Study Evaluating LAMICTAL Extended-Release Therapy Added To Current Seizure Treatments In Patients With Primary Generalized Tonic-Clonic Seizures (PGTC) Seizures

Study Overview
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Brief Summary
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This study is being conducted to compare the efficacy and safety of LAMICTAL (lamotrigine) extended-release with placebo in the treatment of Primary Generalized Tonic-Clonic (PGTC) seizures. LAMICTAL extended-release is an investigational drug. Placebo tablets look like LAMICTAL extended-release tablets but do not contain active medication. In this study, LAMICTAL extended-release or placebo tablets will be added to current seizure treatments.

Official Title
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A Multicenter, Double-blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-Release Adjunctive Therapy in Patients With Primary Generalized Tonic-Clonic Seizures

Conditions
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Epilepsy, Tonic-Clonic

Intervention / Treatment
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* Drug: lamotrigine (LAMICTAL) extended-release
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: 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 stability of prescribed dosages of background antiepileptic drugs (AEDs) 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: VNS has been in place for at least 24 weeks prior to the Baseline Phase. The settings must remain the same for at least 28 days prior to the Baseline Phase. The settings must remain the same during the Baseline, Escalation, Maintenance and Transition Phases. The battery is expected to last for the duration of the study. 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: 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). 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.

Ages Eligible for Study
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Minimum Age: 13 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo control<br>|
| Experimental: lamotrigine (LAMICTAL) extended-relesase<br> | Drug: lamotrigine (LAMICTAL) extended-release<br>* Primary experimental dosage form<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Weekly Primary Generalized Tonic-clonic (PGTC) Seizure Frequency During the Entire Double-Blind Treatment Phase | Percent change from baseline is calculated as the number of seizures by week during the Double-Blind Treatment Phase (Treatment Week 1 up to Week 19) compared to the number of seizures per week during the Baseline Phase (Baseline Week 1 up to Week 8). A positive number equals a reduction in seizure frequency. PGTC seizures are more commonly known as gran mal seizures. | Baseline through end of Double-Blind Treatment Phase (up to Week 19) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With >=25%, >=50%, >=75%, or 100% Reduction in PGTC Seizure Frequency During the Entire Double-Blind (DB)Treatment Phase (TP), the Escalation Phase, the Maintenance Phase, and the Last 8 Weeks of the Maintenance Phase | Change in seizure frequency was calculated as the average seizure frequency during each of the following: the Entire DB Treatment Phase (Treatment Week 1 up to Week 19); the Escalation Phase (Treatment Week 1 up to Week 7); the Maintenance Phase (Treatment Week 8 up to Week 19); and the last 8 weeks of the Maintenance Phase (Treatment Week 12 up to Week 19), minus the seizure frequency at Baseline. | Entire DB Treatment Phase (Treatment Week 1 up to Week 19), Escalation Phase (Treatment Week 1 up to Week 7), Maintenance Phase (Treatment Week 8 up to Week 19), and the last 8 weeks of the Maintenance Phase (Treatment Week 12 up to Week 19) | 
| Percent Change From Baseline in PGTC Seizure Frequency During the Escalation Phase, the Maintenance Phase, and During the Last 8 Weeks of the Maintenance Phase of the Double-Blind Treatment Phase | Percent change from baseline is calculated as the number of seizures by week during the Escalation Phase (Treatment Week 1 up to Week 7), the Maintenance Phase (Treatment Week 8 up to Week 19), and during the last 8 weeks of the Maintenance Phase (Treatment Week 12 up to Week 19) compared to the number of seizures per week during the Baseline Phase (Baseline Week 1 up to Week 8). A positive number equals a reduction in seizure frequency. | Escalation Phase (Treatment Week 1 up to Week 7), Maintenance Phase (Treatment Week 8 up to Week 19), and the last 8 weeks of the Maintenance Phase (Week 12 up to Week 19) | 
| Number of Participants With the Indicated Time to >=50% Reduction in Seizure Frequency in the Double-Blind Treatment Phase | 50% reduction in seizure frequency is defined as the time at which a participant first achieved and maintained a >=50% reduction in seizure frequency following exposure to at least 1 week of study drug. | Baseline through end of Double-Blind Treatment Phase (up to Week 19) | 
| Change From Baseline in Body Weight at Week 19 of the Double-Blind Treatment Phase | Change from baseline in body weight is calculated as the Week 19 (or last on-study measurement in Double-Blind Treatment Phase) value minus the Baseline value. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Number of Participants With Improved Clinical Status on the Investigator's Global Assessment in the Double-Blind Treatment Phase | The investigators rated the participants' overall clinical status based on 7 clinical factors and an overall factor: seizure frequency, duration, and intensity; adverse experiences; social, intellectual, and motor functioning. Using a 7-point scale (marked deterioration [1], moderate deterioration [2], mild deterioration [3], no change [4], mild improvement [5], moderate improvement [6], or marked improvement [7]), the investigators assessed the participants' status compared to their condition prior to initiating study medication. | Week 19 (or last on-study assessment in Double-Blind Treatment Phase) | 
| Number of Participants With Improved Satisfaction With Seizure Control on the Subject Satisfaction Questionnaire in the Double-Blind Treatment Phase | Participants were asked to rate their satisfaction with their seizure control compared to their seizure control prior to initiating study drug on a 7 point scale: marked deterioration (1), moderate deterioration (2), mild deterioration (3), no change (4), mild improvement (5), moderate improvement (6), or marked improvement (7). | Week 19 (or last on-study assessment in Double-Blind Treatment Phase) | 
| Percent Change From Baseline in Weekly PGTC Seizure Frequency During the Entire Continuation Phase (CP), the Transition Phase, the Open-Label Phase, and the Last 8 Weeks of the Open-Label Phase | Percent change from baseline is calculated as the number of seizures by week during the entire CP (CP Week 1 up to Week 52), the Transition Phase (CP Week 1 up to Week 7), the Open-Label Phase (CP Week 8 up to Week 52), and the last 8 weeks of the Open-Label Phase (CP Week 45 up to Week 52) minus the number of seizures per week during the Baseline Phase (Baseline Week 1 through Week 8). A positive number equals a reduction in seizure frequency. | Entire CP (CP Week 1 up to Week 52), the Transition Phase (CP Week 1 up to Week 7), the Open-Label Phase (CP Week 8 up to Week 52), and the last 8 weeks of the Open-Label Phase (CP Week 45 up to Week 52) | 
| Number of Participants With >=25%, >=50%, >=75%, or 100% Reduction or >=50% Increase From Baseline in Weekly PGTC Seizure Frequency for the Entire Continuation Phase, the Transition Phase, the Open-Label (OL) Phase, and the Last 8 Weeks of the OL Phase. | Change in seizure frequency was calculated as the average seizure frequency during each of the following: the Entire CP (CP Week 1 up to Week 52); the Transition Phase (CP Week 1 up to Week 7); the Open-Label (OL) Phase (CP Week 8 up to Week 52); and the last 8 weeks of the Open Label Phase (CP Week 45 up to Week 52) minus the seizure frequency at Baseline. W, Week. | Entire CP (CP Week 1 up to Week 52), the Transition Phase (CP Week 1 up to Week 7), the Open-Label Phase (CP Week 8 up to Week 52), and the last 8 weeks of the Open-Label Phase (CP Week 45 up to Week 52) | 
| Mean Change From Baseline in the Profile of Mood State (POMS) Mood Disturbance Total Score at Week 19 of the Double-Blind Treatment Phase | The POMS is a self-administered 65-item questionnaire that evaluates the participants' perception of their mood state in 6 areas: tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment. Items are rated on a 5-point Likert scale from 0 (not at all) to 4 (extremely), with higher scores indicating a more negative mood state. A total score (from 0 to 24) is obtained by summing the scores of the six domains. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Mean Change From Baseline in the Center for Epidemiological Studies-Depression Scale (CES-D) Total Score at Week 19 of the Double-Blind Treatment Phase | The 20-item CES-D questionnaire is self-administered and asks respondents to report the frequency to which the 20 events were experienced over the past week. A 4-point Likert scale is used and ranges from rarely or none of the time (0) to most or all of the time (3). The total score, a sum across the 20 items (ranging from 0 to 60), determines the extent to which a participant may be experiencing depression. Higher scores indicate a higher severity of depression. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Mean Change From Baseline in the Neurological Disorders Depression Inventory-Epilepsy (NDDI-E) 6-Item Total Score at Week 19 of the Double-Blind Treatment Phase | The NDDI-E is a self-reported questionnaire composed of 46 brief phrases/words to identify mood disorders across the spectrum of depression. It was developed to capture depressive moods that are co-morbid with the disease of epilepsy or its treatment as well as to measure the depressive state of the participant. All phrases are measured on a 4-point Likert scale of Never (1) to Always/often (4) and refer to the participants' mood over the past week. Scoring is comprised of a total mood score calculated by summing the scores of 6 specific items (from 6=never to 24=always or often). | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Mean Change From Baseline in the Quality of Life in Epilepsy-31-P (QOLIE-31P) Overall Score at Week 19 of the Double-Blind Treatment Phase | The QOLIE-31 is a 31-item questionnaire that evaluates the participants' perception of his or her quality of life in 7 domains: seizure worry, emotional well being, energy/fatigue, cognitive functioning, medication effects, social functioning, and overall quality of life. Each domain (with scores ranging from 0 to 100) is summed and divided by the total number of questions that were answered. The overall score is derived by weighting and then summing up the seven domain scores. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Mean Change From Baseline in the Adverse Experience Profile (AEP) Total Score at Week 19 of the Double-Blind Treatment Phase | The AEP is a list of 19 items covering many possible side effects attributable to drug treatment. The participants respond by assessing how much each event has been a problem for them over the past 4 weeks (1=Never a Problem to 4=Always a Problem). Each individual item can be examined; an overall adverse events score is calculated as the sum of the scores across the 19 items. The AEP total score ranges from 19 to 76, with a higher score indicating a higher degree of adverse event severity. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Mean Change From Baseline in the Seizure Severity Questionnaire (SSQ) Global Bother Score at Week 19 Double-Blind Treatment Phase | The SSQ is a self-reported instrument developed to assess the severity of seizures and seizure symptoms. The scale consists of 10 major clinical features/symptoms of seizures that the participants rate on a 7-point Likert scale (ranging from very mild/helpful/no bother at all [1] to very severe/no help/bothersome [7]). The Global Bother Domain is the primary score used for the analysis of the SSQ and has scores ranging from 1 to 7. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Mean Change From Baseline in the Epworth Sleepiness Scale (ESS) 8-Item Total Score at Week 19 of the Double-Blind Treatment Phase | The ESS is an 8-item, self-administered questionnaire that measures excessive daytime sleepiness in adults. The instrument captures information on the extent to which the participant would be likely, or not, to fall asleep in certain situations. The stimulus question is: How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? Questions are answered on a 4-point scale (would never doze [0] to high chance of dozing [3]). The total score ranges from 0 to 24, where a higher score indicates a higher chance of dozing. | Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase) | 
| Serum Concentrations and Population (POP) Pharmacokinetic Parameters for Lamotrigine | Serum samples for participants on lamotrigine were analyzed with a validated analytical method based on solid phase extraction of serum followed by High-Performance Liquid Chromatography (HPLC) Mass Spectrometry (MS)/MS analysis. The lower limit of quantification (LLQ) for serum lamotrigine was 4 nanograms (ng)/milliliter (mL), using a 50 microliter (µL) aliquot of human serum with a higher limit of quantification (HLQ) of 4,000 ng/mL. PK data cannot be reported, as PK data from several different studies have been combined into one POP/PK analysis and cannot be separated by study. | Blood samples drawn at Treatment Weeks 11, 15, and 19 (or last on-study measurement in Double-Blind Treatment Phase) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antiepileptic drugs, seizures, primary generalized tonic-clonic seizures, Epilepsy, lamotrigine, anticonvulsants, LAMICTAL