Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets in Healthy Subjects Under Non-Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01149473
• Collaborator: (none)
• Enrollment: 80
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 78.5

Study Details

Study Description

Brief Summary

The objective of this study is to compare the relative bioavailability of Losartan potassium/Hydrochlorothiazide 100/25 mg tablets (manufactured by Teva Pharmaceutical Industries, Ltd. and distributed by Teva Pharmaceuticals USA) with that of Hyzaar® 100/25 mg tablets (Merck) in healthy, adult, non-smoking subjects under non-fasting conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Losartan potassium/Hydrochlorothiazide; Drug: Losartan potassium/Hydrochlorothiazide	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA Bioequivalence Statistical Methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: A Relative Bioavailability Study of Losartan Potassium/Hydrochlorothiazide 100/25 mg Tablets Under Non-Fasting Conditions
• Study Start Date: Mar 1, 2004
• Actual Primary Completion Date: Apr 1, 2004
• Actual Study Completion Date: Apr 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Generic Test Product Losartan potassium/Hydrochlorothiazide 100/25 mg Tablets	Drug: Losartan potassium/Hydrochlorothiazide; 100/25 mg Tablets
Active Comparator: Reference Listed Drug Hyzaar® 100/25 mg Tablets	Drug: Losartan potassium/Hydrochlorothiazide; 100/25 mg Tablets; Other Names: Hyzaar®

Outcome Measures

Primary Outcome Measures

1. Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma) [Blood samples collected over a 48 hour period.]

   Bioequivalence based on Losartan Cmax.

2. AUC0-t of Losartan(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [Blood samples collected over a 48 hour period.]

   Bioequivalence based on Losartan AUC0-t.

3. AUC0-inf of Losartan(Area Under the Concentration-time Curve From Time Zero to Infinity) [Blood samples collected over a 48 hour period.]

   Bioequivalence based on Losartan AUC0-inf.

4. Cmax of Hydrochlorothiazide(Maximum Observed Concentration of Drug Substance in Plasma) [Blood samples collected over a 48 hour period.]

   Bioequivalence based on Hydrochlorothiazide Cmax.

5. AUC0-t of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [Blood samples collected over a 48 hour period.]

   Bioequivalence based on Hydrochlorothiazide AUC0-t.

6. AUC0-inf of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Infinity) [Blood samples collected over a 48 hour period.]

   Bioequivalence based on Hydrochlorothiazide AUC0-inf.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Healthy, non-smoking, male and female subjects at least 18 years of age.

• BMI (body mass index) of 30 or less.

• Females in this study must be physically unable to become pregnant (postmenopausal for at least 6 months or surgically sterile).

• Successful completion of a physical examination within 28 days of initiation of the study.

• Negative serum pregnancy test (females).

Exclusion Criteria:

• Subjects with a significant recent history of chronic alcohol consumption (past 2 years), drug addiction, or serious gastrointestinal, renal, hepatic, or cardiovascular disease, tuberculosis, epilepsy, asthma (past 5 years), diabetes, psychosis, or glaucoma will not be eligible for this study.

• Subjects whose clinical laboratory test values are outside the reference range and are deemed clinically significant by the Principle Investigator.

• Subjects who have a history of allergic responses to the classes of drugs being tested will be excluded from the study.

• Subjects who use tobacco in any form will not be eligible to participate in the study. 3 months abstinence is required.

• Subjects found to have urine concentrations of any of the tested drugs of abuse will not be allowed to participate.

• Subjects should not have donated blood and/or plasma for at least 30 days prior to the first dosing of the study.

• Subjects who have taken any investigational drug within 30 days prior to the first dosing of the study will not be allowed to participate.

• Female subjects who are pregnant or who are able (women with child bearing potential) to become pregnant during the study will not be allowed to participate.

• All female subjects will be screened for pregnancy at check-in each study period. Subjects with positive or inconclusive results will be withdrawn from the study.

• Subjects who do not tolerate venipuncture will not be allowed to participate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PRACS Institute, Ltd.	Fargo	North Dakota	United States	58104

Sponsors and Collaborators

• Teva Pharmaceuticals USA

Investigators

• Principal Investigator: James D Carlson, Pharm D, PRACS Institute, Ltd.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01149473
• Other Study ID Numbers: B046515
• First Posted: Jun 23, 2010
• Last Update Posted: Sep 14, 2010
• Last Verified: Aug 1, 2010

• Keywords provided by , ,: Bioequivalence; Healthy Subjects
• Additional relevant MeSH terms: Losartan; Hydrochlorothiazide

Study Results

Participant Flow

Arm/Group Title	Losartan/HCTZ (Test) First	Hyzaar® (Reference) First
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in first period followed by 100/25 mg Hyzaar® Tablets reference product dosed in the second period.	100/25 mg Hyzaar® Tablets reference product dosed in first period followed by 100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in the second period.
Period Title: First Intervention
STARTED	40	40
COMPLETED	39	39
NOT COMPLETED	1	1
Period Title: First Intervention
STARTED	39	39
COMPLETED	38	38
NOT COMPLETED	1	1
Period Title: First Intervention
STARTED	38	38
COMPLETED	38	38
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Losartan/HCTZ (Test) First	Hyzaar® (Reference) First	Total
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in first period followed by 100/25 mg Hyzaar® Tablets reference product dosed in the second period.	100/25 mg Hyzaar® Tablets reference product dosed in first period followed by 100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in the second period.	Total of all reporting groups
Overall Participants	40	40	80
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	40 100%	39 97.5%	79 98.8%
>=65 years	0 0%	1 2.5%	1 1.3%
Sex: Female, Male (Count of Participants)
Female	7 17.5%	7 17.5%	14 17.5%
Male	33 82.5%	33 82.5%	66 82.5%
Race/Ethnicity, Customized (participants) [Number]
Asian	1 2.5%	2 5%	3 3.8%
Black	3 7.5%	2 5%	5 6.3%
Caucasian	35 87.5%	36 90%	71 88.8%
Hispanic	1 2.5%	0 0%	1 1.3%
Region of Enrollment (participants) [Number]
United States	40 100%	40 100%	80 100%

Outcome Measures

1. Primary Outcome

Title	Cmax of Losartan(Maximum Observed Concentration of Drug Substance in Plasma)
Description	Bioequivalence based on Losartan Cmax.
Time Frame	Blood samples collected over a 48 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Losartan/HCTZ (Test)	Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.	100/25 mg Hyzaar® Tablets reference product dosed in either period.
Measure Participants	76	76
Mean (Standard Deviation) [ng/mL]	458.29 (323.345)	409.324 (251.876)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan/HCTZ (Test), Hyzaar® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	109
	Confidence Interval	(2-Sided) 90%; 98.1 to 120
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

2. Primary Outcome

Title	AUC0-t of Losartan(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Description	Bioequivalence based on Losartan AUC0-t.
Time Frame	Blood samples collected over a 48 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Losartan/HCTZ (Test)	Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.	100/25 mg Hyzaar® Tablets reference product dosed in either period.
Measure Participants	76	76
Mean (Standard Deviation) [ng*h/mL]	959.41 (480.988)	939.492 (465.001)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan/HCTZ (Test), Hyzaar® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	102
	Confidence Interval	(2-Sided) 90%; 98.8 to 106
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

3. Primary Outcome

Title	AUC0-inf of Losartan(Area Under the Concentration-time Curve From Time Zero to Infinity)
Description	Bioequivalence based on Losartan AUC0-inf.
Time Frame	Blood samples collected over a 48 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Losartan/HCTZ (Test)	Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.	100/25 mg Hyzaar® Tablets reference product dosed in either period.
Measure Participants	76	76
Mean (Standard Deviation) [ng*h/mL]	957.445 (465.781)	956.046 (467.567)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan/HCTZ (Test), Hyzaar® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	101
	Confidence Interval	(2-Sided) 90%; 98.6 to 104
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

4. Primary Outcome

Title	Cmax of Hydrochlorothiazide(Maximum Observed Concentration of Drug Substance in Plasma)
Description	Bioequivalence based on Hydrochlorothiazide Cmax.
Time Frame	Blood samples collected over a 48 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Losartan/HCTZ (Test)	Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.	100/25 mg Hyzaar® Tablets reference product dosed in either period.
Measure Participants	76	76
Mean (Standard Deviation) [ng/mL]	136.361 (33.311)	132.717 (35.468)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan/HCTZ (Test), Hyzaar® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	103
	Confidence Interval	(2-Sided) 90%; 98.8 to 108
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

5. Primary Outcome

Title	AUC0-t of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Description	Bioequivalence based on Hydrochlorothiazide AUC0-t.
Time Frame	Blood samples collected over a 48 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Losartan/HCTZ (Test)	Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.	100/25 mg Hyzaar® Tablets reference product dosed in either period.
Measure Participants	76	76
Mean (Standard Deviation) [ng*h/mL]	917.034 (212.109)	919.631 (210.684)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan/HCTZ (Test), Hyzaar® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	99.7
	Confidence Interval	(2-Sided) 95%; 98.6 to 101
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

6. Primary Outcome

Title	AUC0-inf of Hydrochlorothiazide(Area Under the Concentration-time Curve From Time Zero to Infinity)
Description	Bioequivalence based on Hydrochlorothiazide AUC0-inf.
Time Frame	Blood samples collected over a 48 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Losartan/HCTZ (Test)	Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.	100/25 mg Hyzaar® Tablets reference product dosed in either period.
Measure Participants	76	76
Mean (Standard Deviation) [ng*h/mL]	943.22 (217.842)	945.592 (217.269)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Losartan/HCTZ (Test), Hyzaar® (Reference)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of the T/R geometric mean x 100
	Estimated Value	99.7
	Confidence Interval	(2-Sided) 90%; 98.7 to 101
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.

Adverse Events

Time Frame	Adverse event data was collected over the course of the study, which was approximately 2 weeks in duration.
Adverse Event Reporting Description	Volunteers were monitored throughout the study for any adverse experiences. AEs were collected through both solicited and unsolicited methods. The volunteers were encouraged to report signs, symptoms, and any changes in health to the clinic staff.
Arm/Group Title	Losartan/HCTZ (Test)		Hyzaar® (Reference)
Arm/Group Description	100/25 mg Losartan potassium/Hydrochlorothiazide test product dosed in either period.		100/25 mg Hyzaar® Tablets reference product dosed in either period.
All Cause Mortality
	Losartan/HCTZ (Test)		Hyzaar® (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Losartan/HCTZ (Test)		Hyzaar® (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/80 (0%)		0/80 (0%)
Other (Not Including Serious) Adverse Events
	Losartan/HCTZ (Test)		Hyzaar® (Reference)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/80 (0%)		0/80 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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