Characterization of Epilepsy Patients BEEP 2b

NCT02707965 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 15-107DHHSF223201400188C
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Epilepsy

Keywords

Generic brittle; Anti-epileptic drug; Bioequivalence

Outcome Measures

Primary Outcomes (3)

• Mean AUC0-last_ss (Test vs. Reference)

  Average AUC (area under the drug plasma curve.

  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.

• Mean Cmax_ss (Test vs. Reference)

  Average maximum drug plasma concentration;

  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.

• Mean Cmin_ss (Test vs. Reference)

  Average minimum drug plasma concentration (Cmin);

  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 (2)

• Number of Adverse Events

  Through the approximately 2 week period when the treatment is given.

• Number of Seizures Reported

  Through the approximately 2 week period when the treatment is given.

Study Arms (2)

Sequence 1

ACTIVE COMPARATOR

This is a crossover study with 4 treatment periods consisting of 2 Test periods(generic drug) and 2 Reference periods (brand name drug). Each treatment period lasts about 2 weeks, and patients will be randomized into one of the two sequences. All drugs are administered orally, and dosage will depend on a patient.

Drug: Oxcarbazepine (brand name vs generic drugs); Drug: Divalproex Sodium (brand name vs generic drugs); Drug: Carbamazepine (brand name vs generic drugs); Drug: Lamotrigine (brand name vs generic drugs); Drug: levetiracetam (brand name vs generic drugs); Drug: Topiramate (brand name vs generic drugs); Drug: Zonisamide (brand name vs generic drugs); Drug: Phenytoin sodium (brand name vs generic drugs)

Sequence 2

ACTIVE COMPARATOR

This is a crossover study with 4 treatment periods consisting of 2 Test periods(generic drug) and 2 Reference periods (brand name drug). Each treatment period lasts about 2 weeks, and patients will be randomized into one of the two sequences. All drugs are administered orally, and dosage will depend on a patient.

Drug: Oxcarbazepine (brand name vs generic drugs); Drug: Divalproex Sodium (brand name vs generic drugs); Drug: Carbamazepine (brand name vs generic drugs); Drug: Lamotrigine (brand name vs generic drugs); Drug: levetiracetam (brand name vs generic drugs); Drug: Topiramate (brand name vs generic drugs); Drug: Zonisamide (brand name vs generic drugs); Drug: Phenytoin sodium (brand name vs generic drugs)

Interventions

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

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.

Sequence 1; Sequence 2

Eligibility Criteria

• Age: 18 Years - 76 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Subject is male or female between 18 and 76 years of age inclusive.
• Subject has a diagnosis of epilepsy including focal or primary generalized epilepsy.
• Subject is taking at least one study antiepileptic drug for the treatment of epilepsy.
• Subject is an acceptable candidate for venipuncture.
• Subject is willing to be switched between brand and generic drug.
• Subject is willing to stop all non-routine OTC medications for 24 hours prior to and during pharmacokinetic study visits.
• Subject is willing to maintain stable doses of all other AEDs, including Vagus Nerve Stimulation parameters for the duration of the study.

You may not qualify if:

• 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.
• 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.
• Subject has a history of previous or current significant psychiatric disorder that would interfere with conduct of the study.
• Subject is pregnant or lactating.
• 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).
• Subject has severe renal impairment as assessed by creatinine clearance lower than 30mL/min, using the Cockcroft-Gault formula.
• 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.
• Subject is not willing or able to be adherent to study protocol (e.g. study medication dosing and any interacting comedication).

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• University of Maryland, Baltimore: collaborator

Study Sites (1)

University of Maryland, Baltimore

Baltimore, Maryland, 21201, United States

Location

Related Publications (13)

• Andermann F, Duh MS, Gosselin A, Paradis PE. Compulsory generic switching of antiepileptic drugs: high switchback rates to branded compounds compared with other drug classes. Epilepsia. 2007 Mar;48(3):464-9. doi: 10.1111/j.1528-1167.2007.01007.x.

  PMID: 17346246 BACKGROUND

• Zachry WM 3rd, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia. 2009 Mar;50(3):493-500. doi: 10.1111/j.1528-1167.2008.01703.x. Epub 2008 Jun 26.

  PMID: 18616554 BACKGROUND

• Rascati KL, Richards KM, Johnsrud MT, Mann TA. Effects of antiepileptic drug substitutions on epileptic events requiring acute care. Pharmacotherapy. 2009 Jul;29(7):769-74. doi: 10.1592/phco.29.7.769.

  PMID: 19558250 BACKGROUND

• Fitzgerald CL, Jacobson MP. Generic substitution of levetiracetam resulting in increased incidence of breakthrough seizures. Ann Pharmacother. 2011 May;45(5):e27. doi: 10.1345/aph.1P765. Epub 2011 Apr 26.

  PMID: 21521860 BACKGROUND

• Bialer M, Midha KK. Generic products of antiepileptic drugs: a perspective on bioequivalence and interchangeability. Epilepsia. 2010 Jun;51(6):941-50. doi: 10.1111/j.1528-1167.2010.02573.x. Epub 2010 Apr 8.

  PMID: 20384761 BACKGROUND

• Liow K, Barkley GL, Pollard JR, Harden CL, Bazil CW; American Academy of Neurology. Position statement on the coverage of anticonvulsant drugs for the treatment of epilepsy. Neurology. 2007 Apr 17;68(16):1249-50. doi: 10.1212/01.wnl.0000259400.30539.cc. No abstract available.

  PMID: 17438213 BACKGROUND

• Shaw SJ, Hartman AL. The Controversy over Generic Antiepileptic Drugs. J Pediatr Pharmacol Ther. 2010 Apr;15(2):81-93.

  PMID: 22477799 BACKGROUND

• McAuley JW, Chen AY, Elliott JO, Shneker BF. An assessment of patient and pharmacist knowledge of and attitudes toward reporting adverse drug events due to formulation switching in patients with epilepsy. Epilepsy Behav. 2009 Jan;14(1):113-7. doi: 10.1016/j.yebeh.2008.08.009. Epub 2008 Sep 26.

  PMID: 18768168 BACKGROUND

• Ting TY, Jiang W, Lionberger R, Wong J, Jones JW, Kane MA, Krumholz A, Temple R, Polli JE. Generic lamotrigine versus brand-name Lamictal bioequivalence in patients with epilepsy: A field test of the FDA bioequivalence standard. Epilepsia. 2015 Sep;56(9):1415-24. doi: 10.1111/epi.13095. Epub 2015 Jul 23.

  PMID: 26201987 BACKGROUND

• Stevens RE, Limsakun T, Evans G, Mason DH Jr. Controlled, multidose, pharmacokinetic evaluation of two extended-release carbamazepine formulations (Carbatrol and Tegretol-XR). J Pharm Sci. 1998 Dec;87(12):1531-4. doi: 10.1021/js980203+.

  PMID: 10189261 BACKGROUND

• Rouits E, Burton I, Guenole E, Troenaru MM, Stockis A, Sargentini-Maier ML. Pharmacokinetics of levetiracetam XR 500mg tablets. Epilepsy Res. 2009 Apr;84(2-3):224-31. doi: 10.1016/j.eplepsyres.2009.02.001. Epub 2009 Mar 4.

  PMID: 19264451 BACKGROUND

• Elger C, Bialer M, Falcao A, Vaz-da-Silva M, Nunes T, Almeida L, Soares-da-Silva P. Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers. Epilepsia. 2013 Aug;54(8):1453-61. doi: 10.1111/epi.12242. Epub 2013 Jun 12.

  PMID: 23758485 BACKGROUND

• Cawello W, Bonn R. No pharmacokinetic interaction between lacosamide and valproic acid in healthy volunteers. J Clin Pharmacol. 2012 Nov;52(11):1739-48. doi: 10.1177/0091270011426875. Epub 2011 Dec 8.

  PMID: 22162508 BACKGROUND

MeSH Terms

Conditions

Epilepsy

Interventions

Oxcarbazepine; Valproic Acid; Carbamazepine; Lamotrigine; Levetiracetam; Topiramate; Zonisamide; Phenytoin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Triazines; Heterocyclic Compounds, 1-Ring; Acetamides; Amides; Acetates; Pyrrolidinones; Pyrrolidines; Fructose; Hexoses; Monosaccharides; Sugars; Carbohydrates; Ketoses; Sulfonamides; Sulfones; Sulfur Compounds; Isoxazoles; Azoles; Hydantoins; Imidazolidines; Imidazoles

Limitations and Caveats

The research was exploratory. The study was not a bioequivalence study.

Results Point of Contact

• Title: Dr. James Polli
• Organization: University of Maryland, School of Pharmacy

jpolli@rx.umaryland.edu

410-706-8292

Study Officials

• James E Polli, Ph.D

  University of Maryland School of Pharmacy

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2016
• First Posted: March 14, 2016
• Study Start: June 8, 2017
• Primary Completion: August 30, 2018
• Study Completion: September 4, 2018
• Last Updated: March 27, 2020
• Results First Posted: March 27, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)