2

Study Details

Study Description

Brief Summary

The objective of this study is to compare the rate and extent of absorption of amoxicillin-clavulanic acid 400 mg-57 mg chewable tablets (test) versus Augmentin® (reference) administered as 1 x 400 mg-57 mg chewable tablet under fed conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: amoxicillin-clavulanic acid; Drug: Augmentin®	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA bioequivalence statistical methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Randomized, 2-Way Crossover, Bioequivalence Study of Amoxicillin-Clavulanic Acid 400 mg-57 mg Chewable Tablets and AUGMENTIN® 400 mg-57 mg Chewable Tablets Administered as 1 x 400 mg-57 mg Chewable Tablet in Healthy Subjects Under Fed Conditions
• Study Start Date: Sep 1, 2003
• Actual Primary Completion Date: Sep 1, 2003
• Actual Study Completion Date: Sep 1, 2003

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amoxicillin Calvulanic Acid Amoxicillin Clavulanic Acid 400-57 mg Chewable Tablet (test) dosed in first period followed by Augmentin® 40-57 mg Chewable Tablet (reference) dosed in second period	Drug: amoxicillin-clavulanic acid; 400 mg-57 mg chewable tablet
Active Comparator: Augmentin® Augmentin® 400-57 mg Chewable Tablet (test) dosed in first period followed by Amoxicillin Clavulanic Acid 400-57 mg Chewable Tablet (reference) dosed in second period	Drug: Augmentin®; 400 mg-57 mg chewable tablet

Outcome Measures

Primary Outcome Measures

1. Cmax (Maximum Observed Concentration) - Amoxicillin [Blood samples collected over 10 hour period]

   Bioequivalence based on Cmax

2. AUC0-inf - [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Amoxicillin [Blood samples collected over 10 hour period]

   Bioequivalence based on AUC0-inf

3. AUC0-t - [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Amoxicillin [Blood samples collected over 10 hour period]

   Bioequivalence based on AUC0-t

4. Cmax (Maximum Observed Concentration) - Clavulanic Acid [Blood samples were collected over 10 hour period]

   Bioequivalence based on Cmax

5. AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Clavunlanic Acid [Blood samples collected over 10 hour period]

   Bioequivalence based on AUC0-inf

6. AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant) - Clavulanic Acid [Blood samples collected over 10 hour period]

   Bioequivalence based on AUC0-t

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria

• Subjects will be females and/or males, non-smokers, 18 years of age and older.

Exclusion Criteria

• Clinically significant illnesses within 4 weeks of the administration of study medication.

• Clinically significant surgery within 4 weeks prior to the administration of the study medication.

• Any clinically significant abnormality found during medical screening.

• Any reason which, in the opinion of the medical subinvestigator, would prevent the subject from participating in the study.

• Abnormal laboratory tests judged clinically significant.

• Positive urine drug screen at screening.

• Positive testing for hepatitis B, hepatitis C or HIV at screening.

• ECG abnormalities (clinically significant) or vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, or diastolic blood pressure lower than 50 or over 90; or heart rate less than 50 bpm) at screening.

• Subjects with BMI ≥30.0.

• History of significant alcohol abuse within six months of the screening visit or any indication of the regular use of more than two units of alcohol per day (1 Unit = 150 mL of wine or 360 mL of beer or 45 mL of alcohol 40%).

• History of drug abuse or use of illegal drugs: use of soft drugs (such as marijuana) within 3 months of the screening visit or hard drugs (such as cocaine, phencyclidine (PCP) and crack) within 1 year of the screening visit.

• Any food allergy, intolerance, restriction or special diet that, in the opinion of the medical subinvestigator, contraindicates the subject's participation in this study.

• History of allergic or hypersensitivity reactions to amoxicillin or clavulanic acid or other related drugs (e.g. penicillin, cephalosporins, cephamycins).

• Use of any drugs known to induce or inhibit hepatic drug metabolism (examples of inducers: barbiturates, carbamazepine, phenytoin, glucocorticoids, rifampin/rifabutin; examples of inhibitors: antidepressants, cimetidine, diltiazem, erythromycin, ketoconazole, MAO inhibitors, neuroleptics, verapamil, quinidine, valproic acid) use of an investigational drug or participation on an investigation study within 30 days prior to the administration of the study medication.

• Clinically significant history or presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of the drug.

• Any clinically significant history or presence of clinically significant neurological, endocrinal, cardiovascular, pulmonary, hematologic, immunologic, psychiatric or metabolic disease.

• Any food allergy, intolerance, restriction or special diet that could, in the opinion of the Medical Subinvestigator, contraindicate the subject's participation in this study.

• Use of prescription medication within 14 days prior to administration of study medication or over-the-counter products )including natural products, vitamins, garlic as a supplement) within 7 days prior to administration of study medication, except for topical products without systemic absorption.

• Subjects who have had a depot injection or an implant of any drug 3 months prior to administration of study medication.

• Donation of plasma (500 mL) within 7 days. Donation or loss of whole blood prior to administration of the study medication as follows:

• less than 300 mL of whole blood within 30 days, or

• 300 mL to 500 mL of whole blood within 45 days, or

• more than 500 mL of whole blood within 56 days.

• Positive alcohol breath test at screening.

• Subjects who have used tobacco in any form within the 90 days preceding study drug administration.

• Intolerance to venipunctures.

• Subjects with a clinically significant history of tuberculosis, epilepsy, asthma, diabetes, psychosis, or glaucoma will not be eligible for this study.

• Any history of known Augmentin-associated cholestatic jaundice/hepatic dysfunction

• Any known active mononucleosis

• Subjects with dentures or braces.

Additional exclusion criteria for female subjects only:

• Breast feeding subjects.

• Positive urine pregnancy test at screening (performed on all females).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anapharm Inc.	Montreal	Quebec	Canada	H3X 2H9

Sponsors and Collaborators

• Teva Pharmaceuticals USA

Investigators

• Principal Investigator: Richard Larouche, MD, Anapharm

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00836901
• Other Study ID Numbers: 30074
• First Posted: Feb 4, 2009
• Last Update Posted: Aug 18, 2009
• Last Verified: Jul 1, 2009

• Keywords provided by , ,: Bioequivalence; Healthy Subjects
• Additional relevant MeSH terms: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Clavulanic Acids; Clavulanic Acid

Study Results

Participant Flow

Arm/Group Title	Amoxicillin Clavulanic Acid (Test) First	Augmentin® (Reference) First
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in first period followed by Augmentin® 400/57 mg chewable tablet (reference) dosed in second period	Augmentin® 400/57 mg chewable tablet (reference) dosed in first period followed by Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in second period
Period Title: First Intervention
STARTED	24	28
COMPLETED	23	28
NOT COMPLETED	1	0
Period Title: First Intervention
STARTED	23	28
COMPLETED	23	28
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Amoxicillin Clavulanic Acid (Test) First	Augmentin® (Reference) First	Total
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in first period followed by Augmentin® 400/57 mg chewable tablet (reference) dosed in second period	Augmentin® 400/57 mg chewable tablet (reference) dosed in first period followed by Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in second period	Total of all reporting groups
Overall Participants	24	28	52
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	24 100%	28 100%	52 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	19 79.2%	17 60.7%	36 69.2%
Male	5 20.8%	11 39.3%	16 30.8%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	20 83.3%	21 75%	41 78.8%
American Hispanic	3 12.5%	5 17.9%	8 15.4%
Black	1 4.2%	2 7.1%	3 5.8%
Region of Enrollment (participants) [Number]
Canada	24 100%	28 100%	52 100%

Outcome Measures

1. Primary Outcome

Title	Cmax (Maximum Observed Concentration) - Amoxicillin
Description	Bioequivalence based on Cmax
Time Frame	Blood samples collected over 10 hour period

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed the study were included in the statistical analysis.

Arm/Group Title	Amoxicillin Clavulanic Acid	Augmentin®
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in either period	Augmentin® 400/57 mg chewable tablet (reference) dosed in either period
Measure Participants	51	51
Mean (Standard Deviation) [ng/mL]	4482.26 (1157.70)	4549.67 (1116.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin Clavulanic Acid, Augmentin®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Using GLM procedures in SAS, analysis of variance (ANOVA)was performed on log-transformed AUC0-t, AUC0-inf and Cmax at the significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	97.70
	Confidence Interval	() 90%; 93.19 to 102.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

2. Primary Outcome

Title	AUC0-inf - [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Amoxicillin
Description	Bioequivalence based on AUC0-inf
Time Frame	Blood samples collected over 10 hour period

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed the study were included in the statistical analysis.

Arm/Group Title	Amoxicillin Clavulanic Acid	Augmentin®
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in either period	Augmentin® 400/57 mg chewable tablet (reference) dosed in either period
Measure Participants	51	51
Mean (Standard Deviation) [ng*h/mL]	19403.12 (4003.43)	19518.22 (3573.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin Clavulanic Acid, Augmentin®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Using GLM procedures in SAS, analysis of variance (ANOVA)was performed on log-transformed AUC0-t, AUC0-inf and Cmax at the significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	99.28
	Confidence Interval	() 90%; 97.09 to 101.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

3. Primary Outcome

Title	AUC0-t - [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant)] - Amoxicillin
Description	Bioequivalence based on AUC0-t
Time Frame	Blood samples collected over 10 hour period

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed the study were included in the statistical analysis

Arm/Group Title	Amoxicillin Clavulanic Acid	Augmentin®
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in either period	Augmentin® 400/57 mg chewable tablet (reference) dosed in either period
Measure Participants	51	51
Mean (Standard Deviation) [ng*h/mL]	18299.44 (3147.95)	18746.55 (3331.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin Clavulanic Acid, Augmentin®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Using GLM procedures in SAS, analysis of variance (ANOVA)was performed on log-transformed AUC0-t, AUC0-inf and Cmax at the significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	97.64
	Confidence Interval	() 90%; 96.12 to 99.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

4. Primary Outcome

Title	Cmax (Maximum Observed Concentration) - Clavulanic Acid
Description	Bioequivalence based on Cmax
Time Frame	Blood samples were collected over 10 hour period

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed the study were included in the statistical analysis

Arm/Group Title	Amoxicillin Clavulanic Acid	Augmentin®
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in either period	Augmentin® 400/57 mg chewable tablet (reference) dosed in either period
Measure Participants	51	51
Mean (Standard Deviation) [ng/mL]	734.20 (300.57)	766.38 (299.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin Clavulanic Acid, Augmentin®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Using GLM procedures in SAS, analysis of variance (ANOVA)was performed on log-transformed AUC0-t, AUC0-inf and Cmax at the significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	94.59
	Confidence Interval	() 90%; 85.64 to 104.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

5. Primary Outcome

Title	AUC0-inf [Area Under the Concentration-time Curve From Time Zero to Infinity (Extrapolated)] - Clavunlanic Acid
Description	Bioequivalence based on AUC0-inf
Time Frame	Blood samples collected over 10 hour period

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed the study were included in the statistical analysis

Arm/Group Title	Amoxicillin Clavulanic Acid	Augmentin®
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in either period	Augmentin® 400/57 mg chewable tablet (reference) dosed in either period
Measure Participants	51	51
Mean (Standard Deviation) [ng*h/mL]	1772.85 (664.55)	1864.33 (676.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin Clavulanic Acid, Augmentin®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Using GLM procedures in SAS, analysis of variance (ANOVA)was performed on log-transformed AUC0-t, AUC0-inf and Cmax at the significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	94.44
	Confidence Interval	() 90%; 87.83 to 101.54
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

6. Primary Outcome

Title	AUC0-t [Area Under the Concentration-time Curve From Time Zero to Time of Last Non-zero Concentration (Per Participant) - Clavulanic Acid
Description	Bioequivalence based on AUC0-t
Time Frame	Blood samples collected over 10 hour period

Outcome Measure Data

Analysis Population Description

Data from all subjects who completed the study were included in the statistical analysis

Arm/Group Title	Amoxicillin Clavulanic Acid	Augmentin®
Arm/Group Description	Amoxicillin-Clavulanic Acid 400/57 mg chewable tablet (test) dosed in either period	Augmentin® 400/57 mg chewable tablet (reference) dosed in either period
Measure Participants	51	51
Mean (Standard Deviation) [ng*h/mL]	1693.67 (654.95)	1785.27 (661.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amoxicillin Clavulanic Acid, Augmentin®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Using GLM procedures in SAS, analysis of variance (ANOVA)was performed on log-transformed AUC0-t, AUC0-inf and Cmax at the significance level of 0.05.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	94.08
	Confidence Interval	() 90%; 87.19 to 101.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

Adverse Events

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Principal Investigator is not permitted to discuss or publish trial results.