Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design

NCT01713777 | Completed Phase 4 DMC

• 2 other identifiers: EQUIGEN Chronic DoseEpilepsy Foundation
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 8

Brief 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 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.

Conditions

Epilepsy

Keywords

Seizures

Outcome Measures

Primary Outcomes (1)

• 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

  18 months

Secondary Outcomes (1)

• Intra-subject variances

  18 months

Other Outcomes (4)

• Individual Bioequivalence

  18 months

• Bioequivalence for subjects receiving inducers compared to not receiving inducers

  18 months

• Bioequivalence by gender

  18 months

Study Arms (2)

Lamotrigine Generic "A"/Generic "B"

EXPERIMENTAL

Crossover trial. Each arm will receive generic "A" for two periods and generic "B" for two periods.

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"

Drug: Lamotrigine Generic "A"; Drug: Lamotrigine generic "B"

Interventions

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"

Eligibility Criteria

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

You may qualify if:

• Eligible subjects must satisfy the criteria below at the time of enrollment:
• 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.
• 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.

You may not qualify if:

• \. 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.
• \. Progressive CNS disorder that could influence adverse effects or seizure control.
• \. Known medication non-adherence. Non-adherence is assessed by the investigator based on the procedures defined in the manual of procedures.
• \. Use of valproate (as divalproex sodium or valproic acid), any form of estrogens, rifampin, orlistat, felbamate or sertraline within 28 days of study entry.
• \. 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.
• \. 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.
• \. 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.
• \. Pregnant or lactating within 56 days of enrollment. 11. Unstable seizure control that makes AED changes likely during the course of the study.
• \. Use of rescue AEDs (e.g. benzodiazepines) during more than two weeks of the 2 months prior to enrollment.
• \. 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.

Sponsors & Collaborators

• University of Cincinnati: lead
• Epilepsy Foundation: collaborator
• American Epilepsy Society: collaborator

Study Sites (8)

University of Alabama at Birmingham

Birmingham, Alabama, 35294, United States

Location

Drake University

Des Moines, Iowa, 50311-4505, United States

Location

University of Kansas

Kansas City, Kansas, 66160, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Michel J. Berg, MD

Rochester, New York, 14642, United States

Location

Michael Privitera, MD

Cincinnati, Ohio, 45267, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Wisconsin-Madison

Madison, Wisconsin, 53705, United States

Location

Related Publications (1)

• 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.

  PMID: 26875743 DERIVED

MeSH Terms

Conditions

Epilepsy; Seizures

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Michael D Privitera, MD

  University of Cincinnati

  PRINCIPAL INVESTIGATOR

• Michel J Berg, MD

  University of Rochester

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Director Cincinnati Epilepsy Center

Study Record Dates

• First Submitted: October 10, 2012
• First Posted: October 25, 2012
• Study Start: April 1, 2013
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: October 1, 2015

Record last verified: 2015-09

Locations

US (8)