Valacyclovir 1000 mg Tablet Under Fed Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01149460
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 2

Study Details

Study Description

Brief Summary

The objective of this study was to compare the rate and extent of absorption of Teva Pharmaceuticals USA valacyclovir and GlaxoSmithKline, USA (Valtrex) valacyclovir, administered as 1 x 1000 mg tablet under fed conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Valacyclovir; Drug: Valacyclovir	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: Randomized, 2-Way Crossover, Bioequivalence Study of Valacyclovir 1000 mg Tablet and Valtrex Administered as 1 x 1000 mg Tablet in Healthy Subjects Under Fed Conditions
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Sep 1, 2004
• Actual Study Completion Date: Sep 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Valacyclovir Test 1000 mg Tablet	Drug: Valacyclovir; Test 1000 mg Tablet
Active Comparator: Valtrex Reference Listed Valacyclovir 1000 mg Tablet	Drug: Valacyclovir; Reference Listed Valacyclovir 1000 mg Tablet; Other Names: Valtrex

Outcome Measures

Primary Outcome Measures

1. Cmax (Maximum Observed Concentration of Drug Substance in Plasma) - Valacyclovir [Blood samples collected over 12 hour period]

   Bioequivalence based on Cmax

2. AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) - Valacyclovir [Blood samples collected over 12 hour period]

   Bioequivalence based on AUC0-t

3. AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) - Valacyclovir [Blood samples collected over 12 hour period]

   Bioequivalence based on AUC0-inf

Secondary Outcome Measures

1. Cmax (Maximum Observed Concentration of Drug Substance in Plasma) - Acyclovir [Blood samples collected over 24 hour period]

2. AUC0-t (Area Under Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) - Acyclovir [Blood samples collected over 24 hour period]

3. AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) - Acyclovir [Blood samples collected over 24 hour period]

Eligibility Criteria

Criteria

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

Inclusion Criteria

• Male or female, non-smokers, 18 years of age and older.

• Capable of consent

Exclusion Criteria

Subjects to whom any of the following applies will be excluded from the study:

• Clinically significant illnesses or surgery within 4 weeks of the administration of 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 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 mmHg; or heart rate less than 50 or over 100 bpm) at screening.

• BMI less than 19.0 or greater than or equal to 30.0 kg/m2.

• History of significant alcohol abuse within six months prior to the screening visit (more than fourteen units of alcohol per week [1 Unit = 150 mL of wine or 360 mL of beer or 45 mL of alcohol 40% alcohol]) or positive urine drug screen at screening.

• 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 prior to the screening visit or positive urine drug screen at screening.

• History of allergic reactions to heparin, valacyclovir, acyclovir, or other related drugs.

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

• Use of an investigational drug or participation in 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.

• Use of prescription medication 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.

• Use of any tobacco products in the 90 days preceding drug administration.

• Any food allergy, intolerance, restriction or special diet that, in the opinion of the medical subinvestigator, could contraindicate the subjects 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.

• Intolerance to venipunctures.

• Clinically significant history of renal, hepatic or cardiovascular disease, tuberculosis, epilepsy, asthma, diabetes, psychosis or glaucoma will not be eligible for this study.

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

• Breast-feeding.

• Positive urine pregnancy test at screening.

• Female subjects of childbearing potential having unprotected sexual intercourse with any non-sterile male partner (i.e. male who has not been sterilized by vasectomy for at least 6 months) within 14 days prior to study drug administration. Acceptable methods of contraception:

• Intra-uterine contraceptive device (placed at least 4 weeks prior to study drug administration),

• Condom or diaphragm + spermicide

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Teva Pharmaceuticals USA

Investigators

• Principal Investigator: Benoit Girard, MD, Anapharm

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01149460
• Other Study ID Numbers: 40280
• First Posted: Jun 23, 2010
• Last Update Posted: Sep 14, 2010
• Last Verified: Aug 1, 2010

• Additional relevant MeSH terms: Malnutrition; Valacyclovir

Study Results

Participant Flow

Arm/Group Title	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Period Title: Overall Study
STARTED	18	18
COMPLETED	18	16
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Valacyclovir	Valtrex®	Total
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period	Total of all reporting groups
Overall Participants	18	18	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	17 94.4%	35 97.2%
>=65 years	0 0%	1 5.6%	1 2.8%
Sex: Female, Male (Count of Participants)
Female	7 38.9%	10 55.6%	17 47.2%
Male	11 61.1%	8 44.4%	19 52.8%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	18 100%	18 100%	36 100%
Region of Enrollment (participants) [Number]
Canada	18 100%	18 100%	36 100%

Outcome Measures

1. Primary Outcome

Title	Cmax (Maximum Observed Concentration of Drug Substance in Plasma) - Valacyclovir
Description	Bioequivalence based on Cmax
Time Frame	Blood samples collected over 12 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	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Measure Participants	18	16
Mean (Standard Deviation) [ng/mL]	385.35 (139.10)	350.86 (133.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Valtrex®
	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 Least Squares Means (T/R)
	Estimated Value	111.34
	Confidence Interval	(2-Sided) 90%; 100.54 to 123.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the test (T) and reference (R) product fall within the interval of 80-125%.

2. Primary Outcome

Title	AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) - Valacyclovir
Description	Bioequivalence based on AUC0-t
Time Frame	Blood samples collected over 12 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	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Measure Participants	18	16
Mean (Standard Deviation) [ng*h/mL]	549.32 (137.87)	551.77 (140.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Valtrex®
	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 Least Squares Means (T/R)
	Estimated Value	100.01
	Confidence Interval	(2-Sided) 90%; 96.34 to 103.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the test (T) and reference (R) product fall within the interval of 80-125%.

3. Primary Outcome

Title	AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) - Valacyclovir
Description	Bioequivalence based on AUC0-inf
Time Frame	Blood samples collected over 12 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	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Measure Participants	18	16
Mean (Standard Deviation) [ng*h/mL]	552.17 (138.76)	554.53 (140.97)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Valtrex®
	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 Least Squares Means (T/R)
	Estimated Value	100.01
	Confidence Interval	(2-Sided) 90%; 96.38 to 103.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the test (T) and reference (R) product fall within the interval of 80-125%.

4. Secondary Outcome

Title	Cmax (Maximum Observed Concentration of Drug Substance in Plasma) - Acyclovir
Time Frame	Blood samples collected over 24 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	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Measure Participants	18	16
Mean (Standard Deviation) [ng/mL]	6485.51 (1469.43)	6283.25 (1375.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Valtrex®
	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 Least Squares Means (T/R)
	Estimated Value	103.48
	Confidence Interval	(2-Sided) 90%; 97.87 to 109.41
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the test (T) and reference (R) product fall within the interval of 80-125%.

5. Secondary Outcome

Title	AUC0-t (Area Under Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) - Acyclovir
Time Frame	Blood samples collected over 24 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	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Measure Participants	18	16
Mean (Standard Deviation) [ng*h/mL]	22514.36 (4316.76)	22675.85 (4063.20)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Valtrex®
	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 Least Squares Means (T/R)
	Estimated Value	99.20
	Confidence Interval	(2-Sided) 90%; 97.14 to 101.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the test (T) and reference (R) product fall within the interval of 80-125%.

6. Secondary Outcome

Title	AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) - Acyclovir
Time Frame	Blood samples collected over 24 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	Valacyclovir	Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period	Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
Measure Participants	18	16
Mean (Standard Deviation) [ng*h/mL]	22705.17 (4336.16)	22887.99 (4065.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Valtrex®
	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 Least Squares Means
	Estimated Value	99.10
	Confidence Interval	(2-Sided) 90%; 97.04 to 101.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the test (T) and reference (R) product fall within the interval of 80-125%.

Adverse Events

Arm/Group Title	Valacyclovir		Valtrex®
Arm/Group Description	Test 1000 mg Tablet dosed in first period follwed by Reference Listed 1000 mg Valtrex® tablet in second period		Reference Listed Valtrex® 1000 mg Tablet dosed in first period followed by Test 1000 mg Valacyclovir tablet in second period
All Cause Mortality
	Valacyclovir		Valtrex®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Valacyclovir		Valtrex®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/36 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Valacyclovir		Valtrex®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/36 (19.4%)		10/36 (27.8%)
Blood and lymphatic system disorders
Low Hemoglobin Level	2/36 (5.6%)	2	1/36 (2.8%)	1
Gastrointestinal disorders
Abdominal Pain/Cramp	0/36 (0%)	0	4/36 (11.1%)	4
Loose/Soft Stools	1/36 (2.8%)	1	2/36 (5.6%)	2
Nausea	0/36 (0%)	0	2/36 (5.6%)	2
General disorders
Fatigue/Drowsiness	0/36 (0%)	0	2/36 (5.6%)	2
Musculoskeletal and connective tissue disorders
Back Pain	1/36 (2.8%)	1	3/36 (8.3%)	3
Nervous system disorders
Headache	2/36 (5.6%)	2	4/36 (11.1%)	4
Dizziness	3/36 (8.3%)	3	2/36 (5.6%)	3

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.