EpilepsyPhase 4Chronic DoseNCT01713777
Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design
A Phase 4 study testing Lamotrigine Generic "A" and Lamotrigine generic "B" in people with Epilepsy, run by University of Cincinnati at 8 sites in United States.
Trial summary
The United States Food and Drug Administration (FDA) has specific rules generic drug companies must follow to get a generic copy of a seizure medication approved. Currently, the FDA approves generic drugs by requiring studies on normal volunteers who don't have epilepsy and who take just one dose of the generic drug… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Epilepsy
- What is being tested?
- Lamotrigine Generic "A" and Lamotrigine generic "B"
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 35 participants
- Where
- 8 sitesUnited States
- Study dates
- Apr 2013to Sep 2015
- Phase
- Phase 4
- Are there results?
- None posted in the registry
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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Eligible subjects must satisfy the criteria below at the time of enrollment:
- 18 years or older.
- BMI not less than 18.5 and weight not less than 110 pounds.
- Not donated blood within 56 days of the first pharmacokinetic testing.
- Agrees not to donate blood at any time during the trial and for 56 days after the final PK in-facility admission.
- Has had epilepsy for at least one year based on site PIs assessment.
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- Receiving conventional (not extended release) lamotrigine as an antiepileptic drug in twice daily dosing at either 100 mg twice per day, 200 mg twice per day, 300 mg twice per day, or 400 mg twice per day.
- No changes in AED regimen (lamotrigine or concomitant AED) for at least 28 days prior to first pharmacokinetic testing.
- Have the ability to understand the informed consent form and be willing to provide informed consent.
- Willing to remain on same AED regimen through entire study. Subjects will be responsible to supply all of their concomitant medications (except for the study medication, lamotrigine).
- Willing to stay approximately 14 hours in the research facility on four separate occasions for pharmacokinetic testing.
- Willing to fast overnight and the morning of each of the four pharmacokinetic testing sessions.
- Willing to have at least 21 blood samples collected during the pharmacokinetic testing including the in-facility session and outpatient portion for each period. The in-facility blood collections will mainly be performed using an inserted catheter. In the event of difficulty with the catheter or by subject preference, samples may be drawn by venipuncture. The outpatient portion consists of morning trough levels within +/-1 hour of the morning scheduled dose time on the 2 days prior to each research facility PK admission drawn by venipuncture for each of the 4 periods. The total amount of blood during each PK session will be equal to about 12 teaspoons (58.5 milliliters). The total amount of blood drawn throughout the entire study will be about 62 teaspoons (309.5 milliliters) or less. For reference, this amount is approximately two-thirds of the quantity of blood drawn during a standard blood donation by the Red Cross.
- Willing to completely abstain from alcohol consumption for at least 72-hours prior to each PK in-facility admission (that is from 1 day prior to the first outpatient steady state level) until after the last sample is drawn for each period. Investigators encourage no or minimal alcohol use throughout the study, but alcohol is not restricted at other times.
- Willing to remain on a consistent regimen of concomitant medications including over-the-counter drugs and herbal drugs, if they are being used and deemed to possibly affect the metabolism of the study medication.
- Willing to not eat grapefruit or drink grapefruit juice through the duration of the study.
- If a tobacco user, willing to continue with the same pattern of tobacco use except that no tobacco use is permitted during the PK facility admissions of approximately 14 hours (includes all tobacco products).
- Willing to complete the subject diary as outlined in the protocol.
- Willing to adhere to all other protocol requirements as outlined in the informed consent document.
- Females must be either of non-childbearing potential (defined as having undergone surgical sterilization or postmenopausal (greater than 50 years old and amenorrhea for greater than or equal to 12 months) or must be using at least one acceptable method of contraception as follows:
- Double-barrier method (e.g. condom plus spermicide, condom plus diaphragm with spermicide)
- Hormonal contraceptive treatment (progesterone only agents - use of any agents containing estrogen are an exclusion for the lamotrigine testing)
- Intrauterine Device (IUD)
- Monogamous relationship with a vasectomized partner
- Abstinent for 8 weeks prior to and throughout the study.
- Subject must be at least 28 days from last participation in any other study.
Who cannot join
- 1. Use of an extended release formulation of LTG within 28 days of study entry. 2. Subject is receiving LTG at a total daily dose above 800 mg per day within 28 days of study entry.
- 3. Progressive CNS disorder that could influence adverse effects or seizure control.
- 4. Known medication non-adherence. Non-adherence is assessed by the investigator based on the procedures defined in the manual of procedures.
- 5. Use of valproate (as divalproex sodium or valproic acid), any form of estrogens, rifampin, orlistat, felbamate or sertraline within 28 days of study entry.
- 6. Subject has a history of alcohol or substance abuse within 1 year prior to screening of study participation, or is currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner, which, in the opinion of the Investigator, indicates abuse.
- 7. History of psychogenic seizures within the past 2 years. 8. Any clinically significant psychiatric illness or psychological or behavioral problem which, in the opinion of the investigator, could interfere with the subject being able to participate in the study or comply with the study requirements.
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- 9. Any clinically significant laboratory abnormality or illness which, in the opinion of the investigator, could interfere with the conduct or interpretation of the study or put the subject at risk.
- 10. Pregnant or lactating within 56 days of enrollment. 11. Unstable seizure control that makes AED changes likely during the course of the study.
- 12. Use of rescue AEDs (e.g. benzodiazepines) during more than two weeks of the 2 months prior to enrollment.
- 13. Subject is in the process of quitting smoking within 28 days of study entry or plans to quit smoking during the period of time the study will be conducted.
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
United States8 sites
University of Alabama at Birmingham
Birmingham, Alabama, 35294
Brigham and Women's Hospital
Boston, Massachusetts, 02115
Michael Privitera, MD
Cincinnati, Ohio, 45267
Drake University
Des Moines, Iowa, 50311-4505
University of Kansas
Kansas City, Kansas, 66160
University of Wisconsin-Madison
Madison, Wisconsin, 53705
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Michel J. Berg, MD
Rochester, New York, 14642
About this study
Official title: Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design (EQUIGEN Chronic-Dose Study)
The United States Food and Drug Administration (FDA) has specific rules generic drug companies must follow to get a generic copy of a seizure medication approved. Currently, the FDA approves generic drugs by requiring studies on normal volunteers who don't have epilepsy and who take just one dose of the generic drug followed by a series of blood tests. Some people with epilepsy and their physicians have complained about side effects or loss of seizure control when taking generic drugs, but no one knows if these complaints are truly because of problems with the generic drugs.
When the FDA tests generic copies of lamotrigine (LTG), the blood levels measured after volunteers receive the generic lamotrigine tablets are allowed to fall within a specific range. This research will test whether two different manufacturer's generic lamotrigine, that fall in different parts of that range, perform in a similar way when given to people with epilepsy every day over a several week period. The two products will be called GENERIC A and GENERIC B.
The generic forms of the study drug lamotrigine to be tested in this study are approved by the FDA for the treatment of seizures.
Read the detailed description
Qualified subjects will be screened and upon fulfilling inclusion/exclusion criteria and signing the informed consent will be enrolled into the study and enter the randomization phase (2-30 days). Subjects will be randomized according to a sealed allocation list that will be balanced for sequence and provided to each site prior to the first subject enrollment. Subjects that withdraw prior to completing the second period will be replaced in a randomized manner. The randomization list will be generated by the study statistical group. There are four test periods in two sequences for a sequence-randomized study. During two test periods subjects will receive twice daily dosing of the "low" generic product and during the other two periods subjects will receive twice daily dosing of the "high" generic product. Each subject will return at the end of the 14+/-1 day stable dosing period for an in-facility 12-hour pharmacokinetic (PK) session to collect samples to determine Cmax and AUCs (area under curve). Each in-facility pharmacokinetic testing will be separated by a 14+/-1 day stable dosing period. A final follow-up phone evaluation will be conducted 12-16 days (target 14 days) after the last dose of study medication. A single make-up period will be permitted if there are issues during any single period. During the study the subjects will continue their usual concomitant medications, including AEDs (anti epilepsy drugs), without change.
Investigators will compare the AED levels as measured by Cmax and AUC in each group using average bioequivalence (ABE) and individual bioequivalence (IBE) criteria. Average bioequivalence will be established if the 90% confidence intervals of the geometric mean of Cmax and AUCs for the most disparate generic products compared to each other are entirely within the 80%-125% range (the FDA criteria for bioequivalence) using the two one-sided standard analyses. Otherwise the products will be considered to not be bioequivalent.
Study Population: Approximately 36 subjects (30 subjects to completion).
Number of centers: 3 sites enrolling approximately 12 subjects each.
Duration of study: Approximately 1 year.
- Conditions
- Epilepsy
- Being tested
- Lamotrigine Generic "A", Lamotrigine generic "B"
- Keywords
- Seizures
- Medical subject headings
- Epilepsy, Seizures
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Lamotrigine Generic "A"Drug
Lamotrigine generic "B"Drug
| Study group | Role | What they receive |
|---|---|---|
| Lamotrigine Generic "A"/Generic "B" | Experimental | Crossover trial. Each arm will receive generic "A" for two periods and generic "B" for two periods. Receives: Drug: Lamotrigine Generic "A"; Drug: Lamotrigine generic "B" |
| Lamotrigine Generic "B"/Generic "A" | Experimental | Crossover trial. Each participant will have two periods of generic "A" and two periods of generic "B" Receives: Drug: Lamotrigine Generic "A"; Drug: Lamotrigine generic "B" |
What is being measured
The primary outcome is the main question the study is designed to answer.
Bioequivalence for generic 1 compared to generic 2
To determine if Cmax or AUC are significantly different in the high generic product compared to the low generic product taking one as the reference and the other as the test product. Bioequivalence will be established per the current FDA ABE criteria if the 90% confidence interval of the geometric mean of Cmax and AUC for the high generic product compared to the low generic product are entirely within the 80%-125% range using the two one-sided standard analyses
Measured: 18 months
Secondary outcomes (1)
Intra-subject variances
To measure the intra-subject variances of the investigated generic products, as well as subject-by-interaction variances, by using two replicate periods for each generic product. These estimated variances will be used to investigate individual bioequivalence and detect subject-by-formulation interaction outliers
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Oct 2012 (estimated)
- Study startApr 2013
- Primary completionSep 2015
- Study completionSep 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for EpilepsyStudies of the same condition, open and under way.
- More trials run by University of CincinnatiThe sponsor's other registered studies.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 35 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cincinnati
- Sponsor type
- University, hospital or other
- Collaborators
- Epilepsy Foundation, American Epilepsy Society
- Responsible party
- Principal investigator, Michael Privitera, University of Cincinnati
- Investigators
- Michael D Privitera, MD, Principal investigator, University of CincinnatiMichel J Berg, MD, Principal investigator, University of Rochester
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01713777
- Sponsor's protocol ID
- EQUIGEN Chronic Dose
- Other IDs
- Epilepsy Foundation
- Acronym
- Chronic Dose
- Status last verified
- Sep 2015
- First submitted
- 10 Oct 2012
- Last updated
- 1 Oct 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Privitera MD, Welty TE, Gidal BE, Diaz FJ, Krebill R, Szaflarski JP, Dworetzky BA, Pollard JR, Elder EJ Jr, Jiang W, Jiang X, Berg M. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol. 2016 Apr;15(4):365-72. doi: 10.1016/S1474-4422(16)00014-4. Epub 2016 Feb 12.
PubMed 26875743
Study at a glance
From the registry record, last updated by the sponsor on 1 Oct 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design (EQUIGEN Chronic-Dose Study)
- ClinicalTrials.gov ID
- NCT01713777
- Acronym / sponsor ID
- Chronic Dose / EQUIGEN Chronic Dose
- Conditions
- Epilepsy
- Keywords
- Seizures
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 35 participants (actual)
- Lead sponsor
- University of CincinnatiUniversity, hospital or other
- Collaborators
- Epilepsy Foundation, American Epilepsy Society
- Study start
- Apr 2013
- Primary completion
- Sep 2015 (actual)
- Study completion
- Sep 2015 (actual)
- First posted
- 25 Oct 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The United States Food and Drug Administration (FDA) has specific rules generic drug companies must follow to get a generic copy of a seizure medication approved. Currently, the FDA approves generic drugs by requiring studies on normal volunteers who don't have epilepsy and who take just one dose of the generic drug followed by a series of blood tests. Some people with epilepsy and their physicians have complained about side effects or loss of seizure control when taking generic drugs, but no one knows if these complaints are truly because of problems with the generic drugs.
When the FDA tests generic copies of lamotrigine (LTG), the blood levels measured after volunteers receive the generic lamotrigine tablets are allowed to fall within a specific range. This research will test whether two different manufacturer's generic lamotrigine, that fall in different parts of that range, perform in a similar way when given to people with epilepsy every day over a several week period. The two products will be called GENERIC A and GENERIC B.
The generic forms of the study drug lamotrigine to be tested in this study are approved by the FDA for the treatment of seizures.
Detailed description
Qualified subjects will be screened and upon fulfilling inclusion/exclusion criteria and signing the informed consent will be enrolled into the study and enter the randomization phase (2-30 days). Subjects will be randomized according to a sealed allocation list that will be balanced for sequence and provided to each site prior to the first subject enrollment. Subjects that withdraw prior to completing the second period will be replaced in a randomized manner. The randomization list will be generated by the study statistical group. There are four test periods in two sequences for a sequence-randomized study. During two test periods subjects will receive twice daily dosing of the "low" generic product and during the other two periods subjects will receive twice daily dosing of the "high" generic product. Each subject will return at the end of the 14+/-1 day stable dosing period for an in-facility 12-hour pharmacokinetic (PK) session to collect samples to determine Cmax and AUCs (area under curve). Each in-facility pharmacokinetic testing will be separated by a 14+/-1 day stable dosing period. A final follow-up phone evaluation will be conducted 12-16 days (target 14 days) after the last dose of study medication. A single make-up period will be permitted if there are issues during any single period. During the study the subjects will continue their usual concomitant medications, including AEDs (anti epilepsy drugs), without change.
Investigators will compare the AED levels as measured by Cmax and AUC in each group using average bioequivalence (ABE) and individual bioequivalence (IBE) criteria. Average bioequivalence will be established if the 90% confidence intervals of the geometric mean of Cmax and AUCs for the most disparate generic products compared to each other are entirely within the 80%-125% range (the FDA criteria for bioequivalence) using the two one-sided standard analyses. Otherwise the products will be considered to not be bioequivalent.
Study Population: Approximately 36 subjects (30 subjects to completion).
Number of centers: 3 sites enrolling approximately 12 subjects each.
Duration of study: Approximately 1 year.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Lamotrigine Generic "A"/Generic "B" | Experimental | Drug: Lamotrigine Generic "A", Drug: Lamotrigine generic "B"Crossover trial. Each arm will receive generic "A" for two periods and generic "B" for two periods. |
| Lamotrigine Generic "B"/Generic "A" | Experimental | Drug: Lamotrigine Generic "A", Drug: Lamotrigine generic "B"Crossover trial. Each participant will have two periods of generic "A" and two periods of generic "B" |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- 18 years or older.
- BMI not less than 18.5 and weight not less than 110 pounds.
- Not donated blood within 56 days of the first pharmacokinetic testing.
- Agrees not to donate blood at any time during the trial and for 56 days after the final PK in-facility admission.
- Has had epilepsy for at least one year based on site PIs assessment.
Key exclusion criteria (10 listed)
- 1. Use of an extended release formulation of LTG within 28 days of study entry. 2. Subject is receiving LTG at a total daily dose above 800 mg per day within 28 days of study entry.
- 3. Progressive CNS disorder that could influence adverse effects or seizure control.
- 4. Known medication non-adherence. Non-adherence is assessed by the investigator based on the procedures defined in the manual of procedures.
- 5. Use of valproate (as divalproex sodium or valproic acid), any form of estrogens, rifampin, orlistat, felbamate or sertraline within 28 days of study entry.
- 6. Subject has a history of alcohol or substance abuse within 1 year prior to screening of study participation, or is currently using alcohol, drugs of abuse, or any prescribed or over-the-counter medication in a manner, which, in the opinion of the Investigator, indicates abuse.
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 |
|---|---|---|
| Lamotrigine Generic "A" | Drug | Lamotrigine Generic "A"/Generic "B", Lamotrigine Generic "B"/Generic "A" |
| Lamotrigine generic "B" | Drug | Lamotrigine Generic "A"/Generic "B", Lamotrigine Generic "B"/Generic "A" |
Primary outcome
Bioequivalence for generic 1 compared to generic 2
Time frame: 18 months
To determine if Cmax or AUC are significantly different in the high generic product compared to the low generic product taking one as the reference and the other as the test product. Bioequivalence will be established per the current FDA ABE criteria if the 90% confidence interval of the geometric mean of Cmax and AUC for the high generic product compared to the low generic product are entirely within the 80%-125% range using the two one-sided standard analyses
1 secondary outcome
Intra-subject variances
Time frame: 18 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Oct 2015.
- Derived from this study: PubMed 26875743Privitera MD, Welty TE, Gidal BE, Diaz FJ, Krebill R, Szaflarski JP, Dworetzky BA, Pollard JR, Elder EJ Jr, Jiang W, Jiang X, Berg M. Generic-to-generic lamotrigine switches in people with epilepsy: the randomised controlled EQUIGEN trial. Lancet Neurol. 2016 Apr;15(4):365-72. doi: 10.1016/S1474-4422(16)00014-4. Epub 2016 Feb 12.
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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.
Michael D Privitera, MD principal investigator
University of Cincinnati
Michel J Berg, MD principal investigator
University of Rochester
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Lamotrigine Generic "A" and Lamotrigine generic "B" in people with Epilepsy, run by University of Cincinnati at 8 sites in United States.
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 26 inclusion and 10 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 1 Oct 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Bioequivalence for generic 1 compared to generic 2 (time frame: 18 months). 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 NCT01713777, which also lists 1 linked publication.
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 1 Oct 2015; AzTrials last refreshed its copy on 8 Nov 2026.