Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design (Chronic Dose)
The United States Food and Drug Administration (FDA) has specific rules generic drug companies must follow to get a generic copy of a seizure medication approved. Currently, the FDA approves generic drugs by requiring studies on normal volunteers who don't have epilepsy and who take just one dose of the generic drug followed by a series of blood tests. Some people with epilepsy and their physicians have complained about side effects or loss of seizure control when taking generic drugs, but no one knows if these complaints are truly because of problems with the generic drugs.
When the FDA tests generic copies of lamotrigine (LTG), the blood levels measured after volunteers receive the generic lamotrigine tablets are allowed to fall within a specific range. This research will test whether two different manufacturer's generic lamotrigine, that fall in different parts of that range, perform in a similar way when given to people with epilepsy every day over a several week period. The two products will be called GENERIC A and GENERIC B.
The generic forms of the study drug lamotrigine to be tested in this study are approved by the FDA for the treatment of seizures.
Drug: Lamotrigine Generic "A"
Drug: Lamotrigine generic "B"
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design (EQUIGEN Chronic-Dose Study)|
- Bioequivalence for generic 1 compared to generic 2 [ Time Frame: 18 months ] [ Designated as safety issue: No ]To determine if Cmax or AUC are significantly different in the high generic product compared to the low generic product taking one as the reference and the other as the test product. Bioequivalence will be established per the current FDA ABE criteria if the 90% confidence interval of the geometric mean of Cmax and AUC for the high generic product compared to the low generic product are entirely within the 80%-125% range using the two one-sided standard analyses
- Intra-subject variances [ Time Frame: 18 months ] [ Designated as safety issue: No ]To measure the intra-subject variances of the investigated generic products, as well as subject-by-interaction variances, by using two replicate periods for each generic product. These estimated variances will be used to investigate individual bioequivalence and detect subject-by-formulation interaction outliers
- Individual Bioequivalence [ Time Frame: 18 months ] [ Designated as safety issue: No ]To examine individual bioequivalence by comparing the two generic products. Individual bioequivalence (IBE) will be determined using the FDA 2001 guidance criteria. To determine the number of subjects who are outliers and to identify these subjects for potential further study.
- Bioequivalence for subjects receiving inducers compared to not receiving inducers [ Time Frame: 18 months ] [ Designated as safety issue: No ]To compare the generic1/generic2 ratios for Cmax and AUC in subjects on a concomitant enzyme inducing AED compared to subjects not on a concomitant enzyme AED
- Bioequivalence by gender [ Time Frame: 18 months ] [ Designated as safety issue: No ]To compare the generic1/generic2 ratios for Cmax and AUC male subjects compared to female subjects
- Bioequivalence in enriched population [ Time Frame: 18 months ] [ Designated as safety issue: No ]To compare the generic1/generic2 ratios for Cmax and AUC in the population of subjects who had reported loss of seizure control or unanticipated adverse effects after a generic switch
|Study Start Date:||April 2013|
|Estimated Study Completion Date:||June 2014|
|Estimated Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
Experimental: Lamotrigine Generic "A"/Generic "B"
Crossover trial. Each arm will receive generic "A" for two periods and generic "B" for two periods.
|Drug: Lamotrigine Generic "A" Drug: Lamotrigine generic "B"|
Experimental: Lamotrigine Generic "B"/Generic "A"
Crossover trial. Each participant will have two periods of generic "A" and two periods of generic "B"
|Drug: Lamotrigine Generic "A" Drug: Lamotrigine generic "B"|
Qualified subjects will be screened and upon fulfilling inclusion/exclusion criteria and signing the informed consent will be enrolled into the study and enter the randomization phase (2-30 days). Subjects will be randomized according to a sealed allocation list that will be balanced for sequence and provided to each site prior to the first subject enrollment. Subjects that withdraw prior to completing the second period will be replaced in a randomized manner. The randomization list will be generated by the study statistical group. There are four test periods in two sequences for a sequence-randomized study. During two test periods subjects will receive twice daily dosing of the "low" generic product and during the other two periods subjects will receive twice daily dosing of the "high" generic product. Each subject will return at the end of the 14+/-1 day stable dosing period for an in-facility 12-hour pharmacokinetic (PK) session to collect samples to determine Cmax and AUCs (area under curve). Each in-facility pharmacokinetic testing will be separated by a 14+/-1 day stable dosing period. A final follow-up phone evaluation will be conducted 12-16 days (target 14 days) after the last dose of study medication. A single make-up period will be permitted if there are issues during any single period. During the study the subjects will continue their usual concomitant medications, including AEDs (anti epilepsy drugs), without change.
Investigators will compare the AED levels as measured by Cmax and AUC in each group using average bioequivalence (ABE) and individual bioequivalence (IBE) criteria. Average bioequivalence will be established if the 90% confidence intervals of the geometric mean of Cmax and AUCs for the most disparate generic products compared to each other are entirely within the 80%-125% range (the FDA criteria for bioequivalence) using the two one-sided standard analyses. Otherwise the products will be considered to not be bioequivalent.
Study Population: Approximately 36 subjects (30 subjects to completion).
Number of centers: 3 sites enrolling approximately 12 subjects each.
Duration of study: Approximately 1 year.
|United States, Alabama|
|University of Alabama at Birmingham||Recruiting|
|Birmingham, Alabama, United States, 35294|
|Contact: Nancy Cohen, RN 205-934-7244 firstname.lastname@example.org|
|Principal Investigator: Jerzy P. Szaflarski, MD,PhD|
|United States, Massachusetts|
|Brigham and Women's Hospital||Recruiting|
|Boston, Massachusetts, United States, 02115|
|Contact: Nichelle Llewellyn, Clinical Research Coordinator 1-617-732-5423 email@example.com|
|Principal Investigator: Barbara Dworetzky, MD|
|United States, New York|
|Michel J. Berg, MD||Recruiting|
|Rochester, New York, United States, 14642|
|Contact: Diane E Smith, Coordinator 585-275-0404 DianeE_Smith@urmc.rochester.edu|
|Principal Investigator: Michel J Berg, MD|
|United States, Ohio|
|Michael Privitera, MD||Recruiting|
|Cincinnati, Ohio, United States, 45267|
|Contact: Donna R Schwieterman, Coordinator 513-558-3975 firstname.lastname@example.org|
|Contact: Lucy C Mendoza, Coordinator 513-558-3020 email@example.com|
|Principal Investigator: Michael D Privitera, MD|
|Principal Investigator:||Michael D Privitera, MD||University of Cincinnati|
|Principal Investigator:||Michel J Berg, MD||University of Rochester|