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

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00104416
• Collaborator: (none)
• Enrollment: 153
• Locations: 146
• Arms: 2
• Duration (Months): 43
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy, Tonic-Clonic	Drug: lamotrigine (LAMICTAL) extended-release; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 153 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-blind, Randomized, Parallel-group Evaluation of LAMICTAL Extended-Release Adjunctive Therapy in Patients With Primary Generalized Tonic-Clonic Seizures
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo control
Experimental: lamotrigine (LAMICTAL) extended-relesase	Drug: lamotrigine (LAMICTAL) extended-release; Primary experimental dosage form

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Weekly Primary Generalized Tonic-clonic (PGTC) Seizure Frequency During the Entire Double-Blind Treatment Phase [Baseline through end of Double-Blind Treatment Phase (up to Week 19)]

   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.

Secondary Outcome Measures

1. 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 [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)]

   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.

2. 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 [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)]

   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.

3. Number of Participants With the Indicated Time to >=50% Reduction in Seizure Frequency in the Double-Blind Treatment Phase [Baseline through end of Double-Blind Treatment Phase (up to Week 19)]

   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.

4. Change From Baseline in Body Weight at Week 19 of the Double-Blind Treatment Phase [Baseline and Week 19 (or last on-study measurement in 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.

5. Number of Participants With Improved Clinical Status on the Investigator's Global Assessment in the Double-Blind Treatment Phase [Week 19 (or last on-study assessment in 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.

6. Number of Participants With Improved Satisfaction With Seizure Control on the Subject Satisfaction Questionnaire in the Double-Blind Treatment Phase [Week 19 (or last on-study assessment in 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).

7. 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 [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)]

   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.

8. 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. [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)]

   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.

9. Mean Change From Baseline in the Profile of Mood State (POMS) Mood Disturbance Total Score at Week 19 of the Double-Blind Treatment Phase [Baseline and Week 19 (or last on-study measurement in 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.

10. 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 [Baseline and Week 19 (or last on-study measurement in 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.

11. 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 [Baseline and Week 19 (or last on-study measurement in 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).

12. 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 [Baseline and Week 19 (or last on-study measurement in 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.

13. Mean Change From Baseline in the Adverse Experience Profile (AEP) Total Score at Week 19 of the Double-Blind Treatment Phase [Baseline and Week 19 (or last on-study measurement in 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.

14. Mean Change From Baseline in the Seizure Severity Questionnaire (SSQ) Global Bother Score at Week 19 Double-Blind Treatment Phase [Baseline and Week 19 (or last on-study measurement in 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.

15. Mean Change From Baseline in the Epworth Sleepiness Scale (ESS) 8-Item Total Score at Week 19 of the Double-Blind Treatment Phase [Baseline and Week 19 (or last on-study measurement in 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.

16. Serum Concentrations and Population (POP) Pharmacokinetic Parameters for Lamotrigine [Blood samples drawn at Treatment Weeks 11, 15, and 19 (or last on-study measurement in Double-Blind Treatment Phase)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Anniston	Alabama	United States	36207
2	GSK Investigational Site	Birmingham	Alabama	United States	35294-0021
3	GSK Investigational Site	Northport	Alabama	United States	35476
4	GSK Investigational Site	Tuscaloosa	Alabama	United States	35406
5	GSK Investigational Site	Phoenix	Arizona	United States	85006
6	GSK Investigational Site	Phoenix	Arizona	United States	85013
7	GSK Investigational Site	Scottsdale	Arizona	United States	85259
8	GSK Investigational Site	Tucson	Arizona	United States	85712
9	GSK Investigational Site	Little Rock	Arkansas	United States	72205
10	GSK Investigational Site	Los Angeles	California	United States	90033
11	GSK Investigational Site	Los Angeles	California	United States	90073
12	GSK Investigational Site	Newport Beach	California	United States	92660
13	GSK Investigational Site	Santa Monica	California	United States	90404
14	GSK Investigational Site	Sepuldeva	California	United States	91343
15	GSK Investigational Site	Washington	District of Columbia	United States	20037
16	GSK Investigational Site	Hollywood	Florida	United States	33021
17	GSK Investigational Site	Maitland	Florida	United States	32751
18	GSK Investigational Site	Ocala	Florida	United States	34471
19	GSK Investigational Site	Atlanta	Georgia	United States	30342
20	GSK Investigational Site	Augusta	Georgia	United States	30912-3200
21	GSK Investigational Site	Marietta	Georgia	United States	30060
22	GSK Investigational Site	Savannah	Georgia	United States	31405
23	GSK Investigational Site	Suwanee	Georgia	United States	30024
24	GSK Investigational Site	Chicago	Illinois	United States	60612
25	GSK Investigational Site	Flossmoor	Illinois	United States	60422
26	GSK Investigational Site	Springfield	Illinois	United States	62702
27	GSK Investigational Site	Des Moines	Iowa	United States	50309-1426
28	GSK Investigational Site	Wichita	Kansas	United States	67214
29	GSK Investigational Site	Crestview Hills	Kentucky	United States	41017
30	GSK Investigational Site	Louisville	Kentucky	United States	40202
31	GSK Investigational Site	Lafayette	Louisiana	United States	70503
32	GSK Investigational Site	Boston	Massachusetts	United States	02118
33	GSK Investigational Site	Detroit	Michigan	United States	48202
34	GSK Investigational Site	Grand Rapids	Michigan	United States	49525
35	GSK Investigational Site	Traverse City	Michigan	United States	49684
36	GSK Investigational Site	Minneapolis	Minnesota	United States	55422
37	GSK Investigational Site	Minneapolis	Minnesota	United States	55455
38	GSK Investigational Site	Chesterfield	Missouri	United States	63017
39	GSK Investigational Site	Kansas City	Missouri	United States	64111
40	GSK Investigational Site	Las Vegas	Nevada	United States	89106
41	GSK Investigational Site	Edison	New Jersey	United States	08818
42	GSK Investigational Site	West Orange	New Jersey	United States	07052
43	GSK Investigational Site	Amherst	New York	United States	14226
44	GSK Investigational Site	New York	New York	United States	10016
45	GSK Investigational Site	Asheville	North Carolina	United States	28801
46	GSK Investigational Site	Greenville	North Carolina	United States	27834
47	GSK Investigational Site	Raleigh	North Carolina	United States	27607
48	GSK Investigational Site	Columbus	Ohio	United States	43210-1250
49	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73104
50	GSK Investigational Site	Oklahoma City	Oklahoma	United States	73112
51	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19107
52	GSK Investigational Site	Philadelphia	Pennsylvania	United States	19140
53	GSK Investigational Site	Pittsburgh	Pennsylvania	United States	15215
54	GSK Investigational Site	Germantown	Tennessee	United States	38138
55	GSK Investigational Site	Dallas	Texas	United States	75230
56	GSK Investigational Site	Galveston	Texas	United States	77555
57	GSK Investigational Site	Houston	Texas	United States	77005
58	GSK Investigational Site	San Antonio	Texas	United States	78258
59	GSK Investigational Site	Wichita Falls	Texas	United States	76301
60	GSK Investigational Site	Salt Lake City	Utah	United States	84107
61	GSK Investigational Site	Burlington	Vermont	United States	05401
62	GSK Investigational Site	Richmond	Virginia	United States	23220
63	GSK Investigational Site	Madison	Wisconsin	United States	53715
64	GSK Investigational Site	Milwaukee	Wisconsin	United States	53215
65	GSK Investigational Site	Capital Federal	Buenos Aires	Argentina	1181
66	GSK Investigational Site	Ciudad Autonoma de Buenos Aires		Argentina	C1221ADC
67	GSK Investigational Site	Ciudad Autónoma de Buenos Aires		Argentina	1425
68	GSK Investigational Site	Curitiba	Paraná	Brazil	80069-900
69	GSK Investigational Site	Campinas	São Paulo	Brazil	13083-970
70	GSK Investigational Site	São Paulo		Brazil	05403-900
71	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile	7571831
72	GSK Investigational Site	Santiago	Región Metro De Santiago	Chile
73	GSK Investigational Site	Singen	Baden-Wuerttemberg	Germany	78224
74	GSK Investigational Site	Ulm	Baden-Wuerttemberg	Germany	89073
75	GSK Investigational Site	Alzenau	Bayern	Germany	63755
76	GSK Investigational Site	Bamberg	Bayern	Germany	96047
77	GSK Investigational Site	Fuerth	Bayern	Germany	90762
78	GSK Investigational Site	Muenchen	Bayern	Germany	80331
79	GSK Investigational Site	Neuoetting	Bayern	Germany	84524
80	GSK Investigational Site	Straubing	Bayern	Germany	94315
81	GSK Investigational Site	Unterhaching	Bayern	Germany	82008
82	GSK Investigational Site	Wuerzburg	Bayern	Germany	97070
83	GSK Investigational Site	Bernau	Brandenburg	Germany	16321
84	GSK Investigational Site	Ludwigsfelde	Brandenburg	Germany	14974
85	GSK Investigational Site	Bad Homburg	Hessen	Germany	61348
86	GSK Investigational Site	Frankfurt	Hessen	Germany	60594
87	GSK Investigational Site	Wismar	Mecklenburg-Vorpommern	Germany	23966
88	GSK Investigational Site	Wismar	Mecklenburg-Vorpommern	Germany	23970
89	GSK Investigational Site	Bueckeburg	Niedersachsen	Germany	31675
90	GSK Investigational Site	Goettingen	Niedersachsen	Germany	37075
91	GSK Investigational Site	Osnabrueck	Niedersachsen	Germany	49074
92	GSK Investigational Site	Baesweiler	Nordrhein-Westfalen	Germany	52499
93	GSK Investigational Site	Bochum	Nordrhein-Westfalen	Germany	44795
94	GSK Investigational Site	Bochum	Nordrhein-Westfalen	Germany	44892
95	GSK Investigational Site	Essen	Nordrhein-Westfalen	Germany	45122
96	GSK Investigational Site	Essen	Nordrhein-Westfalen	Germany	45138
97	GSK Investigational Site	Hattingen	Nordrhein-Westfalen	Germany	45525
98	GSK Investigational Site	Koeln	Nordrhein-Westfalen	Germany	50767
99	GSK Investigational Site	Moenchengladbach	Nordrhein-Westfalen	Germany	41061
100	GSK Investigational Site	Muenster	Nordrhein-Westfalen	Germany	48149
101	GSK Investigational Site	Limburgerhof	Rheinland-Pfalz	Germany	67117
102	GSK Investigational Site	Bernburg	Sachsen-Anhalt	Germany	06406
103	GSK Investigational Site	Halle	Sachsen-Anhalt	Germany	06118
104	GSK Investigational Site	Koethen	Sachsen-Anhalt	Germany	06366
105	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39104
106	GSK Investigational Site	Magdeburg	Sachsen-Anhalt	Germany	39124
107	GSK Investigational Site	Naumburg	Sachsen-Anhalt	Germany	06618
108	GSK Investigational Site	Floeha	Sachsen	Germany	09557
109	GSK Investigational Site	Leipzig	Sachsen	Germany	04105
110	GSK Investigational Site	Leipzig	Sachsen	Germany	04157
111	GSK Investigational Site	Kiel	Schleswig-Holstein	Germany	24105
112	GSK Investigational Site	Jena	Thueringen	Germany	07743
113	GSK Investigational Site	Berlin		Germany	10117
114	GSK Investigational Site	Berlin		Germany	10969
115	GSK Investigational Site	Berlin		Germany	13353
116	GSK Investigational Site	Hamburg		Germany	20249
117	GSK Investigational Site	Hamburg		Germany	21029
118	GSK Investigational Site	Hamburg		Germany	22083
119	GSK Investigational Site	Hamburg		Germany	22523
120	GSK Investigational Site	Hamburg		Germany	22527
121	GSK Investigational Site	Hyderabad, Andhra Pradesh		India	500482
122	GSK Investigational Site	Lucknow		India	226003
123	GSK Investigational Site	New Delhi		India
124	GSK Investigational Site	Daejeon		Korea, Republic of	301-721
125	GSK Investigational Site	Seoul		Korea, Republic of	110-744
126	GSK Investigational Site	Seoul		Korea, Republic of	120-752
127	GSK Investigational Site	Seoul		Korea, Republic of	135-710
128	GSK Investigational Site	Seoul		Korea, Republic of	139-711
129	GSK Investigational Site	Kubang Kerian		Malaysia	16150
130	GSK Investigational Site	San German		Puerto Rico	00683
131	GSK Investigational Site	San Juan		Puerto Rico	00918
132	GSK Investigational Site	San Juan		Puerto Rico	00936
133	GSK Investigational Site	Ekaterinburg		Russian Federation	620102
134	GSK Investigational Site	Moscow		Russian Federation	105066
135	GSK Investigational Site	Moscow		Russian Federation	107076
136	GSK Investigational Site	Moscow		Russian Federation	111539
137	GSK Investigational Site	Moscow		Russian Federation	117049
138	GSK Investigational Site	Moscow		Russian Federation	119334
139	GSK Investigational Site	Moscow		Russian Federation	125412
140	GSK Investigational Site	Samara		Russian Federation	443095
141	GSK Investigational Site	St'Petersburg		Russian Federation	197136
142	GSK Investigational Site	St.-Petersburg		Russian Federation	193019
143	GSK Investigational Site	St.-Petersburg		Russian Federation	194291
144	GSK Investigational Site	Kharkiv		Ukraine	61068
145	GSK Investigational Site	Kyiv		Ukraine	02660
146	GSK Investigational Site	Lviv		Ukraine	79021

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT00104416
• Other Study ID Numbers: LAM100036
• First Posted: Mar 1, 2005
• Last Update Posted: Jan 2, 2017
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by GlaxoSmithKline: antiepileptic drugs; seizures; primary generalized tonic-clonic seizures; Epilepsy; lamotrigine; anticonvulsants; LAMICTAL
• Additional relevant MeSH terms: Epilepsy; Seizures; Epilepsy, Tonic-Clonic; Epilepsy, Generalized; Lamotrigine

Study Results

Participant Flow

Recruitment Details	All participants (par.) that complete the Treatment Phase (TP) and all Baseline Failures (par. who did not meet randomization seizure criteria necessary to qualify for the TP) are eligible to enter the Continuation Phase (CP). The CP is for long-term safety exposure to lamotrigine (LTG) extended release (XR); it is not a cross-over phase.
Pre-assignment Detail	The number of par. starting the CP does not equal the number completing the TP, as 1) the CP was optional, 2) not everyone from the TP was eligible to enter the CP, and 3) Baseline Failures were allowed to enter the CP, however they were not included in the "started" count for the TP.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR	Continuation Phase: Placebo/LTG	Continuation Phase: LTG/LTG	Baseline Failures
Arm/Group Description	Control - matching placebo once daily	Lamotrigine (LTG) extended release (XR) once daily	Participants who received placebo in the Double-Blind Phase and then entered the CP, in which they received LTG	Participants who received LTG XR in the Double-Blind Phase and then entered the CP, in which they received LTG	Baseline failures who entered the CP without receiving treatment in the Double-Blind Phase. Baseline Failures were participants that successfully progressed through the Screening Phase and completed the Baseline Phase of the Double-blind Study, but ultimately did not meet the seizure frequency criteria for randomization into the Double-Blind Treatment Phase of the study. As a result, they were not counted as having started in the Double-Blind Study, but were eligible to enter the CP of the study.
Period Title: Double-Blind Phase
STARTED	77	76	0	0	0
COMPLETED	69	66	0	0	0
NOT COMPLETED	8	10	0	0	0
Period Title: Double-Blind Phase
STARTED	0	0	69	67	32
COMPLETED	0	0	63	65	27
NOT COMPLETED	0	0	6	2	5

Baseline Characteristics

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR	Total
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily	Total of all reporting groups
Overall Participants	73	70	143
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.4 (11.48)	29.4 (12.78)	28.9 (12.10)
Gender (Count of Participants)
Female	38 52.1%	32 45.7%	70 49%
Male	35 47.9%	38 54.3%	73 51%
Race/Ethnicity, Customized (participants) [Number]
African American/African Heritage	1 1.4%	2 2.9%	3 2.1%
Asian	31 42.5%	31 44.3%	62 43.4%
White	38 52.1%	37 52.9%	75 52.4%
American Indian or Alaskan Native and White	2 2.7%	0 0%	2 1.4%
Asian and White	1 1.4%	0 0%	1 0.7%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Weekly Primary Generalized Tonic-clonic (PGTC) Seizure Frequency During the Entire Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline through end of Double-Blind Treatment Phase (up to Week 19)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants who took at least one dose of study drug and had at least one post-baseline efficacy assessment in the Double-Blind Treatment Phase. One participant in each treatment group did not have any PGTC seizures during the Baseline Phase.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	72	69
Median (Full Range) [percent change]	32.1	75.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-Blind Phase: Placebo, Double-Blind Phase: LTG XR
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	31.6
	Confidence Interval	() 95%; 15.8 to 48.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	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
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

ITT Population. One participant in each treatment group did not have any PGTC seizures during the Baseline Phase, as a result they were not counted in this efficacy endpoint; an additional 2 and 1 participants in the Placebo and LTG XR group, respectively, were not counted in the Maintenance Phase (MP) or last 8 weeks of MP due to study withdrawal.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	72	69
>=25% reduction, Entire DB TP, n=72, 69	43 58.9%	56 80%
>=50% reduction, Entire DB TP, n=72, 69	23 31.5%	48 68.6%
>=75% reduction, Entire DB TP, n=72, 69	14 19.2%	35 50%
100% reduction, Entire DB TP, n=72, 69	7 9.6%	14 20%
>=25% reduction, Escalation Phase, n=72, 69	39 53.4%	51 72.9%
>=50% reduction, Escalation Phase, n=72, 69	23 31.5%	38 54.3%
>=75% reduction, Escalation Phase, n=72, 69	14 19.2%	24 34.3%
100% reduction, Escalation Phase, n=72, 69	9 12.3%	15 21.4%
>=25% reduction, Maintenance Phase, n=70, 68	46 63%	60 85.7%
>=50% reduction, Maintenance Phase, n=70, 68	29 39.7%	51 72.9%
>=75% reduction, Maintenance Phase, n=70, 68	14 19.2%	40 57.1%
100% reduction, Maintenance Phase, n=70, 68	10 13.7%	31 44.3%
>=25% reduction, Last 8 Weeks of MP, n=70, 68	47 64.4%	61 87.1%
>=50% reduction, Last 8 Weeks of MP, n=70, 68	29 39.7%	54 77.1%
>=75% reduction, Last 8 Weeks of MP, n=70, 68	18 24.7%	44 62.9%
100% reduction, Last 8 Weeks of MP, n=70, 68	15 20.5%	35 50%

3. Secondary Outcome

Title	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
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

ITT Population. One participant in each treatment group did not have any PGTC seizures during the Baseline Phase as a result they were not counted for this efficacy endpoint; an additional 2 and 1 participants in the Placebo and LTG XR group, respectively, were not counted in the Maintenance Phase (MP) or last 8 weeks of MP due to study withdrawal.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	72	69
Escalation Phase, n=72, 69	30.6	61.9
Maintenance Phase, n=70, 68	33.3	89.7
Last 8 weeks of the Maintenance Phase, n=70, 68	35.4	100.0

4. Secondary Outcome

Title	Number of Participants With the Indicated Time to >=50% Reduction in Seizure Frequency in the Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline through end of Double-Blind Treatment Phase (up to Week 19)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	73	70
2 weeks	12 16.4%	22 31.4%
4 weeks	12 16.4%	28 40%
8 weeks	14 19.2%	39 55.7%
12 weeks	20 27.4%	43 61.4%
16 weeks	23 31.5%	48 68.6%

5. Secondary Outcome

Title	Change From Baseline in Body Weight at Week 19 of the Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	73	70
Median (Full Range) [kilograms]	1.00	0.00

6. Secondary Outcome

Title	Number of Participants With Improved Clinical Status on the Investigator's Global Assessment in the Double-Blind Treatment Phase
Description	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.
Time Frame	Week 19 (or last on-study assessment in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. Overall clinical status not assessed for 2 participants in each of the Placebo and LTG XR groups, respectively.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	71	68
Any improvement, score of 5-7	36 49.3%	57 81.4%
No change, score of 4	33 45.2%	10 14.3%
Any deterioration, score of 1-3	2 2.7%	1 1.4%

7. Secondary Outcome

Title	Number of Participants With Improved Satisfaction With Seizure Control on the Subject Satisfaction Questionnaire in the Double-Blind Treatment Phase
Description	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).
Time Frame	Week 19 (or last on-study assessment in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. Participant satisfaction was not assessed for 2 participants in each of the Placebo and LTG XR groups, respectively.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	71	68
Any improvement, score of 5-7	53 72.6%	60 85.7%
No change, score of 4	13 17.8%	6 8.6%
Any deterioration, score of 1-3	5 6.8%	2 2.9%

8. Secondary Outcome

Title	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
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

ITT Population for CP: all participants who took at least one dose of study medication during the CP and had at least one post baseline seizure assessment during the CP. Variability in participant numbers are due to not having any PGTC seizures during the Baseline Phase and study withdrawal prior to progressing to the next phase.

Arm/Group Title	Continuation Phase: Placebo/LTG	Continuation Phase: LTG/LTG	Baseline Failures
Arm/Group Description	Placebo participants who entered the CP	LTG XR participants who entered the CP	Baseline failures who entered the CP
Measure Participants	68	66	24
Entire Continuation Phase, n=68, 66, 24	85.2	95.1	21.7
Transition Phase, n=68, 66, 20	73.1	100.0	100.0
Open-Label Phase, n=68, 64, 23	89.2	95.0	31.7
Last 8 weeks of Open-Label Phase, n=68, 63, 19	100.0	100.0	100.0

9. Secondary Outcome

Title	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.
Description	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.
Time Frame	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)

Outcome Measure Data

Analysis Population Description

ITT Population for CP. Variability in participant numbers are due to not having any PGTC seizures during the Baseline Phase and study withdrawal prior to progressing to the next phase.

Arm/Group Title	Continuation Phase: Placebo/LTG	Continuation Phase: LTG/LTG	Baseline Failures
Arm/Group Description	Placebo participants who entered the CP	LTG XR participants who entered the CP	Baseline failures who entered the CP
Measure Participants	68	66	24
>=25% reduction, Entire CP, n=68, 66, 24	59 80.8%	63 90%	11 7.7%
>=50% reduction, Entire CP, n=68, 66, 24	57 78.1%	59 84.3%	11 7.7%
>=75% reduction, Entire CP, n=68, 66, 24	46 63%	49 70%	8 5.6%
100% reduction, Entire CP, n=68, 66, 24	16 21.9%	28 40%	6 4.2%
>=50% increase, Entire CP, n=68, 66, 24	2 2.7%	1 1.4%	10 7%
>=25% reduction, Transition Phase, n=68, 66, 20	51 69.9%	60 85.7%	13 9.1%
>=50% reduction, Transition Phase, n=68, 66, 20	44 60.3%	56 80%	12 8.4%
>=75% reduction, Transition Phase, n=68, 66, 20	33 45.2%	46 65.7%	12 8.4%
100% reduction, Transition Phase, n=68, 66, 20	27 37%	41 58.6%	12 8.4%
>=50% increase, Transition Phase, n=68, 66, 20	3 4.1%	1 1.4%	3 2.1%
>=25% reduction, Open-Label Phase, n=68, 64, 23	61 83.6%	61 87.1%	12 8.4%
>=50% reduction, Open-Label Phase, n=68, 64, 23	56 76.7%	57 81.4%	10 7%
>=75% reduction, Open-Label Phase, n=68, 64, 23	47 64.4%	49 70%	8 5.6%
100% reduction, Open-Label Phase, n=68, 64, 23	21 28.8%	28 40%	6 4.2%
>=50% increase, Open-Label Phase, n=68, 64, 23	2 2.7%	1 1.4%	10 7%
>=25% reduction, Last 8 W of OL Phase,n=68, 63, 19	60 82.2%	60 85.7%	10 7%
>=50% reduction, Last 8 W of OL Phase,n=68, 63, 19	53 72.6%	53 75.7%	10 7%
>=75% reduction, Last 8 W of OL Phase,n=68, 63, 19	45 61.6%	47 67.1%	10 7%
100% reduction, Last 8 W of OL Phase, n=68, 63, 19	35 47.9%	41 58.6%	10 7%
>=50% increase, Last 8 W of OL Phase, n=68, 63, 19	2 2.7%	1 1.4%	4 2.8%

10. Secondary Outcome

Title	Mean Change From Baseline in the Profile of Mood State (POMS) Mood Disturbance Total Score at Week 19 of the Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 53 and 57 participants in the Placebo and LTG XR groups, respectively. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	20	13
Least Squares Mean (Standard Error) [points on a scale]	2.4 (6.97)	9.7 (8.65)

11. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 64 and 59 participants in the Placebo and LTG XR groups, respectively. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	9	11
Least Squares Mean (Standard Error) [points on a scale]	2.9 (2.81)	2.4 (2.54)

12. Secondary Outcome

Title	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
Description	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).
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 65 participants in both the Placebo and LTG XR groups. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	8	5
Least Squares Mean (Standard Error) [points on a scale]	-0.1 (0.98)	-2.4 (1.24)

13. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 55 participants in both the Placebo and LTG XR groups. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	18	15
Least Squares Mean (Standard Error) [points on a scale]	-6.5 (3.97)	-8.5 (4.35)

14. Secondary Outcome

Title	Mean Change From Baseline in the Adverse Experience Profile (AEP) Total Score at Week 19 of the Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 65 participants in both the Placebo and LTG XR groups. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	8	5
Least Squares Mean (Standard Error) [points on a scale]	3.0 (2.16)	1.4 (2.77)

15. Secondary Outcome

Title	Mean Change From Baseline in the Seizure Severity Questionnaire (SSQ) Global Bother Score at Week 19 Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 68 and 67 participants in the Placebo and LTG XR groups, respectively. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	5	3
Least Squares Mean (Standard Error) [points on a scale]	0.86 (0.84)	1.23 (1.08)

16. Secondary Outcome

Title	Mean Change From Baseline in the Epworth Sleepiness Scale (ESS) 8-Item Total Score at Week 19 of the Double-Blind Treatment Phase
Description	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.
Time Frame	Baseline and Week 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

ITT Population. The questionnaire was not completed by 55 and 51 participants in the Placebo and LTG XR groups, respectively. Only participants completing the questionnaire were included in the analysis of this outcome measure.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	18	19
Least Squares Mean (Standard Error) [points on a scale]	-0.6 (0.69)	1.0 (0.67)

17. Secondary Outcome

Title	Serum Concentrations and Population (POP) Pharmacokinetic Parameters for Lamotrigine
Description	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.
Time Frame	Blood samples drawn at Treatment Weeks 11, 15, and 19 (or last on-study measurement in Double-Blind Treatment Phase)

Outcome Measure Data

Analysis Population Description

PK Population: Number of participants analyzed for 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.

Arm/Group Title	Double-Blind Phase: Placebo	Double-Blind Phase: LTG XR
Arm/Group Description	Control - matching placebo once daily	LTG XR once daily
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	Serious adverse events (SAEs) and adverse events (AEs) were collected for all participants in the Safety Population. The Safety Population was defined as all participants who took at least one dose of study drug.
Arm/Group Title	Double-Blind Phase: Placebo		Double-Blind Phase: LTG XR		Continuation Phase: Placebo/LTG		Continuation Phase: LTG/LTG		Baseline Failures
Arm/Group Description	Control - matching placebo once daily		Lamotrigine (LTG) extended release (XR) once daily		Participants who received placebo in the Double-Blind Phase and then entered the CP, in which they received LTG		Participants who received LTG XR in the Double-Blind Phase and then entered the CP, in which they received LTG		Baseline failures who entered the CP without receiving treatment in the Double-Blind Phase. Baseline Failures were participants that successfully progressed through the Screening Phase and completed the Baseline Phase of the Double-blind Study, but ultimately did not meet the seizure frequency criteria for randomization into the Double-Blind Treatment Phase of the study. As a result, they were not counted as having started in the Double-Blind Study, but were eligible to enter the CP of the study.
All Cause Mortality
	Double-Blind Phase: Placebo		Double-Blind Phase: LTG XR		Continuation Phase: Placebo/LTG		Continuation Phase: LTG/LTG		Baseline Failures
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Double-Blind Phase: Placebo		Double-Blind Phase: LTG XR		Continuation Phase: Placebo/LTG		Continuation Phase: LTG/LTG		Baseline Failures
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/74 (0%)		1/72 (1.4%)		3/69 (4.3%)		3/67 (4.5%)		1/32 (3.1%)
Gastrointestinal disorders
Abdominal pain	0/74 (0%)		0/72 (0%)		0/69 (0%)		0/67 (0%)		1/32 (3.1%)
Nausea	0/74 (0%)		0/72 (0%)		0/69 (0%)		0/67 (0%)		1/32 (3.1%)
Vomiting	0/74 (0%)		0/72 (0%)		0/69 (0%)		0/67 (0%)		1/32 (3.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bile duct cancer	0/74 (0%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		0/32 (0%)
Uterine leiomyoma	0/74 (0%)		0/72 (0%)		0/69 (0%)		1/67 (1.5%)		0/32 (0%)
Nervous system disorders
Altered state of consciousness	0/74 (0%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		0/32 (0%)
Ataxia	0/74 (0%)		0/72 (0%)		0/69 (0%)		0/67 (0%)		1/32 (3.1%)
Hemiparesis	0/74 (0%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		0/32 (0%)
Hydrocephalus	0/74 (0%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		0/32 (0%)
Nystagmus	0/74 (0%)		0/72 (0%)		0/69 (0%)		0/67 (0%)		1/32 (3.1%)
Syncope vasovagal	0/74 (0%)		0/72 (0%)		0/69 (0%)		1/67 (1.5%)		0/32 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/74 (0%)		0/72 (0%)		0/69 (0%)		1/67 (1.5%)		0/32 (0%)
Psychiatric disorders
Confusional state	0/74 (0%)		1/72 (1.4%)		0/69 (0%)		0/67 (0%)		0/32 (0%)
Conversion disorder	0/74 (0%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		0/32 (0%)
Suicide attempt	0/74 (0%)		0/72 (0%)		0/69 (0%)		0/67 (0%)		1/32 (3.1%)
Other (Not Including Serious) Adverse Events
	Double-Blind Phase: Placebo		Double-Blind Phase: LTG XR		Continuation Phase: Placebo/LTG		Continuation Phase: LTG/LTG		Baseline Failures
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/74 (28.4%)		27/72 (37.5%)		29/69 (42%)		21/67 (31.3%)		18/32 (56.3%)
Eye disorders
Diplopia	1/74 (1.4%)		4/72 (5.6%)		4/69 (5.8%)		1/67 (1.5%)		2/32 (6.3%)
Vision blurred	0/74 (0%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		2/32 (6.3%)
Gastrointestinal disorders
Vomiting	3/74 (4.1%)		7/72 (9.7%)		5/69 (7.2%)		2/67 (3%)		2/32 (6.3%)
Nausea	4/74 (5.4%)		5/72 (6.9%)		1/69 (1.4%)		1/67 (1.5%)		5/32 (15.6%)
Diarrhoea	0/74 (0%)		1/72 (1.4%)		3/69 (4.3%)		1/67 (1.5%)		2/32 (6.3%)
Abdominal pain	3/74 (4.1%)		0/72 (0%)		1/69 (1.4%)		0/67 (0%)		2/32 (6.3%)
General disorders
Pyrexia	4/74 (5.4%)		5/72 (6.9%)		7/69 (10.1%)		5/67 (7.5%)		3/32 (9.4%)
Pain	2/74 (2.7%)		2/72 (2.8%)		3/69 (4.3%)		2/67 (3%)		2/32 (6.3%)
Fatigue	2/74 (2.7%)		1/72 (1.4%)		1/69 (1.4%)		0/67 (0%)		3/32 (9.4%)
Infections and infestations
Nasopharyngitis	1/74 (1.4%)		2/72 (2.8%)		4/69 (5.8%)		4/67 (6%)		2/32 (6.3%)
Nervous system disorders
Headache	12/74 (16.2%)		10/72 (13.9%)		11/69 (15.9%)		5/67 (7.5%)		9/32 (28.1%)
Dizziness	5/74 (6.8%)		4/72 (5.6%)		7/69 (10.1%)		4/67 (6%)		7/32 (21.9%)
Tremor	0/74 (0%)		4/72 (5.6%)		5/69 (7.2%)		3/67 (4.5%)		3/32 (9.4%)
Ataxia	0/74 (0%)		0/72 (0%)		2/69 (2.9%)		2/67 (3%)		2/32 (6.3%)
Somnolence	0/74 (0%)		1/72 (1.4%)		1/69 (1.4%)		2/67 (3%)		2/32 (6.3%)
Skin and subcutaneous tissue disorders
All rash	4/74 (5.4%)		2/72 (2.8%)		2/69 (2.9%)		1/67 (1.5%)		2/32 (6.3%)

Limitations/Caveats

[Not Specified]

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Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.