Divalproex Sodium Delayed-Release Tablets Under Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00834639
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2

Study Details

Study Description

Brief Summary

This study will compare the relative bioavailability of 500 mg Divalproex Sodium Delayed-Release Tablets with that of 500 mg Depakote® Tablets following a single oral dose (1 x 500 mg tablets)in healthy subjects under fasting conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: divalproex sodium; Drug: Depakote®	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA bioequivalence statistical methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: A Relative Bioavailability Study of 500 mg Divalproex Sodium Delayed-Release Tablets Under Fasting 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: 1	Drug: divalproex sodium; delayed-release 500 mg tablet
Active Comparator: 2	Drug: Depakote®; delayed-release 500 mg tablet

Outcome Measures

Primary Outcome Measures

1. Cmax (Maximum Observed Concentration) [Blood samples collected over a 72 hour period.]

   Bioequivalence based on Cmax.

2. AUC0-t (Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) [Blood samples collected over a 72 hour period.]

   Bioequivalence based on AUC0-t.

3. AUC0-inf (Area Under the Concentration-time Curve From Time Zero to Infinity) [Blood samples collected over a 72 hour period.]

   Bioequivalence based on AUC0-inf.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria

• Screening Demographics: All subjects selected for this study will be healthy men or women 18-65 years of age, inclusive, at the time of dosing. The subject's body mass index (BMI) should be less than or equal to 30.

• Screening Procedures: Each subject will complete the screening process within 28 days prior to period I dosing. Consent documents for both the screening evaluation and HIV antibody determination will be reviewed, discussed and signed by each potential participant before full implementation of screening procedures.

Screening will include general observations, physical examination, demographics, medical and medication history, an electrocardiogram, sitting blood pressure and heart rate, respiratory rate and temperature. The physical examination will include, but may not be limited to, an evaluation of the cardiovascular, gastrointestinal, respiratory and central nervous systems.

The screening clinical laboratory procedures will include:

• HEMATOLOGY: hematocrit, hemoglobin, WBC count with differential, RBC count, platelet count

• CLINICAL CHEMISTRY: serum creatinine, BUN, glucose, AST(GOT), ALT(GPT), albumin, total bilirubin, total protein, and alkaline phosphatase

• HIV antibody, hepatitis B surface antigen, hepatitis C antibody screens

• URINALYSIS: by dipstick; full microscopic examination if dipstick positive

• URINE DRUG SCREEN: ethyl alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, opiates and phencyclidine

• SERUM PREGNANCY SCREEN (female subjects only)

• FOLLICLE STIMULATING HORMONE (FSH; female subjects only): verify postmenopausal status

If female and:

• Is postmenopausal for at least 1 year with postmenopausal status defined as: > 60 years of age and amenorrheic for at least one year; if 60 years of age or younger, must also have a serum FSH level > 30 IU/L; or

• Is surgically sterile for at least 6 months (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy)

Exclusion Criteria

• Subjects with a recent history of drug or alcohol addiction or abuse.

• Subjects with the presence of a clinically significant disorder involving the cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine, or neurologic system(s) or psychiatric disease (as determined by the clinical investigators).

• Subjects whose clinical laboratory test values are outside the accepted reference range and when confirmed on re-examination are deemed to be clinically significant.

• Subjects demonstrating a positive hepatitis B surface antigen screen, a positive hepatitis C antibody screen, or a reactive HIV antibody screen.

• Subjects demonstrating a positive drug abuse screen when screened for this study.

• Female subjects demonstrating a positive pregnancy screen.

• Female subjects who are currently breastfeeding.

• Subjects with a history of allergic response(s) to divalproex sodium or related drugs.

• Subjects with a history of clinically significant allergies including drug allergies.

• Subjects with a clinically significant illness during the 4 weeks prior to Period I dosing (as determined by the clinical investigators).

• Subjects who currently or report using tobacco products within 90 days of Period I dose administration.

• Subjects who have taken any drug known to induce or inhibit hepatic drug metabolism in the 28 days prior to Period I dosing.

• Subjects who report donating greater than 150 mL of blood within 28 days prior to Period I dosing. All subjects will be advised not to donate blood for four weeks after completing the study.

• Subjects who have donated plasma (e.g. plasmapheresis) within 14 days prior to Period I dosing. All subjects will be advised not to donate plasma for four weeks after completing the study.

• Subjects who report receiving any investigational drug within 28 days prior to Period I dosing.

• Subjects who report taking any systemic prescription medication in the 14 days prior to Period I dosing.

• Subjects who report an intolerance of direct venipuncture.

• Subjects who report consuming an abnormal diet during the 28 days prior to Period I dosing.

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00834639
• Other Study ID Numbers: R03-592
• First Posted: Feb 3, 2009
• Last Update Posted: Aug 20, 2009
• Last Verified: Aug 1, 2009

• Keywords provided by , ,: Bioequivalence; Healthy Subjects
• Additional relevant MeSH terms: Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Divalproex Sodium First	Depakote® First
Arm/Group Description	500 mg Divalproex Sodium Delayed Release Tablets test product dosed in first period followed by 500 mg Depakote® Delayed Release Tablets reference product dosed in the second period.	500 mg Depakote® Delayed Release Tablets reference product dosed in first period followed by 500 mg Divalproex Sodium Delayed Release Tablets test product dosed in the second period.
Period Title: First Intervention
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	12	12
COMPLETED	12	10
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Divalproex Sodium First	Depakote® First	Total
Arm/Group Description	500 mg Divalproex Sodium Delayed Release Tablets test product dosed in first period followed by 500 mg Depakote® Delayed Release Tablets reference product dosed in the second period.	500 mg Depakote® Delayed Release Tablets reference product dosed in first period followed by 500 mg Divalproex Sodium Delayed Release Tablets test product dosed in the second period.	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	12 100%	24 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	1 8.3%	1 4.2%
Male	12 100%	11 91.7%	23 95.8%
Race/Ethnicity, Customized (participants) [Number]
Black	1 8.3%	1 8.3%	2 8.3%
White	11 91.7%	10 83.3%	21 87.5%
Hispanic	0 0%	1 8.3%	1 4.2%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	Cmax (Maximum Observed Concentration)
Description	Bioequivalence based on Cmax.
Time Frame	Blood samples collected over a 72 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Divalproex Sodium	Depakote®
Arm/Group Description	500 mg Divalproex Sodium Delayed Release Tablets test product dosed in either period.	500 mg Depakote® Delayed Release Tablets reference product dosed in either period.
Measure Participants	22	22
Mean (Standard Deviation) [µg/mL]	53.89 (5.15)	55.19 (5.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divalproex Sodium, Depakote®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The pharmacokinetic parameters were evaluated statistically by an analysis of variance (ANOVA) appropriate for the experimental design of this study.
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	97.36
	Confidence Interval	() 90%; 93.68 to 101.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference and test 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)
Description	Bioequivalence based on AUC0-t.
Time Frame	Blood samples collected over a 72 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Divalproex Sodium	Depakote®
Arm/Group Description	500 mg Divalproex Sodium Delayed Release Tablets test product dosed in either period.	500 mg Depakote® Delayed Release Tablets reference product dosed in either period.
Measure Participants	22	22
Mean (Standard Deviation) [µg*h/mL]	905.18 (195.96)	898.24 (205.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divalproex Sodium, Depakote®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The pharmacokinetic parameters were evaluated statistically by an analysis of variance (ANOVA) appropriate for the experimental design of this study.
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	100.59
	Confidence Interval	() 90%; 97.07 to 104.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference and test 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)
Description	Bioequivalence based on AUC0-inf.
Time Frame	Blood samples collected over a 72 hour period.

Outcome Measure Data

Analysis Population Description

All participants that completed the study had their samples analyzed.

Arm/Group Title	Divalproex Sodium	Depakote®
Arm/Group Description	500 mg Divalproex Sodium Delayed Release Tablets test product dosed in either period.	500 mg Depakote® Delayed Release Tablets reference product dosed in either period.
Measure Participants	22	22
Mean (Standard Deviation) [µg*h/mL]	982.25 (223.64)	978.75 (235.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Divalproex Sodium, Depakote®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The pharmacokinetic parameters were evaluated statistically by an analysis of variance (ANOVA) appropriate for the experimental design of this study.
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	100.36
	Confidence Interval	() 90%; 97.35 to 103.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference and test product fall within the interval of 80-125%.

Adverse Events

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.