Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Single-Dose 6-Period Replicate Design (EQUIGEN Single-Dose Study)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
American Epilepsy Society
Epilepsy Foundation
Information provided by (Responsible Party):
Michael Privitera, University of Cincinnati
ClinicalTrials.gov Identifier:
NCT01733394
First received: November 2, 2012
Last updated: October 13, 2014
Last verified: October 2014
  Purpose

The United States Food and Drug Administration (FDA) has specific rules which generic drug companies must follow to get a generic copy of a seizure medication approved. Currently, 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.

This research is to determine whether several different generic versions and the brand version of the medication lamotrigine perform in a similar way when given to people with epilepsy.

The study drug Lamictal® (lamotrigine) and both of the generic forms of lamotrigine to be tested are approved by the FDA for the treatment of seizures.


Condition Intervention Phase
Epilepsy
Drug: Lamotrigine Generic "A" Lamotrigine Generic "B" Lamotrigine "Brand"
Drug: lamotrigine
Drug: Lamotrigine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Single-Dose 6-Period Replicate Design (EQUIGEN Single-Dose Study)

Resource links provided by NLM:


Further study details as provided by University of Cincinnati:

Primary Outcome Measures:
  • Bioequivalence for generic 1 compared to generic 2 [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    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


Secondary Outcome Measures:
  • Intra-subject variances [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    To measure the intra-subject variances of the investigated REFERENCE (BRAND) AND generic products, as well as subject-by-interaction variances, by using two replicate periods for THE REFERENCE PRODUCT AND TWO REPLICATE PERIODS FOR each generic product. These estimated variances will be used to investigate individual bioequivalence and detect subject-by-formulation interaction outliers


Other Outcome Measures:
  • Individual Bioequivalence [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    To examine individual bioequivalence by comparing the BRAND TO EACH OF THE two generic products. Individual bioequivalence (IBE) will be determined using the FDA 2001 guidance criteria. To determine the number of subjects who are outliers and to identify these subjects for potential further study.

  • Bioequivalence for subjects receiving inducers compared to not receiving inducers [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    To compare the REFERENCE/generic and generic1 /generic2 ratios for Cmax and AUC in subjects on a concomitant enzyme inducing AED compared to subjects not on a concomitant enzyme AED

  • Bioequivalence by gender [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    To compare the REFERENCE/generic and generic1/generic2 ratios for Cmax and AUC in male subjects compared to female subjects

  • Bioequivalence in enriched population [ Time Frame: 18 months ] [ Designated as safety issue: No ]
    To compare the REFERENCE/generic and generic1/generic2 ratios for Cmax and AUC in the population of subjects who had reported loss of seizure control or unanticipated adverse effects after a generic switch.


Estimated Enrollment: 54
Study Start Date: April 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Generic A - Generic B - Brand - Generic A - Brand - Generic B
Sequence 1
Drug: Lamotrigine Generic "A" Lamotrigine Generic "B" Lamotrigine "Brand"
Other Name: Lamotrigine
Drug: lamotrigine Drug: Lamotrigine
Experimental: Generic B - Brand - Generic A - Generic B - Generic A - Brand
Sequence 2
Drug: Lamotrigine Generic "A" Lamotrigine Generic "B" Lamotrigine "Brand"
Other Name: Lamotrigine
Drug: lamotrigine Drug: Lamotrigine
Experimental: Brand - Generic A - Generic B - Brand - Generic B- Generic A
Sequence 3
Drug: Lamotrigine Generic "A" Lamotrigine Generic "B" Lamotrigine "Brand"
Other Name: Lamotrigine
Drug: lamotrigine Drug: Lamotrigine

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

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

  1. 18 years or older.
  2. BMI not less than 18.5 and weight not less than 110 pounds.
  3. Not donated blood within the past 56 days before the first pharmacokinetic testing.
  4. Agrees not to donate blood at any time during the trial and for 56 days after the final PK in-facility admission.
  5. Has epilepsy for at least one year based on site PIs assessment.
  6. Taking at least one AED, which is not the study medication (lamotrigine).
  7. No changes in AED regimen for at least 28 days prior to first pharmacokinetic testing.
  8. Have the ability to understand the informed consent form and be willing to provide informed consent.
  9. 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).
  10. Willing to stay approximately 14 hours in the research facility on six separate occasions for pharmacokinetic testing.
  11. Willing to fast overnight and the morning of each of the six pharmacokinetic testing sessions.
  12. Willing to have at least 23 blood samples collected during the pharmacokinetic testing including the in-facility session and each of the following four mornings for 96 hours post the study medication dose to complete the sample collection for each of the 6 periods. The in-facility blood collections will mainly be performed using an inserted catheter. In the event of difficulty with the catheter, samples may be drawn by venipuncture. The outpatient collections will be drawn by venipuncture. The total amount of blood during each PK session will be equal to about 14 teaspoons (66.5 milliliters). The total amount of blood drawn throughout the entire study will be about 96 teaspoons (478.5 milliliters) or less. For reference, this amount is approximately equal to the quantity of blood drawn during a standard blood donation by the Red Cross.
  13. Willing to completely abstain from alcohol consumption for at least 24 hours prior to each pharmacokinetic testing admission until after the last sample is drawn for each period (~96 hours after the initial dose at each pharmacokinetic admission). We encourage no or minimal alcohol use throughout the study, but alcohol is not restricted at other times.
  14. 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.
  15. Willing to not eat grapefruit or drink grapefruit juice through the duration of the study.
  16. 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).
  17. Willing to complete the subject diary as outlined in the protocol.
  18. Willing to adhere to all other protocol requirements as outlined in the informed consent document.
  19. 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:

    1. Double-barrier method (e.g. condom plus spermicide, condom plus diaphragm with spermicide)
    2. Hormonal contraceptive treatment (progesterone only agents - use of any agents containing estrogen are an exclusion for the lamotrigine testing)
    3. Intrauterine Device (IUD)
    4. Monogamous relationship with a vasectomized partner
    5. Abstinent for 8 weeks prior to and throughout the study.
  20. Subject must be at least 28 days from last participation in any other study.

Exclusion Criteria

  1. Progressive CNS disorder that could influence adverse effects or seizure control.
  2. Known medication non-adherence. Non-adherence is assessed by the investigator based on the procedures defined in the manual of procedures.
  3. Taking the study medication (lamotrigine) within 28 days of enrollment.
  4. Use of valproate (as divalproex sodium or valproic acid), any form of estrogens, rifampin, orlistat, felbamate or sertraline within 28 days of study entry.
  5. Subject has a history of alcohol or substance abuse within 1 year prior to screening for 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.
  6. History of psychogenic seizures within the past 2 years.
  7. 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. .
  8. Any clinically significant laboratory abnormality or illness which, in the opinion of the investigator, could interfere with the conducting or interpretation of the study or put the subject at risk.
  9. History of allergic reaction with past use of the study medication (lamotrigine).
  10. More than two allergic reactions (actual allergy, not medication intolerance) to an AED or one serious hypersensitivity reaction to an AED.
  11. History of adverse effect associated with past use of the study medication (lamotrigine) which, in the opinion of the investigator, could pose substantial risk to the subject if it occurred during the trial.
  12. Pregnant or lactating within 56 days of enrollment.
  13. Unstable seizure control that makes AED changes likely during the course of the study.
  14. Use of rescue AEDs (e.g. benzodiazepines) during more than two weeks of the 2 months prior to enrollment.
  15. 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01733394

Locations
United States, Alabama
University of Alabama at Birmingham
Birmingham, Alabama, United States, 35294
United States, Iowa
Drake University
Des Moines, Iowa, United States, 50311-4505
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
University of Rochester Medical Center
Rochester, New York, United States, 14642-8673
United States, Ohio
University of Cincinnati Medical Center
Cincinnati, Ohio, United States, 45267-0525
United States, Wisconsin
University of Wisconsin-Madison
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
University of Cincinnati
American Epilepsy Society
Epilepsy Foundation
Investigators
Principal Investigator: Michael D. Privitera, MD University of Cincinnati
Principal Investigator: Michel J Berg, MD University of Rochester
  More Information

No publications provided

Responsible Party: Michael Privitera, Director Cincinnati Epilepsy Center, University of Cincinnati
ClinicalTrials.gov Identifier: NCT01733394     History of Changes
Other Study ID Numbers: EQUIGEN Single Dose Protocol, 005-1005
Study First Received: November 2, 2012
Last Updated: October 13, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Cincinnati:
Epilepsy
Generic

Additional relevant MeSH terms:
Epilepsy
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Anticonvulsants
Lamotrigine
Calcium Channel Blockers
Cardiovascular Agents
Central Nervous System Agents
Excitatory Amino Acid Agents
Excitatory Amino Acid Antagonists
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sodium Channel Blockers
Therapeutic Uses
Voltage-Gated Sodium Channel Blockers

ClinicalTrials.gov processed this record on October 20, 2014