Please select the eligibility criteria that correspond to the clinical trial below.
Title: Vagus Nerve Stimulation for Pediatric Intractable Epilepsy (VNS-PIE)
Brief Summary: Children with refractory epilepsy who are candidates for a treatment with vagus nerve stimulation will be prospectively randomized into 2 arms. Vagus nerve stimulation parameters are programmed and adjusted during outpatient clinic visits, within the normal clinical practice.


Options:
A: 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 56 days of 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 had epilepsy for at least one year based on site PIs assessment.
6. 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.
7. No changes in AED regimen (lamotrigine or concomitant AED) 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 four separate occasions for pharmacokinetic testing.
11. Willing to fast overnight and the morning of each of the four pharmacokinetic testing sessions.
12. 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.
13. 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.
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. 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.

  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.
B: Inclusion Criteria:

* Is ≥13 years of age (male or female).
* Has a confident diagnosis of epilepsy with PGTC seizures for more than 24 weeks prior to the Baseline Phase.
* Has electroencephalogram (EEG) evidence of either spike-and-wave discharges consistent with PGTC, or at least 2 EEGs with no indication of focal abnormalities. The EEG may be historical or prospective. Investigators may use a historical EEG as long as there is appropriate documentation.
* Has a documented history of PGTC seizures with or without other generalized seizure type(s) with no focal onset, and at least 1 PGTC seizure during the eight consecutive weeks (i.e., 56 consecutive days) prior to starting the 8-week Baseline Phase.
* Has at least 3 PGTC seizures occurring anytime during an 8-week (i.e., 56 days) prospective Baseline Phase.

  * NOTE: When a historical baseline is used, the same time period cannot count for documentation of inclusion criteria 4 and 5. Additionally, innumerable seizure activity will not count towards the number of seizures required for randomization.
  * NOTE: With authorization from GSK, a maximum of four weeks (i.e., 28 days) of historical seizure data may replace up to four weeks (i.e., 28 days) of the prospective Baseline Phase for subjects providing reliable documentation of the following:

    1. complete daily seizure diary that includes the number of seizures experienced each day along with the exact classification of each seizure type for consecutive days prior to the prospective Baseline Phase
    2. stability of prescribed dosages of background antiepileptic drugs (AEDs)
    3. compliance with background AEDs.
  * All subjects permitted to use historical seizure data must complete a minimum of four weeks (i.e., 28 days) of the prospective Baseline Phase. The historical Baseline Phase and the prospective Baseline Phase must equal 56 consecutive days.
* Is currently treated with a stable regimen of one or two AED(s) for at least four weeks prior to starting the Baseline Phase (historical or prospective).

  * NOTE: Benzodiazepines used chronically will be considered to be concurrent AEDs.
  * NOTE: Subjects with surgically implanted vagal nerve stimulators (VNS) will be allowed to enter the study provided that all of the following conditions are met:

    1. VNS has been in place for at least 24 weeks prior to the Baseline Phase.
    2. The settings must remain the same for at least 28 days prior to the Baseline Phase.
    3. The settings must remain the same during the Baseline, Escalation, Maintenance and Transition Phases.
    4. The battery is expected to last for the duration of the study.
    5. VNS is counted as a "concurrent AED."
* Is able and willing to maintain an accurate and complete daily written seizure diary, or has a parent/caregiver who is able and willing to maintain an accurate and complete daily written seizure diary for the entire duration of the study.
* Is able to comply with dosing of study drugs, background AEDs and all study procedures.
* Has given written informed consent, or has a parent/legally authorized representative who has given written informed consent, prior to the performance of any study assessments.
* If female, and of childbearing potential, must be using an acceptable form of birth control, to include one of the following:

  1. Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug (a minimum of 3 weeks).
  2. Consistent and correct use of one of the following methods of birth control:

     * Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject
     * Implants of levonorgestrel
     * Injectable progestogen
     * Oral contraceptive (either combined, with at least 50mcg estrogen for women on enzyme-induced AEDs, or progestogen only)
     * Any intrauterine device (IUD) with a documented failure rate of less than 1% per year
     * Double barrier method consisting of spermicide plus a mechanical barrier (e.g., spermicide plus a male condom or a female diaphragm).
     * NOTE: Women who have had a hysterectomy, tubal ligation, or are post-menopausal are considered to be of non-childbearing potential.

Exclusion Criteria:

* Has a history of partial seizures or interictal expression of partial seizures as evidenced by EEG NOTE: EEG may be historical or prospective.
* Has had status epilepticus within the 24 weeks prior to, or during, the Baseline Phase.
* Is taking three or more background AEDs chronically.
* Has Lennox-Gastaut syndrome.
* Is currently using or has previously used lamotrigine.
* Is currently taking felbamate.
* Is abusing alcohol and/or other substance(s).
* Has taken an investigational drug within the previous 30 days or plans to take an investigational drug anytime during the study.
* Is receiving chronic treatment with any medication that could influence seizure control. NOTE: Use of benzodiazepines is allowed.
* Is currently following the ketogenic diet.
* Is planning surgery to control seizures during the study.
* Is suffering from acute or progressive neurological disease, severe psychiatric disease, or severe mental abnormality that are likely to interfere with the objectives of the study.
* Has any clinically significant cardiac, renal, hepatic condition, or a condition that affects the absorption, distribution, metabolism or excretion of drugs.
* Is pregnant, breastfeeding, or planning to become pregnant during the study or within the three weeks after the last dose of study drug.
C: Inclusion Criteria:

1. Age 3-6
2. At least 6 seizure per month
3. Refractory Epilepsy
4. In good health except epilepsy
5. Patients or his(her) familyscould understand this method and sign the informed consent
6. Patients with good compliance and could complete postoperative follow-up

Exclusion Criteria:

1. Results of MRI remind epilepsy caused by intracranial space-occupying lesions
2. The vagus nerve lesion and damage
3. Tumor, cardiopulmonary anomaly, progressive neurological diseases, asthma，mental disease，pepticulcer，diabetes，bad health etc, and other surgical contraindication
4. Cann't write the epilepsy diary
5. Participating other clinical trial
6. Cann't complate the operation
7. Complete the postoperative follow-up
8. Cann't complete the promgramming
D: 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.

Answer: C