Amlodipine-Benazepril 10mg-20mg Capsules in Healthy Subjects Under Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00834977
• Collaborator: (none)
• Enrollment: 48
• Locations: 2
• Arms: 2
• Duration (Days): 30
• Patients Per Site: 24
• Patients Per Site Per Month: 24.4

Study Details

Study Description

Brief Summary

The objective of this study is to compare the rate and extent of absorption of amlodipine-benzazepril 10 mg-20 mg capsules (test) versus Lotrel® (reference), administered as 1 x 10 mg capsule under fasting conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Amlodipine-benazepril 10 mg-20 mg capsules; Drug: Lotrel® 10 mg-20 mg capsule	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA bioequivalence statistical methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Randomized, 2-Way, Crossover, Bioequivalence Study of Amlodipine-Benazepril 10mg-20mg Capsules and Lotrel® Administered as 1 x 10 mg-20 mg Capsule in Healthy Subjects Under Fasting Conditions.
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: May 1, 2004
• Actual Study Completion Date: May 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Amlodipine Benazepril Amlodipine Benazepril 10mg-20mg Capsule (test) dosed in first period followed by Lotrel® 10mg-20mg Capsule (reference) dosed in second period	Drug: Amlodipine-benazepril 10 mg-20 mg capsules; 1 x 10-20 mg
Active Comparator: Lotrel® Lotrel® 10mg-20mg Capsule (reference) dosed in first period followed by Amlodipine Benazepril 10mg-20mg Capsules (test) dosed in second period	Drug: Lotrel® 10 mg-20 mg capsule; 1 x 10-20 mg

Outcome Measures

Primary Outcome Measures

1. Cmax - Amlodipine [Blood samples collected over 168 hour period]

   Bioequivalence based on Cmax - Maximum observed concentration

2. AUC0-inf - Amlodipine [Blood samples collected over 168 hour period]

   Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)

3. AUC0-t - Amlodipine [Blood samples collected over 168 hour period]

   Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)

4. Cmax - Benazepril [Blood samples collected over 36 hour period]

   Bioequvialence based on Cmax - Maximum observed concentration

5. AUC0-inf - Benazepril [Blood samples collected over 36 hour period]

   Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)

6. AUC0-t - Benazepril [Blood samples collected over 36 hour period]

   Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)

Secondary Outcome Measures

1. Cmax - Benazeprilat [Blood samples collected over 36 hour period]

   Cmax - Maximum observed concentration

2. AUC0-inf - Benazeprilat [Blood samples collected over 36 hour period]

   AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)

3. AUC0-t - Benazaprilat [Blood samples collected over 36 hour period]

   AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male of non-child-bearing potential female, non-smoker, 18 years of age and older.

• Non-child-bearing potential female subjects is defined as follows:

• Post-menopausal state: absence of menses for 12 months prior to drug administration or hysterectomy woth bilateral oophorectomy at least 6 months prior to drug administration.

• Surgically sterile: hysterectomy, bilateral oophorectomy, or tubal ligation at least 6 months prior to drug administration.

• Capable of consent

Exclusion Criteria:

• Clinically significant illnesses within 4 weeks prior to the administration of the 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 Sub-Investigator, would prevent the subject from participating in the study.

• Abnormal laboratory tests judges clinically significant.

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

• EGC abnormalities (clinically significant) or vital sign abnormalities (systolic blood pressure lower than 100 ot over 140 nnHg, diastolic blood pressure lower than 60 or over 90 mmHg, or heart rate less that 60 or over 100 bpm) at screening.

• BMI ≥ 30.0

• History of significant alcohol abuse within six months prior to the screening visit or any indication of the regular use of more than fourteen units of alcohol per week ( 1 Unit= 150 mL of wine, 360 mL of beer, or 45 mL ot 40% alcohol) or positive alcohol breath test at screening.

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

• History of allergic reactions to heparin,amlodipine,benazepril, or other ACE inhibitors, or other related drugs.

• Use of any drugs known to induce hepatic drug metabolism (examples of inducers: barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole; examples of inhibitors: antidepressant (SSRI), cimetidine, diltiazem, macrolides, imidazoles, neuroleptics, verapamil, fluoroquinolones, antihistamines) within 30 days prior to administration of the study medication.

• Use of and investigational drug or participation in an investigational study within 30 days prior to 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 of 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.

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

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

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

• A depot injection or an implant of any drug within 3 months prior to administration of study medication.

• Donation of plasma (500 mL) within 30 days prior to drug administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the screening procedures of this study) prior to administration of the study medication as follows:

• 50 mL to 300 mL of whole blood within 30 days,

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

• more than 500 mL of whole blood within 56 days prior to drug administration.

• Consumption of food or beverages containing grapefruit ( e.g. fresh, canned, or frozen) within 7 days prior to administration of the study medication.

• Intolerance to venipunctures

• Unable to understand or unwilling to sign the Informed Consent Form.

• Clinically significant history of angioedema. Subjects with a clinically significant history or active hypotension. Subjects with a significant history of active neutropenia and/or agranulocytosis.

• Breast-feeding subject.

• Positive urine pregnancy test at screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Anapharm Inc.	Montreal	Quebec	Canada	H3X H29
2	SFBC Anapharm	Sainte-Foy	Quebec	Canada	G1V 2K8

Sponsors and Collaborators

• Teva Pharmaceuticals USA

Investigators

• Principal Investigator: Richard Larouche, M.D., Anapharm

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00834977
• Other Study ID Numbers: 40012
• First Posted: Feb 3, 2009
• Last Update Posted: Aug 18, 2009
• Last Verified: Jul 1, 2009

• Keywords provided by , ,: Bioequivalence; Healthy Subjects
• Additional relevant MeSH terms: Amlodipine; Benazepril

Study Results

Participant Flow

Arm/Group Title	Amlodipine Benazepril (Test) First	Lotrel® (Reference) First
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in first period followed by Lotrel® 10/20 mg capsule (reference) in second period	Lotrel® 10/20 mg capsule (reference) dosed in first period followed by Amlodipine Benazepril 10/20 mg capsule (test) dosed in second period
Period Title: First Intervention
STARTED	24	24
COMPLETED	24	24
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	24	24
COMPLETED	24	24
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Amlodipine Benazepril (Test) First	Lotrel® (Reference) First	Total
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in first period followed by Lotrel® 10/20 mg capsule (reference) in second period	Lotrel® 10/20 mg capsule (reference) dosed in first period followed by Amlodipine Benazepril 10/20 mg capsule (test) dosed in second period	Total of all reporting groups
Overall Participants	24	24	48
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	23 95.8%	21 87.5%	44 91.7%
>=65 years	1 4.2%	3 12.5%	4 8.3%
Sex: Female, Male (Count of Participants)
Female	8 33.3%	7 29.2%	15 31.3%
Male	16 66.7%	17 70.8%	33 68.8%
Race/Ethnicity, Customized (participants) [Number]
Asian	0 0%	1 4.2%	1 2.1%
White	21 87.5%	20 83.3%	41 85.4%
Hispanic	3 12.5%	3 12.5%	6 12.5%
Region of Enrollment (participants) [Number]
Canada	24 100%	24 100%	48 100%

Outcome Measures

1. Primary Outcome

Title	Cmax - Amlodipine
Description	Bioequivalence based on Cmax - Maximum observed concentration
Time Frame	Blood samples collected over 168 hour period

Outcome Measure Data

Analysis Population Description

One subject was excluded from all statistical analysis for Amlodipine based on a pre-dose plasma concentration greater than 5% of the Cmax value.

Arm/Group Title	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	47	47
Mean (Standard Deviation) [pg/mL]	6299.49 (1917.69)	6185.06 (1697.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	101.08
	Confidence Interval	() 90%; 97.23 to 105.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

2. Primary Outcome

Title	AUC0-inf - Amlodipine
Description	Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)
Time Frame	Blood samples collected over 168 hour period

Outcome Measure Data

Analysis Population Description

One subject was excluded from all statistical analysis for Amlodipine based on a pre-dose plasma concentration greater than 5% of the Cmax value.

Arm/Group Title	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	47	47
Mean (Standard Deviation) [pg*h/mL]	365612.90 (143713.73)	366523.24 (140268.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	99.38
	Confidence Interval	() 90%; 96.63 to 102.22
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

3. Primary Outcome

Title	AUC0-t - Amlodipine
Description	Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)
Time Frame	Blood samples collected over 168 hour period

Outcome Measure Data

Analysis Population Description

One subject was excluded from all statistical analysis for Amlodipine based on a pre-dose plasma concentration greater than 5% of the Cmax value.

Arm/Group Title	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	47	47
Mean (Standard Deviation) [pg*h/mL]	328249.86 (118686.43)	331782.17 (114025.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	98.48
	Confidence Interval	() 90%; 95.80 to 101.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

4. Primary Outcome

Title	Cmax - Benazepril
Description	Bioequvialence based on Cmax - Maximum observed concentration
Time Frame	Blood samples collected over 36 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	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	48	48
Mean (Standard Deviation) [ng/mL]	330.93 (162.44)	340.57 (163.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	98.72
	Confidence Interval	() 90%; 86.95 to 112.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

5. Secondary Outcome

Title	Cmax - Benazeprilat
Description	Cmax - Maximum observed concentration
Time Frame	Blood samples collected over 36 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	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	48	48
Mean (Standard Deviation) [ng/mL]	378.27 (117.87)	397.50 (126.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	95.69
	Confidence Interval	() 90%; 90.54 to 101.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Metabolite presented for informational purposes only.

6. Secondary Outcome

Title	AUC0-inf - Benazeprilat
Description	AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)
Time Frame	Blood samples collected over 36 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	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	48	48
Mean (Standard Deviation) [ng*h/mL]	2027.53 (559.69)	2033.12 (508.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	99.43
	Confidence Interval	() 90%; 96.48 to 102.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Metabolite presented for informational purposes only.

7. Primary Outcome

Title	AUC0-inf - Benazepril
Description	Bioequivalence based on AUC0-inf - Area under the concentration-time curve from time zero to infinity (extrapolated)
Time Frame	Blood samples collected over 36 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	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	48	48
Mean (Standard Deviation) [ng*h/mL]	245.15 (113.78)	253.21 (125.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	97.20
	Confidence Interval	() 90%; 92.82 to 101.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

8. Primary Outcome

Title	AUC0-t - Benazepril
Description	Bioequivalence based on AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)
Time Frame	Blood samples collected over 36 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	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	48	48
Mean (Standard Deviation) [ng*h/mL]	241.65 (113.50)	250.13 (125.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	96.99
	Confidence Interval	() 90%; 92.52 to 101.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80 - 125

9. Secondary Outcome

Title	AUC0-t - Benazaprilat
Description	AUC0-t - Area under the concentration-time curve from time zero to time of last non-zero concentration (per participant)
Time Frame	Blood samples collected over 36 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	Amlodipine Benazepril	Lotrel®
Arm/Group Description	Amlodipine Benazepril 10/20 mg capsule (test) dosed in either period	Lotrel® 10/20 mg capsule (reference) dosed in either period
Measure Participants	48	48
Mean (Standard Deviation) [ng*h/mL]	1981.29 (556.26)	1990.26 (506.70)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Amlodipine Benazepril, Lotrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Parametric analysis of variance (ANOVA)on AUC0-t, AUCinf and Cmax; geometric Confidence Intervals for AUC0-t, AUC0-inf and Cmax
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Least Squares Means
	Estimated Value	99.24
	Confidence Interval	() 90%; 96.21 to 102.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Metabolite presented for informational purposes only.

Adverse Events

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

PI is not permitted to discuss or publish trial results.