EpilepsyPhase 1BEEP2bNCT02707965

Characterization of Epilepsy Patients BEEP 2b

A Phase 1 study testing Oxcarbazepine (brand name vs generic drugs), Divalproex Sodium (brand name vs generic drugs) and Carbamazepine (brand name vs generic drugs) in people with Epilepsy, run by Food and Drug Administration (FDA) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 76 years
Conditions the study is for: Epilepsy
What is being tested?: Oxcarbazepine (brand name vs generic drugs), Divalproex Sodium (brand name vs generic drugs) and Carbamazepine (brand name vs generic drugs)
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 21 participants
Where: 1 siteUnited States
Study dates: 8 Jun 2017to 4 Sep 2018
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 76 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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.

Who cannot join

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).

Trial locations and contacts

1 site in 1 country.

United States1 site

University of Maryland, Baltimore
Baltimore, Maryland, 21201

Other trials in United States

About this study

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

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.

Read the 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.

Conditions: Epilepsy
Being tested: 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)
Keywords: Generic brittle, Anti-epileptic drug, Bioequivalence
Medical subject headings: Epilepsy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

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.

Study groups in NCT02707965
Study group	Role	What they receive
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. Receives: 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. Receives: 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)

What is being measured

The primary outcome is the main question the study is designed to answer.

Mean AUC0-last_ss (Test vs. Reference)
Average AUC (area under the drug plasma curve.
Measured: 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;
Measured: 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);
Measured: 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
summed for each anti-epileptic drug from when taking brand and generic.
Measured: Through the approximately 2 week period when the treatment is given.
Number of Seizures Reported
Number of seizures reported in all groups
Measured: Through the approximately 2 week period when the treatment is given.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

8 Jun 20174 Sep 2018

First posted14 Mar 2016 (estimated)
Study start8 Jun 2017
Primary completion30 Aug 2018
Study completion4 Sep 2018

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (13)Papers the sponsor has linked to this study.
Other trials for EpilepsyStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 21 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02707965
Sponsor's protocol ID: 15-107D
Other IDs: HHSF223201400188C
Acronym: BEEP2b
Status last verified: Mar 2020
First submitted: 26 Feb 2016
Last updated: 27 Mar 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No: There is no plan to make individual participant data available.

Publications

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.
PubMed 17346246
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.
PubMed 18616554
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.
PubMed 19558250
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.
PubMed 21521860
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.
PubMed 20384761
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.
PubMed 17438213
Shaw SJ, Hartman AL. The Controversy over Generic Antiepileptic Drugs. J Pediatr Pharmacol Ther. 2010 Apr;15(2):81-93.
PubMed 22477799
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.
PubMed 18768168
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.
PubMed 26201987
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+.
PubMed 10189261
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.
PubMed 19264451
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.
PubMed 23758485
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.
PubMed 22162508

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 27 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Characterization of Epilepsy Patients At-risk for Adverse Outcomes Related to Switching Antiepileptic Drug Products: BEEP 2b Study
ClinicalTrials.gov ID: NCT02707965
Acronym / sponsor ID: BEEP2b / 15-107D
Conditions: Epilepsy
Keywords: Generic brittle, Anti-epileptic drug, Bioequivalence
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 21 participants (actual)
Lead sponsor: Food and Drug Administration (FDA)US federal agency
Collaborators: University of Maryland, Baltimore
Study start: 8 Jun 2017 (actual)
Primary completion: 30 Aug 2018 (actual)
Study completion: 4 Sep 2018 (actual)
First posted: 14 Mar 2016 (estimated)
Results: Posted 27 Mar 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Sequence 1	Active comparator	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)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.
Sequence 2	Active comparator	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)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.

Who may qualify

Ages: 18 to 76 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (8 listed)

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.

Key exclusion criteria (8 listed)

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).

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Oxcarbazepine (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
Divalproex Sodium (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
Carbamazepine (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
Lamotrigine (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
levetiracetam (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
Topiramate (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
Zonisamide (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2
Phenytoin sodium (brand name vs generic drugs)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.	Drug	Sequence 1, Sequence 2

Primary outcome

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

2 secondary outcomes

Number of Adverse Events
Time frame: Through the approximately 2 week period when the treatment is given.
Number of Seizures Reported
Time frame: Through the approximately 2 week period when the treatment is given.

Results and safety

Results posted to the registry on 27 Mar 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Sequence 1/Topiramate	3	2
Sequence 2/Topiramate	2	1
Sequence 1/Lamotrigine	4	3
Sequence 2/Lamotrigine	0	0
Sequence 1/Levetiracetam IR	2	2
Sequence 2/Levetiracetam IR	1	1
Sequence 1/Carbamazepine ER Tablet	0	0
Sequence 2/Carbamazepine ER Tablet	3	0
Sequence 1/Carbamazepine ER Capsule	1	1
Sequence 2/Carbamazepine ER Capsule	0	0
Sequence 1/Zonisamide	1	1
Sequence 2/Zonisamide	0	0
Sequence 1/Levetiracetam ER	0	0
Sequence 2/Levetiracetam ER	2	2
Sequence 1/Valproic Acid	2	0
Sequence 2/Valproic Acid	0	0

Primary outcome: Mean AUC0-last_ss (Test vs. Reference)

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.. Mean (Standard Deviation). Unit: micro/mL/hr

Measure	Topiramate Tablet n = 5	Lamotrigine ER Tablet n = 3	Levetiracetam IR Tablet n = 3	Levetiracetam ER Tablet n = 2	Carbamazepine ER Capsule n = 1	Carbamazepine ER Tablet n = 1	Zonisamide Capsule n = 1
Test Product	92.884 (45.04955804)	62.76666667 (26.51919556)	419.97 (116.7864209)	260.3 (169.1399421)	114.96 (0)	104.6 (0)	233.16 (0)
Reference Product	94.456 (46.91455403)	67.19333333 (28.83182501)	445.2 (125.97458)	262.305 (176.4584972)	106.45 (0)	115.16 (0)	226.14 (0)

Primary outcome: Mean Cmax_ss (Test vs. Reference)

Measure	Topiramate Tablet n = 5	Lamotrigine ER Tablet n = 3	Levetiracetam IR Tablet n = 3	Levetiracetam ER Tablet n = 2	Carbamazepine ER Capsule n = 1	Carbamazepine ER Tablet n = 1	Zonisamide Capsule n = 1
Test Product	9.874 (4.889389532)	6.24 (2.327853088)	71.02333333 (16.29206658)	31.05 (16.64529363)	10.95 (0)	10.00 (0)	12.29 (0)
Reference Product	9.646 (4.834328288)	6.903333333 (2.460819647)	69.29333333 (15.89970545)	28.04 (17.2675476)	9.91 (0)	10.6 (0)	11.68 (0)

Primary outcome: Mean Cmin_ss (Test vs. Reference)

Measure	Topiramate Tablet n = 5	Lamotrigine ER Tablet n = 3	Levetiracetam IR Tablet n = 3	Levetiracetam ER Tablet n = 2	Carbamazepine ER Capsule n = 1	Carbamazepine ER Tablet n = 1	Zonisamide Capsule n = 1
Test Product	6.326 (2.990924606)	4.053333333 (1.569214241)	15.45333333 (4.702981324)	12.605 (12.21173411)	8.56 (0)	7.37 (0)	8.46 (0)
Reference Product	6.53 (3.261203765)	4.21 (2.343736333)	17.45666667 (6.150612436)	14.395 (12.40972401)	7.66 (0)	7.97 (0)	8.34 (0)

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: Approximately 16 weeks per subject. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Topiramate	0 of 5 (0%)	5 of 5 (100%)	0 of 5
Lamotrigine ER	0 of 3 (0%)	4 of 4 (100%)	0 of 4
Levetiracetam IR	0 of 3 (0%)	2 of 3 (66.7%)	0 of 3
Levetiracetam ER	0 of 2 (0%)	2 of 2 (100%)	0 of 2
Carbamazepine ER Capsule	0 of 1 (0%)	2 of 3 (66.7%)	0 of 1
Zonisamide	0 of 1 (0%)	1 of 1 (100%)	0 of 1
Carbamazepine ER Tablet	0 of 1 (0%)	1 of 1 (100%)	0 of 3
Valproic Acid	0 of 2 (0%)	1 of 2 (50%)	0 of 2

Limitations and caveats (from the sponsor): The research was exploratory. The study was not a bioequivalence study.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 17346246Andermann 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.
Background: PubMed 18616554Zachry 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.
Background: PubMed 19558250Rascati 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.
Background: PubMed 21521860Fitzgerald 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.
Background: PubMed 20384761Bialer 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.
Background: PubMed 17438213Liow 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.
Background: PubMed 22477799Shaw SJ, Hartman AL. The Controversy over Generic Antiepileptic Drugs. J Pediatr Pharmacol Ther. 2010 Apr;15(2):81-93.
Background: PubMed 18768168McAuley 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.
Background: PubMed 26201987Ting 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.
Background: PubMed 10189261Stevens 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+.
Background: PubMed 19264451Rouits 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.
Background: PubMed 23758485Elger 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.
Individual participant dataSharing planned: No. There is no plan to make individual participant data available.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

James E Polli, Ph.D principal investigator

University of Maryland School of Pharmacy

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 27 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean AUC0-last_ss (Test vs. Reference) (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.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02707965, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2020.