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Characterization of Epilepsy Patients BEEP 2b (BEEP2b)

Primary Purpose

Epilepsy

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Oxcarbazepine (brand name vs generic drugs)

Divalproex Sodium (brand name vs generic drugs)

Carbamazepine (brand name vs generic drugs)

Lamotrigine (brand name vs generic drugs)

levetiracetam (brand name vs generic drugs)

Topiramate (brand name vs generic drugs)

Zonisamide (brand name vs generic drugs)

Phenytoin sodium (brand name vs generic drugs)

About this trial

This is an interventional treatment trial for Epilepsy focused on measuring Generic brittle, Anti-epileptic drug, Bioequivalence

Eligibility Criteria

18 Years - 76 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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).

Sites / Locations

University of Maryland, Baltimore

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Sequence 1

Sequence 2

Arm Description

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.

Outcomes

Primary Outcome Measures

Mean AUC0-last_ss (Test vs. Reference)

Average AUC (area under the drug plasma curve.

Mean Cmax_ss (Test vs. Reference)

Average maximum drug plasma concentration;

Mean Cmin_ss (Test vs. Reference)

Average minimum drug plasma concentration (Cmin);

Secondary Outcome Measures

Number of Adverse Events

summed for each anti-epileptic drug from when taking brand and generic.

Number of Seizures Reported

Number of seizures reported in all groups

Full Information

NCT ID

NCT02707965

First Posted

February 26, 2016

Last Updated

March 12, 2020

Sponsor

Food and Drug Administration (FDA)

Collaborators

University of Maryland, Baltimore

1. Study Identification

Unique Protocol Identification Number

NCT02707965

Brief Title

Characterization of Epilepsy Patients BEEP 2b

Acronym

BEEP2b

Official Title

Characterization of Epilepsy Patients At-risk for Adverse Outcomes Related to Switching Antiepileptic Drug Products: BEEP 2b Study

Study Type

Interventional

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Completed

Study Start Date

June 8, 2017 (Actual)

Primary Completion Date

August 30, 2018 (Actual)

Study Completion Date

September 4, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Food and Drug Administration (FDA)

Collaborators

University of Maryland, Baltimore

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Epilepsy

Keywords

Generic brittle, Anti-epileptic drug, Bioequivalence

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Sequence 1

Arm Type

Active Comparator

Arm Description

Arm Title

Sequence 2

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Oxcarbazepine (brand name vs generic drugs)

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Divalproex Sodium (brand name vs generic drugs)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Carbamazepine (brand name vs generic drugs)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Lamotrigine (brand name vs generic drugs)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

levetiracetam (brand name vs generic drugs)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Topiramate (brand name vs generic drugs)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Zonisamide (brand name vs generic drugs)

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Phenytoin sodium (brand name vs generic drugs)

Intervention Description

Primary Outcome Measure Information:

Title

Mean AUC0-last_ss (Test vs. Reference)

Description

Average AUC (area under the drug plasma curve.

Time Frame

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.

Title

Mean Cmax_ss (Test vs. Reference)

Description

Average maximum drug plasma concentration;

Time Frame

Title

Mean Cmin_ss (Test vs. Reference)

Description

Average minimum drug plasma concentration (Cmin);

Time Frame

Secondary Outcome Measure Information:

Title

Number of Adverse Events

Description

summed for each anti-epileptic drug from when taking brand and generic.

Time Frame

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

Title

Number of Seizures Reported

Description

Number of seizures reported in all groups

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

76 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

James E Polli, Ph.D

Organizational Affiliation

University of Maryland School of Pharmacy

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Maryland, Baltimore

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing Plan Description

There is no plan to make individual participant data available.

Citations:

PubMed Identifier

17346246

Citation

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.

Results Reference

background

PubMed Identifier

18616554

Citation

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.

Results Reference

background

PubMed Identifier

19558250

Citation

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.

Results Reference

background

PubMed Identifier

21521860

Citation

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.

Results Reference

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PubMed Identifier

20384761

Citation

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.

Results Reference

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PubMed Identifier

17438213

Citation

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.

Results Reference

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PubMed Identifier

22477799

Citation

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

Results Reference

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PubMed Identifier

18768168

Citation

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.

Results Reference

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PubMed Identifier

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Citation

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.

Results Reference

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PubMed Identifier

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Citation

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+.

Results Reference

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PubMed Identifier

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Citation

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.

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PubMed Identifier

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Citation

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.

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Citation

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.

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Characterization of Epilepsy Patients BEEP 2b

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