BEEP2b: Characterization of Epilepsy Patients BEEP 2b
Sponsor
Food and Drug Administration (FDA) (U.S. Fed)
Overall Status
Completed
CT.gov ID
NCT02707965
Collaborator
University of Maryland, Baltimore (Other)
21
1
2
14.9
1.4
Study Details
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
21 participants
Allocation:
Randomized
Intervention Model:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Characterization of Epilepsy Patients At-risk for Adverse Outcomes Related to Switching Antiepileptic Drug Products: BEEP 2b Study
Actual Study Start Date
:
Jun 8, 2017
Actual Primary Completion Date
:
Aug 30, 2018
Actual Study Completion Date
:
Sep 4, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Sequence 1 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)
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: 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: 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: 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: 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: 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: 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: 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.
|
| Active Comparator: Sequence 2 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)
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: 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: 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: 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: 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: 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: 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: 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.
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 76 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Maryland, Baltimore | Baltimore | Maryland | United States | 21201 |
Sponsors and Collaborators
- Food and Drug Administration (FDA)
- University of Maryland, Baltimore
Investigators
- Principal Investigator: James E Polli, Ph.D, University of Maryland School of Pharmacy
Study Documents (Full-Text)
More Information
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.
- 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. Review.
- 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.
- Elger C, Bialer M, Falcão 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.
- 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.
- 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.
- 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.
- 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.
- Rouits E, Burton I, Guénolé 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.
- Shaw SJ, Hartman AL. The Controversy over Generic Antiepileptic Drugs. J Pediatr Pharmacol Ther. 2010 Apr;15(2):81-93.
- 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.
- 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.
- 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.
Responsible Party:
Food and Drug Administration (FDA)
ClinicalTrials.gov Identifier:
NCT02707965
Other Study ID Numbers:
- 15-107D
- HHSF223201400188C
First Posted:
Mar 14, 2016
Last Update Posted:
Mar 27, 2020
Last Verified:
Mar 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by Food and Drug Administration (FDA)
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Sequence 1/Topiramate | Sequence 2/Topiramate | Sequence 1/Lamotrigine | Sequence 2/Lamotrigine | Sequence 1/Levetiracetam IR | Sequence 2/Levetiracetam IR | Sequence 1/Carbamazepine ER Tablet | Sequence 2/Carbamazepine ER Tablet | Sequence 1/Carbamazepine ER Capsule | Sequence 2/Carbamazepine ER Capsule | Sequence 1/Zonisamide | Sequence 2/Zonisamide | Sequence 1/Levetiracetam ER | Sequence 2/Levetiracetam ER | Sequence 1/Valproic Acid | Sequence 2/Valproic Acid |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Subjects received Topiramate in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Topiramate in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Lamotrigine in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Lamotrigine in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Levetiracetam IR in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Levetiracetam IR in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Carbamazepine ER tablet in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Carbamazepine ER tablet in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Carbamazepine ER capsule in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Carbamazepine ER capsule in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Zonisamide in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Zonisamide in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Levetiracetam in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Levetiracetam ER in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic | Subjects received Valproic acid in the sequence order 1 (TRRT). Test-Reference-Reference-Test Reference: Brand Test: Generic | Subjects received Valproic acid in the sequence order 2 (RTTR). Reference-Test-Test-Reference Reference: Brand Test: Generic |
| Period Title: Overall Study | ||||||||||||||||
| STARTED | 3 | 2 | 4 | 0 | 2 | 1 | 0 | 3 | 1 | 0 | 1 | 0 | 0 | 2 | 2 | 0 |
| COMPLETED | 2 | 1 | 3 | 0 | 2 | 1 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 2 | 0 | 0 |
| NOT COMPLETED | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
Baseline Characteristics
| Arm/Group Title | Topiramate Tablet Group | Lamotrigine IR Tablet Group | Lamotrigine ER Tablet Group | Levetiracetam IR Tablet Group | Levetiracetam ER Tablet Group | Carbamazepine ER Capsule | Carbamazepine ER Tablet | Zonisamide Capsule Group | Valproic Acid ER Tablet Group | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | All subjects who received the Topiramate Tablet. | All subjects who received the Lamotrigine IR Tablet. | All subjects who received the Lamotrigine ER Tablet. | All subjects who received the Levetiracetam IR Tablet. | All subjects who received the Levetiracetam ER Tablet. | All subjects who received the Carbamazepine ER Capsule. | All subjects who received the Carbamazepine ER Tablet. | All subjects who received the Zonisamide Capsule. | All subjects who received the Valproic Acid ER Tablet. | Total of all reporting groups |
| Overall Participants | 5 | 1 | 3 | 3 | 2 | 2 | 1 | 1 | 2 | 20 |
| Age (Count of Participants) | ||||||||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
5
100%
|
1
100%
|
3
100%
|
3
100%
|
2
100%
|
2
100%
|
1
100%
|
1
100%
|
2
100%
|
20
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Sex: Female, Male (Count of Participants) | ||||||||||
| Female |
5
100%
|
1
100%
|
1
33.3%
|
3
100%
|
2
100%
|
2
100%
|
1
100%
|
1
100%
|
2
100%
|
18
90%
|
| Male |
0
0%
|
0
0%
|
2
66.7%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
10%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||||||||
| Hispanic or Latino |
0
0%
|
0
0%
|
0
0%
|
1
33.3%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
5%
|
| Not Hispanic or Latino |
5
100%
|
1
100%
|
3
100%
|
2
66.7%
|
2
100%
|
2
100%
|
1
100%
|
1
100%
|
2
100%
|
19
95%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
3
60%
|
0
0%
|
0
0%
|
2
66.7%
|
2
100%
|
1
50%
|
1
100%
|
1
100%
|
1
50%
|
11
55%
|
| White |
2
40%
|
1
100%
|
3
100%
|
1
33.3%
|
0
0%
|
1
50%
|
0
0%
|
0
0%
|
1
50%
|
9
45%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Topiramate Tablet | Lamotrigine ER Tablet | Levetiracetam IR Tablet | Levetiracetam ER Tablet | Carbamazepine ER Capsule | Carbamazepine ER Tablet | Zonisamide Capsule |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Subjects who received Topiramate for Sequence 1 and 2. | Subjects who received Lamotrigine ER for Sequence 1 and 2. | Subjects who received Levetiracetam IR for Sequence 1 and 2. | Subjects who received Levetiracetam ER for Sequence 1 and 2. | Subjects who received Carbamazepine ER Capsule for Sequence 1 and 2. | Subjects who received Carbamazepine ER Tablet for Sequence 1 and 2. | Subjects who received Zonisamide for Sequence 1 and 2. |
| Measure Participants | 5 | 3 | 3 | 2 | 1 | 1 | 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)
|
| Title | Mean Cmax_ss (Test vs. Reference) |
|---|---|
| Description | Average maximum drug plasma concentration; |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Topiramate Tablet | Lamotrigine ER Tablet | Levetiracetam IR Tablet | Levetiracetam ER Tablet | Carbamazepine ER Capsule | Carbamazepine ER Tablet | Zonisamide Capsule |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Subjects who received Topiramate for Sequence 1 and 2. | Subjects who received Lamotrigine ER for Sequence 1 and 2. | Subjects who received Levetiracetam IR for Sequence 1 and 2. | Subjects who received Levetiracetam ER for Sequence 1 and 2. | Subjects who received Carbamazepine ER Capsule for Sequence 1 and 2. | Subjects who received Carbamazepine ER Tablet for Sequence 1 and 2. | Subjects who received Zonisamide for Sequence 1 and 2. |
| Measure Participants | 5 | 3 | 3 | 2 | 1 | 1 | 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)
|
| Title | Mean Cmin_ss (Test vs. Reference) |
|---|---|
| Description | Average minimum drug plasma concentration (Cmin); |
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Topiramate Tablet | Lamotrigine ER Tablet | Levetiracetam IR Tablet | Levetiracetam ER Tablet | Carbamazepine ER Capsule | Carbamazepine ER Tablet | Zonisamide Capsule |
|---|---|---|---|---|---|---|---|
| Arm/Group Description | Subjects who received Topiramate for Sequence 1 and 2. | Subjects who received Lamotrigine ER for Sequence 1 and 2. | Subjects who received Levetiracetam IR for Sequence 1 and 2. | Subjects who received Levetiracetam ER for Sequence 1 and 2. | Subjects who received Carbamazepine ER Capsule for Sequence 1 and 2. | Subjects who received Carbamazepine ER Tablet for Sequence 1 and 2. | Subjects who received Zonisamide for Sequence 1 and 2. |
| Measure Participants | 5 | 3 | 3 | 2 | 1 | 1 | 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)
|
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Topiramate | Lamotrigine ER | Levetiracetam IR | Levetiracetam ER | Carbamazepine ER Capsule | Zonisamide | Carbamazepine ER Tablet | Valproic Acid |
|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | Subjects who received Topiramate for Sequence 1 and 2. | Subjects who received Lamotrigine ER for Sequence 1 and 2. | Subjects who received Levetiracetam IR for Sequence 1 and 2. | Subjects who received Levetiracetam ER for Sequence 1 and 2. | Subjects who received Carbamazepine ER Capsule for Sequence 1 and 2. | Subjects who received Zonisamide for Sequence 1 and 2. | Subjects who received Carbamazepine ER Tablet for Sequence 1 and 2. | Subjects who received Valproic acid for Sequence 1 and 2. |
| Measure Participants | 5 | 4 | 3 | 2 | 3 | 1 | 1 | 2 |
| Number [events] |
29
|
9
|
17
|
4
|
15
|
6
|
10
|
10
|
| 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Topiramate Tablet Group | Lamotrigine IR Tablet Group | Lamotrigine ER Tablet Group | Levetiracetam IR Tablet Group | Levetiracetam ER Tablet Group | Carbamazepine ER Capsule | Carbamazepine ER Tablet | Zonisamide Capsule Group | Valproic Acid ER Tablet Group |
|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | All subjects who received the Topiramate Tablet. | All subjects who received the Lamotrigine IR Tablet. | All subjects who received the Lamotrigine ER Tablet. | All subjects who received the Levetiracetam IR Tablet. | All subjects who received the Levetiracetam ER Tablet. | All subjects who received the Carbamazepine ER Capsule. | All subjects who received the Carbamazepine ER Tablet. | All subjects who received the Zonisamide Capsule. | All subjects who received the Valproic Acid ER Tablet. |
| Measure Participants | 5 | 1 | 3 | 3 | 2 | 2 | 1 | 1 | 2 |
| Reference Product |
9
|
0
|
44
|
16
|
42
|
3
|
0
|
0
|
12
|
| Test (Generic) |
5
|
0
|
25
|
5
|
72
|
1
|
0
|
0
|
0
|
Adverse Events
| Time Frame | Approximately 16 weeks per subject | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||||||
| Arm/Group Title | Topiramate | Lamotrigine ER | Levetiracetam IR | Levetiracetam ER | Carbamazepine ER Capsule | Zonisamide | Carbamazepine ER Tablet | Valproic Acid | ||||||||
| Arm/Group Description | Subjects who received Topiramate for Sequence 1 and 2. | Subjects who received Lamotrigine ER for Sequence 1 and 2. | Subjects who received Levetiracetam IR for Sequence 1 and 2. | Subjects who received Levetiracetam ER for Sequence 1 and 2. | Subjects who received Carbamazepine ER Capsule for Sequence 1 and 2. | Subjects who received Zonisamide for Sequence 1 and 2. | Subjects who received Carbamazepine ER Tablet for Sequence 1 and 2. | Subjects who received Valproic acid for Sequence 1 and 2. | ||||||||
All Cause Mortality |
||||||||||||||||
| Topiramate | Lamotrigine ER | Levetiracetam IR | Levetiracetam ER | Carbamazepine ER Capsule | Zonisamide | Carbamazepine ER Tablet | Valproic Acid | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/5 (0%) | 0/4 (0%) | 0/3 (0%) | 0/2 (0%) | 0/1 (0%) | 0/1 (0%) | 0/3 (0%) | 0/2 (0%) | ||||||||
Serious Adverse Events |
||||||||||||||||
| Topiramate | Lamotrigine ER | Levetiracetam IR | Levetiracetam ER | Carbamazepine ER Capsule | Zonisamide | Carbamazepine ER Tablet | Valproic Acid | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/5 (0%) | 0/3 (0%) | 0/3 (0%) | 0/2 (0%) | 0/1 (0%) | 0/1 (0%) | 0/1 (0%) | 0/2 (0%) | ||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||
| Topiramate | Lamotrigine ER | Levetiracetam IR | Levetiracetam ER | Carbamazepine ER Capsule | Zonisamide | Carbamazepine ER Tablet | Valproic Acid | |||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | 4/4 (100%) | 2/3 (66.7%) | 2/2 (100%) | 2/3 (66.7%) | 1/1 (100%) | 1/1 (100%) | 1/2 (50%) | ||||||||
| Gastrointestinal disorders | ||||||||||||||||
| Nausea | 1/5 (20%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 1/3 (33.3%) | 1 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Dyspepsia | 1/5 (20%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| General disorders | ||||||||||||||||
| Fatigue | 2/5 (40%) | 3 | 1/4 (25%) | 2 | 1/3 (33.3%) | 4 | 1/2 (50%) | 1 | 1/3 (33.3%) | 2 | 0/1 (0%) | 0 | 1/1 (100%) | 3 | 0/2 (0%) | 0 |
| Injury, poisoning and procedural complications | ||||||||||||||||
| Fall | 1/5 (20%) | 1 | 1/4 (25%) | 1 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||||||||||||
| Shoulder/arm pain | 0/5 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 1/3 (33.3%) | 1 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 1/2 (50%) | 1 |
| Nervous system disorders | ||||||||||||||||
| Worsening of aphrasia | 1/5 (20%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Somnolence | 1/5 (20%) | 3 | 1/4 (25%) | 1 | 1/3 (33.3%) | 4 | 1/2 (50%) | 2 | 1/3 (33.3%) | 1 | 0/1 (0%) | 0 | 1/1 (100%) | 3 | 0/2 (0%) | 0 |
| Headache | 3/5 (60%) | 4 | 2/4 (50%) | 2 | 1/3 (33.3%) | 2 | 1/2 (50%) | 1 | 1/3 (33.3%) | 2 | 1/1 (100%) | 1 | 1/1 (100%) | 2 | 1/2 (50%) | 1 |
| Dizziness | 2/5 (40%) | 2 | 0/4 (0%) | 0 | 1/3 (33.3%) | 2 | 0/2 (0%) | 0 | 1/3 (33.3%) | 2 | 0/1 (0%) | 0 | 1/1 (100%) | 1 | 0/2 (0%) | 0 |
| Tremor | 0/5 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 1/3 (33.3%) | 1 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 1/2 (50%) | 3 |
| Psychiatric disorders | ||||||||||||||||
| Insomnia | 1/5 (20%) | 1 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 1/1 (100%) | 1 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Psychosis | 0/5 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 1/3 (33.3%) | 2 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Irritability | 1/5 (20%) | 1 | 0/4 (0%) | 0 | 1/3 (33.3%) | 1 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Mood swing | 1/5 (20%) | 2 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 0/3 (0%) | 0 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 0/2 (0%) | 0 |
| Anxiety | 0/5 (0%) | 0 | 0/4 (0%) | 0 | 0/3 (0%) | 0 | 0/2 (0%) | 0 | 1/3 (33.3%) | 1 | 0/1 (0%) | 0 | 0/1 (0%) | 0 | 1/2 (50%) | 1 |
Limitations/Caveats
The research was exploratory. The study was not a bioequivalence study.
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. James Polli |
|---|---|
| Organization | University of Maryland, School of Pharmacy |
| Phone | 410-706-8292 |
| jpolli@rx.umaryland.edu |
Responsible Party:
Food and Drug Administration (FDA)
ClinicalTrials.gov Identifier:
NCT02707965
Other Study ID Numbers:
- 15-107D
- HHSF223201400188C
First Posted:
Mar 14, 2016
Last Update Posted:
Mar 27, 2020
Last Verified:
Mar 1, 2020