Leflunomide 20 mg Tablets Under Fasting Conditions

• Sponsor: Teva Pharmaceuticals USA (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00834418
• Collaborator: (none)
• Enrollment: 84
• Location: 1
• Arms: 2
• Duration (Days): 30
• Patients Per Site Per Month: 85.2

Study Details

Study Description

Brief Summary

This study will compare the relative bioavailability (rate and extent of absorption) of 20 mg Leflunomide Tablets by TEVA Pharmaceuticals Industries, Ltd. with that of 20 mg ARAVA™ Tablets by Aventis Pharmaceuticals, Inc. following a single oral dose (1 x 20 mg tablet) in healthy adult subjects under fasting conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Leflunomide 20 mg Tablets; Drug: ARAVA™ 20 mg Tablets	Phase 1

Detailed Description

Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA bioequivalence statistical methods

Study Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: A Relative Bioavailability Study of 20 mg Leflunomide Tablets Under Fasting Conditions
• Study Start Date: Jun 1, 2002
• Actual Primary Completion Date: Jul 1, 2002
• Actual Study Completion Date: Jul 1, 2002

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Leflunomide Leflunomide 20 mg Tablet	Drug: Leflunomide 20 mg Tablets; 1 x 20 mg, single-dose fasting
Active Comparator: Arava™ Arava™ 20 mg Tablet	Drug: ARAVA™ 20 mg Tablets; 1 x 20 mg, single-dose fasting

Outcome Measures

Primary Outcome Measures

1. Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma [Blood samples collected over 72 hour period]

   Bioequivalence based on Cmax

2. AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose - Metabolite A77 1726 [Blood samples collected over 72 hour period]

   Bioequivalence based on AUC0-72

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• 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 years of age or older at the time of dosing. The weight range will not exceed ± 20% for height and body frame as per Desirable Weights for Adults - 1983 Metropolitan Height and Weight Table.

• Screening procedures: Each subject will complete the screening process within 28 days prior to 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:

1. Hematology: hematocrit, hemoglobin, WBC count with differential, RBC count, platelet count;

2. Clinical Chemistry: serum creatinine, BUN, glucose, AST(GOT), ALT(GPT), albumin, total bilirubin, total protein, and alkaline phosphatase;

3. HIV antibody and hepatitis B surface screens;

4. Urinalysis: by dipstick; full microscopic examination if dipstick positive; and

5. Urine Drug Screen: ethyl alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, opiates and phencyclidine.

6. Serum Pregnancy Screen (female subjects only)

7. Follicle Stimulating Hormone [FSH] (females only to verify postmenopausal status)

• If male must be vasectomized (at least 3 months)

• If female and:

1. is postmenopausal for at least 1 year; or

2. is surgically sterile (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 or reactive HIV antibody screen.

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

• Female subjects who are currently breastfeeding.

• Female subjects demonstrating a positive pregnancy screen.

• Subjects with a history of allergic response(s) to leflunomide 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 dosing (as determined by the clinical investigators).

• Subjects who have taken any drug known to induce or inhibit hepatic drug metabolism in the 30 days prior to dosing.

• Subjects who report donating greater than 150 mL of blood within 30 days prior to 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 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 30 days prior to dosing.

• Subjects who report taking any prescription medication in the 14 days prior to dosing, with the exception of postmenopausal women on HRT may continue their HRT and topical products without systemic absorption.

• Subjects who report an intolerance of direct venipuncture.

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

• Subjects who report taking any product containing leflunomide within 180 days of dosing.

• Subjects who report taking any herbal products within 7 days prior to 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, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00834418
• Other Study ID Numbers: R02-561
• First Posted: Feb 3, 2009
• Last Update Posted: Sep 15, 2009
• Last Verified: Sep 1, 2009

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

Study Results

Participant Flow

Arm/Group Title	Leflunomide	Arava™
Arm/Group Description	Leflunomide 20 mg Tablet	Arava™ 20 mg Tablet
Period Title: Overall Study
STARTED	42	42
COMPLETED	42	40
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Leflunomide	Arava™	Total
Arm/Group Description	Leflunomide 20 mg Tablet	Arava™ 20 mg Tablet	Total of all reporting groups
Overall Participants	42	42	84
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	38 90.5%	38 90.5%	76 90.5%
>=65 years	4 9.5%	4 9.5%	8 9.5%
Sex: Female, Male (Count of Participants)
Female	32 76.2%	34 81%	66 78.6%
Male	10 23.8%	8 19%	18 21.4%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	40 95.2%	40 95.2%	80 95.2%
Hispanic	1 2.4%	2 4.8%	3 3.6%
American Indian	1 2.4%	0 0%	1 1.2%
Region of Enrollment (participants) [Number]
United States	42 100%	42 100%	84 100%

Outcome Measures

1. Primary Outcome

Title	Cmax - Maximum Observed Concentration - Metabolite A77 1726 in Plasma
Description	Bioequivalence based on Cmax
Time Frame	Blood samples collected over 72 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	Leflunomide	Arava™
Arm/Group Description	Leflunomide 20 mg Tablet	Arava™ 20 mg Tablet
Measure Participants	42	40
Mean (Standard Deviation) [ng/mL]	2109.286 (407.044)	1974.000 (421.291)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Leflunomide, Arava™
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Analysis of variance (ANOVA) was performed on pharmacokinetic parameters of AUC0-72 and Cmax.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Test/Ref Ratio x 100
	Estimated Value	107
	Confidence Interval	() 90%; 99.6 to 116
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence is established when 90% Confidence Interval falls within 80-125.

2. Primary Outcome

Title	AUC0-72 - Area Under the Concentration-time Curve From Time Zero to 72 Hours Post-dose - Metabolite A77 1726
Description	Bioequivalence based on AUC0-72
Time Frame	Blood samples collected over 72 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	Leflunomide	Arava™
Arm/Group Description	Leflunomide 20 mg Tablet	Arava™ 20 mg Tablet
Measure Participants	42	40
Mean (Standard Deviation) [ng*h/mL]	105806.888 (19068.308)	103905.901 (19933.702)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Leflunomide, Arava™
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Analysis of variance (ANOVA) was performed on pharmacokinetic parameters of AUC0-72 and Cmax.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric Test/Ref Ratio x 100
	Estimated Value	102
	Confidence Interval	() 90%; 95.2 to 109
	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.