Clinical trial NCT02707965: Characterization of Epilepsy Patients BEEP 2b
Official title: Characterization of Epilepsy Patients At-risk for Adverse Outcomes Related to Switching Antiepileptic Drug Products: BEEP 2b Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Epilepsy
Keywords: Generic brittle
Anti-epileptic drug
Bioequivalence
Lead sponsor: Food and Drug Administration (FDA)
Sponsor class: FED
Collaborators: name: University of Maryland, Baltimore
First posted: 2016-03-14
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 76
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: Some epilepsy patients are described as GB when they have worsened seizures or side effects related to switching between brand name and generic, or between generic antiepileptic drug (AED) products. In concert with Aim 1 (protocol BEEP2a), this study will uncover possible reasons for patient problems with the drug switching. Factors that will be studied in GB epilepsy patients include physiologic, psychological, and genetic factors, including in this protocol whether brand and generic AEDs are pharmacokinetically similar in GB individuals.

Detailed description: This pilot study is exploratory research to characterize the "generic brittle" (GB) patient and to identify major causes for generic brittleness in epilepsy patients who are sensitive to antiepileptic drug (AED) formulation changes.

The primary aim of this BEEP2b study is to perform individual pharmacokinetic (PK) similarity testing of brand and generic AEDs in "probably GB" patients (N=12),who were selected on the basis of having GB-defining factors from the BEEP2a study, in order to confirm whether these factors are predictive of a generic brittle response to product switching. The study design involves a randomized, double-blind, multiple-dose, complete four-way replicate crossover design in which one brand and one generic will be compared in each patient from the patient's own AED regimen. Associated adverse events (i.e. seizures and side effects) will also be assessed. Bioequivalence (BE) will not be assessed. Rather, about nine AEDs are expected to be collectively evaluated. Generic brittleness anticipates that, for individual subjects, brand and generic may be the same or different, depending upon the underlying basis for generic brittleness. This exploratory research is focused on understanding individual patient attributes that contribute to GB, and is not focused on either product development or comparison of specific products.

Eligibility criteria: Inclusion Criteria:

1. Subject previously completed BEEP2a study, found to be probably GB, and able to provide informed consent or subject's legally authorized representative is able to provide informed consent.
2. Subject is male or female between 18 and 76 years of age inclusive.
3. Subject has a diagnosis of epilepsy including focal or primary generalized epilepsy.
4. Subject is taking at least one study antiepileptic drug for the treatment of epilepsy.
5. Subject is an acceptable candidate for venipuncture.
6. Subject is willing to be switched between brand and generic drug.
7. Subject is willing to stop all non-routine OTC medications for 24 hours prior to and during pharmacokinetic study visits.
8. Subject is willing to maintain stable doses of all other AEDs, including Vagus Nerve Stimulation parameters for the duration of the study.

Exclusion Criteria:

1. Subject has any medical condition, including a progressive neurological condition, which in the opinion of the investigator, could jeopardize the subject's health or would compromise the subject's ability to participate in the trial.
2. Subject has a history of alcohol or drug abuse, which in the opinion of the investigator, could jeopardize the subject's health or would compromise the subject's ability to participate in this trial.
3. Subject has a history of previous or current significant psychiatric disorder that would interfere with conduct of the study.
4. Subject is pregnant or lactating.
5. Subject has severe liver impairment as assessed by alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels ≥10 times the upper limit of normal (ULN).
6. Subject has severe renal impairment as assessed by creatinine clearance lower than 30mL/min, using the Cockcroft-Gault formula.
7. Female subjects of childbearing potential will not be eligible to participate who are unwilling or unable to use a medically acceptable method of contraception throughout the entire study period and for one week after the study is completed. Medically acceptable methods of contraception that may be used by the subject and/or her partner are: condom with spermicide, diaphragm with spermicide, IUD without progesterone, vaginal spermicidal suppository, surgical sterilization of their partner(s) or abstinence.
8. Subject is not willing or able to be adherent to study protocol (e.g. study medication dosing and any interacting comedication).

Primary outcomes:
measure: Mean AUC0-last_ss (Test vs. Reference)
timeFrame: For all study drugs, time points are: predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hr postdose. For twice-a-day regimen, additional points are:8, 10, and 12 hr postdose. For once-a-day drugs, additional times are:8, 10, 12, 16, and 24 hr postdose.
measure: Mean Cmax_ss (Test vs. Reference)
timeFrame: For all study drugs, time points are: predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hr postdose. For twice-a-day regimen, additional points are:8, 10, and 12 hr postdose. For once-a-day drugs, additional times are:8, 10, 12, 16, and 24 hr postdose.
measure: Mean Cmin_ss (Test vs. Reference)
timeFrame: For all study drugs, time points are: predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, and 6 hr postdose. For twice-a-day regimen, additional points are:8, 10, and 12 hr postdose. For once-a-day drugs, additional times are:8, 10, 12, 16, and 24 hr postdose.
Secondary outcomes:
measure: Number of Adverse Events
timeFrame: Through the approximately 2 week period when the treatment is given.
measure: Number of Seizures Reported
timeFrame: Through the approximately 2 week period when the treatment is given.
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland, Baltimore
state: Maryland
Study officials:
affiliation: University of Maryland School of Pharmacy
name: James E Polli, Ph.D
role: PRINCIPAL_INVESTIGATOR
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