Characterization of Epilepsy Patients BEEP 2b

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.

• Oxcarbazepine (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Divalproex Sodium (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Carbamazepine (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Lamotrigine (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• levetiracetam (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Topiramate (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Zonisamide (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.
• Phenytoin sodium (brand name vs generic drugs) (Drug): This is a cross-over replicate study with 2 sequences (arms) comparing brand name and generic anti-epileptic drugs. Subjects will take a brand name and a generic drug of the same intervention. While there are only 2 sequences, there are 8 possible drugs for this study, and a study patient will only take 1 out of 8 study drugs. Only pharmacists will know which sequence each patient is assigned to.

Primary outcomes

• Mean AUC0-last_ss (Test vs. Reference) [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.]: Average AUC (area under the drug plasma curve.
• Mean Cmax_ss (Test vs. Reference) [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.]: Average maximum drug plasma concentration;
• Mean Cmin_ss (Test vs. Reference) [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.]: Average minimum drug plasma concentration (Cmin);

Secondary outcomes

• Number of Adverse Events [Through the approximately 2 week period when the treatment is given.]: summed for each anti-epileptic drug from when taking brand and generic.
• Number of Seizures Reported [Through the approximately 2 week period when the treatment is given.]: Number of seizures reported in all groups

Sex: All, ages: 18 Years to 76 Years

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).

Participant flow

Outcome results

• Mean AUC0-last_ss (Test vs. Reference) (Primary), Mean, micro/mL/hr: Topiramate Tablet 92.884 +/- 45.04955804; Lamotrigine ER Tablet 62.76666667 +/- 26.51919556; Levetiracetam IR Tablet 419.97 +/- 116.7864209; Levetiracetam ER Tablet 260.3 +/- 169.1399421; Carbamazepine ER Capsule 114.96 +/- 0; Carbamazepine ER Tablet 104.6 +/- 0; Zonisamide Capsule 233.16 +/- 0
• Mean Cmax_ss (Test vs. Reference) (Primary), Mean, microg/mL: Topiramate Tablet 9.874 +/- 4.889389532; Lamotrigine ER Tablet 6.24 +/- 2.327853088; Levetiracetam IR Tablet 71.02333333 +/- 16.29206658; Levetiracetam ER Tablet 31.05 +/- 16.64529363; Carbamazepine ER Capsule 10.95 +/- 0; Carbamazepine ER Tablet 10.00 +/- 0; Zonisamide Capsule 12.29 +/- 0
• Mean Cmin_ss (Test vs. Reference) (Primary), Mean, microg/mL: Topiramate Tablet 6.326 +/- 2.990924606; Lamotrigine ER Tablet 4.053333333 +/- 1.569214241; Levetiracetam IR Tablet 15.45333333 +/- 4.702981324; Levetiracetam ER Tablet 12.605 +/- 12.21173411; Carbamazepine ER Capsule 8.56 +/- 0; Carbamazepine ER Tablet 7.37 +/- 0; Zonisamide Capsule 8.46 +/- 0
• Number of Adverse Events (Secondary), Number, events: Topiramate 29; Lamotrigine ER 9; Levetiracetam IR 17; Levetiracetam ER 4; Carbamazepine ER Capsule 15; Zonisamide 6; Carbamazepine ER Tablet 10; Valproic Acid 10
• Number of Seizures Reported (Secondary), Number, Number of Seizures: Topiramate Tablet Group 9; Lamotrigine IR Tablet Group 0; Lamotrigine ER Tablet Group 44; Levetiracetam IR Tablet Group 16; Levetiracetam ER Tablet Group 42; Carbamazepine ER Capsule 3; Carbamazepine ER Tablet 0; Zonisamide Capsule Group 0; Valproic Acid ER Tablet Group 12

Adverse events

Time frame: Approximately 16 weeks per subject

Other adverse events by term

Limitations and caveats: The research was exploratory. The study was not a bioequivalence study.

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• Study Protocol and Statistical Analysis Plan (PDF, 2018-03-13)

• James E Polli, Ph.D, Principal investigator, University of Maryland School of Pharmacy