Clinical Study of Lamotrigine to Treat Newly Diagnosed Typical Absence Seizure in Children and Adolescents

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01431976
• Collaborator: (none)
• Enrollment: 20
• Locations: 14
• Arm: 1
• Duration (Months): 50
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This is a multi-center, uncontrolled, open-label study to evaluate the efficacy and safety of lamotrigine monotherapy on newly diagnosed typical absence seizure in children and adolescents in Japan and South Korea.

The study period is composed the baseline, fixed escalation phase, escalation phase, maintenance phase, taper phase, and post study examination. During the fixed escalation phase, the investigational product is administered at 0.3 mg/kg/day for 2 weeks (Week 1 to 2), followed by 0.6 mg/kg/day for 2 weeks (Week 3 to 4). Subjects thereafter visit the clinic once every 1 to 2 weeks during the escalation phase to increase the dose by 0.6 mg/kg/day up to a maximum of 10.2 mg/kg/day or 400 mg/day (whichever was less) until patients are confirmed to be seizure-free by HV tests for clinical signs. After seizure free is confirmed by HV-clinical signs, the dose is increased by one level and HV-EEG (electroencephalography) test (first test) is assessed at the next visit. If seizure free is observed by HV-EEG, the same dose is administered. Thereafter, HV-EEG (second test) is assessed at the next visit and if seizure free is confirmed again, the subjects enter the 12-week maintenance phase. During the maintenance phase, patients visit the clinic once every 4 weeks. The dose can be adjusted as necessary within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day (whichever was less) taking into account the status of seizures and the safety. The investigational product is administered once daily (in the evening). However, if the number of tablets is large, twice-daily administration (in the morning and evening) is also allowed. After the completion of maintenance phase, subjects who have responded to lamotrigine without tolerability issues are eligible to enter the extension phase of the study if clinically indicated.

Condition or Disease	Intervention/Treatment	Phase
Epilepsy	Drug: Lamictal	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Uncontrolled, Open-label, Evaluation of Lamotrigine Monotherapy on Newly Diagnosed Typical Absence Seizures in Children and Adolescents
• Study Start Date: Sep 1, 2011
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lamotrigine No comparison	Drug: Lamictal; No comparison

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Were Seizure Free as Confirmed by Hyperventilation (HV)-Electroencephalography (EEG) at the End of the Maintenance Phase (MP) [Week 12 of the Maintenance Phase (up to Study Week 50)]

   EEG is a diagnostic test for epilepsy. The EEG machine records the brain's electrical activity as a series of waveforms. HV is an activation technique used to provoke seizures during an EEG recording. An approximately 30-minute EEG with HV was performed on participants in a supine position. In the HV test, participants breathed through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes using a pin-wheel provided to them.

Secondary Outcome Measures

1. Number of Participants Who Were Seizure Free as Confirmed by HV-EEG at Two Consecutive Visits in the Escalation Phase (EP) [Up to Study Week 49]

   EEG is a diagnostic test for epilepsy. The EEG machine records the brain's electrical activity as a series of waveforms. HV is an activation technique used to provoke seizures during an EEG recording. An approximately 30-minute EEG with HV was performed on participants in a supine position. In the HV test, participants breathed through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute ) for 4 continuous minutes using a pin-wheel provided to them.

2. Number of Participants Who Were Seizure Free as Confirmed by HV-clinical Signs at Each Dose During the Escalation Phase [Up to Study Week 49]

   HV is an activation technique used to provoke seizures. Participants were instructed to breathe through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes while sitting using a pin-wheel and were observed for clinical signs of seizures like impairment of consciousness; staring; eye enrollment; eye blinking; chewing movements; hand movement; other automatisms; atonic, tonic, clonic components; autonomic components; or any other signs. During the Escalation Phase, HV-clinical signs were assessed to confirm a status of seizure free. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).

3. Number of Participants Who Were Seizure Free as Confirmed by HV-clinical Signs During Week 4 and Week 8 of the Maintenance Phase [Week 4 and Week 8 of the Maintenance Phase (up to Study Weeks 42 and 46, respectively)]

   HV is an activation technique used to provoke seizures. Participants were instructed to breathe through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes while sitting using a pin-wheel and were observed for clinical signs of seizures like impairment of consciousness; staring; eye enrollment; eye blinking; chewing movements; hand movement; other automatisms; atonic, tonic, clonic components; autonomic components; or any other signs. During the Maintenace Phase, HV-clinical signs were assessed at Visit 1 (Week 4) and Visit 2 (Week 4).

4. Number of Participants Who Were Seizure Free as Confirmed by HV-EEG at Each Assessment Point in the Extension Phase (ExP) [Extension Week 12 (Extension Visit 1 [Ext-V1]), every 24 weeks after Ext-V1 and until withdrawal]

   EEG is a diagnostic test for epilepsy. The EEG machine records the brain's electrical activity as a series of waveforms. HV is an activation technique used to provoke seizures during an EEG recording. An approximately 30-minute EEG with HV was performed on participants in a supine position. In the HV test, participants breathed through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute ) for 4 continuous minutes using a pin-wheel provided to them. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).

5. Number of Participants Who Were Seizure Free as Confirmed by HV-clinical Signs at Each Assessment Point in the Extension Phase (ExP) [Extension Week 24 (Extension Visit 2 [Ext-V2], every 24 weeks after the Ext-V2 and until withdrawal]

   HV is an activation technique used to provoke seizures. Participants were instructed to breathe through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes while sitting using a pin-wheel and were observed for clinical signs of seizures like impairment of consciousness; staring; eye enrollment; eye blinking; chewing movements; hand movement; other automatisms; atonic, tonic, clonic components; autonomic components; or any other signs. During the ExP, HV-clinical signs were assessed to confirm a status of seizure free. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).

6. Number of Days With Seizure Episodes Per Week in the Main Study Phase (Fixed Escalation Phase [FEP], Escalation Phase [EP], Maintenance Phase [MP]), and FEP+EP+MP) [Up to Study Week 50]

   Participants were asked to record the seizure codes, seizure duration, and their physical condition in a diary provided. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title)

7. Number of Days With Seizure Episodes Per Week in the Extension Phase (ExP) Overall [Extension Week 12 (Extension Visit 1 [Ext-V1], every 12 week after Ext-V1 and until withdrawal]

   Participants were asked to record the seizure codes, seizure duration, and their physical condition in a diary provided.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 15 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Target disease: Subjects with newly diagnosed and untreated typical absence seizure which is classifiable by the International Classification of Seizures.

2. Diagnosis of typical absence seizures is established by at least one of two 4-minute hyperventilation tests as supported by clinical signs and EEG findings.

The following criteria will be used to define a typical absence seizure on the EEG: a discharge of generalized spike-and-wave or multiple spike-and-wave activity lasting ≥3 seconds during the awake state. The frequency of the spike-and-wave should be between 2.5-4.5 Hz.

1. Age (at the time of obtaining consent):

• 2 to 15 years of age in Japan

• 2 to 12 years of age in South Korea

1. Subjects must weigh at least 7 kg

2. Outpatients

3. Parent/guardian must have given written informed consent. Subjects who are intellectually able to understand the concepts and procedures of the protocol must give assent by also signing the consent.

4. Gender: Male or female

5. QTc<450 millisecond (msec) or <480msec for subjects with Bundle Branch Block - values based on either single ECG values or triplicate ECG averaged QTc values obtained over a brief recording period.

Exclusion Criteria:

1. Subjects with partial seizure or generalized seizures other than typical absence.

2. Subjects with a history of rash associated with other treatment.

3. Subjects with any clinically significant chronic cardiac, renal, or hepatic medical condition. Any patient with these conditions will be excluded from the study even if these conditions are being controlled with chronic therapy.

4. Subjects with an acute or chronic illness likely to impair drug absorption, distribution, metabolism or excretion or with any unstable physical symptoms likely to require hospitalization during participation in the study.

5. Subjects with a psychiatric disorder requiring medication, or who had psychiatric conditions in the past that was both judged to be severe and required hospitalization.

6. Subjects with an acute or progressive neurological disorder or an organic disease.

7. Subjects with currently taking any psychoactive drugs to treat hyperactivity disorder or attention deficit disorder.

8. Subjects with an unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

9. Female subjects who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study.

10. Children in foster care: A child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. This can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The definition of a child in care does not include a child who is adopted or who has an appointed legal guardian.

11. Subjects taking inducers of lamotrigine glucuronidation (i.e., rifampicin, lopinavir/ritonavir), atazanavir/ritonavir, risperidone, oral contraceptives or hormone drug which includes estrogen.

12. Subjects having participated in other clinical study in the past 3 months before the start of investigational product.

13. Subjects who have active suicidal plan/intent or have had active suicidal thoughts in the past 3 months before the start of investigational product or who have history of suicide attempt in the last 1 year before the start of investigational product or more than 1 lifetime suicide attempt.

14. Subjects whom the investigator (or subinvestigator) considers ineligible for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Aichi		Japan	453-8511
2	GSK Investigational Site	Ehime		Japan	790-8524
3	GSK Investigational Site	Ehime		Japan	791-0295
4	GSK Investigational Site	Fukuoka		Japan	807-8555
5	GSK Investigational Site	Fukuoka		Japan	814-0180
6	GSK Investigational Site	Hiroshima		Japan	730-8518
7	GSK Investigational Site	Hokkaido		Japan	006-0041
8	GSK Investigational Site	Hokkaido		Japan	060-8648
9	GSK Investigational Site	Kanagawa		Japan	232-8555
10	GSK Investigational Site	Niigata		Japan	950-2085
11	GSK Investigational Site	Okayama		Japan	700-8558
12	GSK Investigational Site	Shizuoka		Japan	430-8558
13	GSK Investigational Site	Tokyo		Japan	113-8603
14	GSK Investigational Site	Seoul		Korea, Republic of	120-752

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: NCT01431976
• Other Study ID Numbers: 115377
• First Posted: Sep 12, 2011
• Last Update Posted: Mar 8, 2017
• Last Verified: Jan 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Seizures; Epilepsy, Absence; Lamotrigine

Study Results

Participant Flow

Recruitment Details	Participants with newly diagnosed and untreated typical absence seizure; aged 2-15 years in Japan, 2-12 years in South Korea at the time of obtaining consent; weighing at least 7 kilograms (kg); without partial seizure or generalized seizures other than typical absence; and without a history of rash associated with other treatment were enrolled.
Pre-assignment Detail	The study consisted of an Escalation Phase (EP), a 12-week (W) Maintenance Phase (MP), a >=2-week Taper Phase, and post-study examination within 1-4 weeks after the last dose of lamotrigine. Participants could have entered the Extension Phase (ExP) until approval for this indication or until 24 months after the Last Subject Last Visit in the MP.

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 milligrams per kilogram per day (mg/kg/day) was administered orally once daily from Week W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, whichever was less (WWL), until a seizure-free (SF) status was confirmed by hyperventilation (HV)-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Period Title: Overall Study
STARTED	20
COMPLETED	6
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Overall Participants	20
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	7.7 (1.95)
Sex: Female, Male (Count of Participants)
Female	13 65%
Male	7 35%
Race/Ethnicity, Customized (participants) [Number]
East Asian Heritage	3 15%
Japanese Heritage	16 80%
South East Asian Heritage	1 5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Were Seizure Free as Confirmed by Hyperventilation (HV)-Electroencephalography (EEG) at the End of the Maintenance Phase (MP)
Description	EEG is a diagnostic test for epilepsy. The EEG machine records the brain's electrical activity as a series of waveforms. HV is an activation technique used to provoke seizures during an EEG recording. An approximately 30-minute EEG with HV was performed on participants in a supine position. In the HV test, participants breathed through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes using a pin-wheel provided to them.
Time Frame	Week 12 of the Maintenance Phase (up to Study Week 50)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all participants who took at least one dose of investigational product and contributed data to at least one efficacy measure after the first dosing of investigational product

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	20
Number [Participants]	7 35%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lamotrigine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	percentage of participants
	Estimated Value	35.0
	Confidence Interval	(2-Sided) 95%; 15.39 to 59.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Who Were Seizure Free as Confirmed by HV-EEG at Two Consecutive Visits in the Escalation Phase (EP)
Description	EEG is a diagnostic test for epilepsy. The EEG machine records the brain's electrical activity as a series of waveforms. HV is an activation technique used to provoke seizures during an EEG recording. An approximately 30-minute EEG with HV was performed on participants in a supine position. In the HV test, participants breathed through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute ) for 4 continuous minutes using a pin-wheel provided to them.
Time Frame	Up to Study Week 49

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	20
Number [Participants]	8 40%

3. Secondary Outcome

Title	Number of Participants Who Were Seizure Free as Confirmed by HV-clinical Signs at Each Dose During the Escalation Phase
Description	HV is an activation technique used to provoke seizures. Participants were instructed to breathe through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes while sitting using a pin-wheel and were observed for clinical signs of seizures like impairment of consciousness; staring; eye enrollment; eye blinking; chewing movements; hand movement; other automatisms; atonic, tonic, clonic components; autonomic components; or any other signs. During the Escalation Phase, HV-clinical signs were assessed to confirm a status of seizure free. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
Time Frame	Up to Study Week 49

Outcome Measure Data

Analysis Population Description

FAS. Only those participants given the indicated dose of investigational product were analyzed.

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	20
0.6 mg/kg, n=17	1 5%
1.2 mg/kg, n=17	1 5%
1.8 mg/kg, n=16	2 10%
2.4 mg/kg, n=16	2 10%
3.0 mg/kg, n=16	2 10%
3.6 mg/kg, n=15	1 5%
4.2 mg/kg, n=15	0 0%
4.8 mg/kg, n=14	4 20%
5.4 mg/kg, n=14	1 5%
6.0 mg/kg, n=11	1 5%
6.6 mg/kg, n=11	0 0%
7.2 mg/kg, n=9	3 15%
7.8 mg/kg, n=9	0 0%
8.4 mg/kg, n=6	2 10%
9.0 mg/kg, n=6	1 5%
9.6 mg/kg, n=1	1 5%

4. Secondary Outcome

Title	Number of Participants Who Were Seizure Free as Confirmed by HV-clinical Signs During Week 4 and Week 8 of the Maintenance Phase
Description	HV is an activation technique used to provoke seizures. Participants were instructed to breathe through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes while sitting using a pin-wheel and were observed for clinical signs of seizures like impairment of consciousness; staring; eye enrollment; eye blinking; chewing movements; hand movement; other automatisms; atonic, tonic, clonic components; autonomic components; or any other signs. During the Maintenace Phase, HV-clinical signs were assessed at Visit 1 (Week 4) and Visit 2 (Week 4).
Time Frame	Week 4 and Week 8 of the Maintenance Phase (up to Study Weeks 42 and 46, respectively)

Outcome Measure Data

Analysis Population Description

FAS. Only those participants who were dosed with investigational product at the indicated time points were analyzed.

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	7
Week 4	7 35%
Week 8	7 35%

5. Secondary Outcome

Title	Number of Participants Who Were Seizure Free as Confirmed by HV-EEG at Each Assessment Point in the Extension Phase (ExP)
Description	EEG is a diagnostic test for epilepsy. The EEG machine records the brain's electrical activity as a series of waveforms. HV is an activation technique used to provoke seizures during an EEG recording. An approximately 30-minute EEG with HV was performed on participants in a supine position. In the HV test, participants breathed through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute ) for 4 continuous minutes using a pin-wheel provided to them. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
Time Frame	Extension Week 12 (Extension Visit 1 [Ext-V1]), every 24 weeks after Ext-V1 and until withdrawal

Outcome Measure Data

Analysis Population Description

FAS. Only those participants given the indicated dose of investigational product were analyzed.

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	20
Extension Week 12, n=7	6 (1.568) 30%
Extension Week 36, n=7	5 (2.114) 25%
Extension Week 60, n=7	6 (0.161) 30%
Extension Week 84, n=6	6 (2.197) 30%
Extension Week 108, n=6	6 30%
Extension Week 132, n=6	6 30%
Extension Week 156, n=2	2 10%

6. Secondary Outcome

Title	Number of Participants Who Were Seizure Free as Confirmed by HV-clinical Signs at Each Assessment Point in the Extension Phase (ExP)
Description	HV is an activation technique used to provoke seizures. Participants were instructed to breathe through their mouths deeply and rapidly (at a rate of approximately 20-25 breaths/minute) for 4 continuous minutes while sitting using a pin-wheel and were observed for clinical signs of seizures like impairment of consciousness; staring; eye enrollment; eye blinking; chewing movements; hand movement; other automatisms; atonic, tonic, clonic components; autonomic components; or any other signs. During the ExP, HV-clinical signs were assessed to confirm a status of seizure free. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title).
Time Frame	Extension Week 24 (Extension Visit 2 [Ext-V2], every 24 weeks after the Ext-V2 and until withdrawal

Outcome Measure Data

Analysis Population Description

FAS. Only those participants given the indicated dose of investigational product were analyzed.

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	20
Extension Week 24, n=7	5 25%
Extension Week 48, n=7	6 30%
Extension Week 72, n=7	5 25%
Extension Week 96, n=6	6 30%
Extension Week 120, n=6	5 25%
Extension Week 144, n=4	2 10%
Extension Week 168, n=1	1 5%

7. Secondary Outcome

Title	Number of Days With Seizure Episodes Per Week in the Main Study Phase (Fixed Escalation Phase [FEP], Escalation Phase [EP], Maintenance Phase [MP]), and FEP+EP+MP)
Description	Participants were asked to record the seizure codes, seizure duration, and their physical condition in a diary provided. Only participants data available at the analysis time point were analyzed (represented as n=X, X, X in category title)
Time Frame	Up to Study Week 50

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	20
Fixed Escalation Phase, n=20	4.93 (1.488)
Escalation Phase, n=17	2.60 (2.060)
Maintenance Phase, n=8	0.06 (0.161)
FEP+EP+MP, n=20	2.98 (1.976)

8. Secondary Outcome

Title	Number of Days With Seizure Episodes Per Week in the Extension Phase (ExP) Overall
Description	Participants were asked to record the seizure codes, seizure duration, and their physical condition in a diary provided.
Time Frame	Extension Week 12 (Extension Visit 1 [Ext-V1], every 12 week after Ext-V1 and until withdrawal

Outcome Measure Data

Analysis Population Description

FAS. Only those participants given the indicated dose of investigational product were analyzed.

Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
Measure Participants	7
Mean (Standard Deviation) [Days]	0.03 (0.048)

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected from study medication start until the end of treatment (up to Study Week 50) (EP, MP, and ExP).
Adverse Event Reporting Description	SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants who had taken at least one dose of investigational product.
Arm/Group Title	Lamotrigine
Arm/Group Description	In the EP, lamotrigine 0.3 mg/kg/day was administered orally once daily from W1 to W2, and 0.6 mg/kg/day from W3 to W4. From W5, the dose was escalated by 0.6 mg/kg/day once every 1 or 2 weeks, up to a maximum of 10.2 mg/kg/day or 400 mg/day, WWL, until a SF status was confirmed by HV-clinical signs. After a SF confirmation, the dose was increased by one level and HV-electroencephalography was assessed twice at the same dose level to confirm the SF status. In the MP, the same dose was continued for 12 weeks. An increase/decrease in dose (0.6 mg/kg/day at >=1-week intervals) was allowed within the range of 1.2 to 10.2 mg/kg/day or 400 mg/day, WWL. In the ExP, doses of 1.2 to 10.2 mg/kg/day or 400 mg/day (WWL) were administered based on seizure status/safety. If a dose <1.2 mg/kg/day or >10.2 mg/kg/day or 400 mg/day (WWL) was necessary, the participant was withdrawn from the study.
All Cause Mortality
	Lamotrigine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lamotrigine
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Other (Not Including Serious) Adverse Events
	Lamotrigine
	Affected / at Risk (%)	# Events
Total	17/20 (85%)
Gastrointestinal disorders
Stomatitis	2/20 (10%)
Abdominal pain	1/20 (5%)
Constipation	1/20 (5%)
Diarrhoea	1/20 (5%)
Enteritis	1/20 (5%)
Enterocolitis	1/20 (5%)
General disorders
Pain	1/20 (5%)
Immune system disorders
Drug hypersensitivity	1/20 (5%)
Seasonal allergy	1/20 (5%)
Infections and infestations
Bronchitis	5/20 (25%)
Nasopharyngitis	7/20 (35%)
Upper respiratory tract infection	3/20 (15%)
Cellulitis	1/20 (5%)
Gastroenteritis	1/20 (5%)
Influenza	5/20 (25%)
Paronychia	1/20 (5%)
Pharyngitis	2/20 (10%)
Pneumonia mycoplasmal	1/20 (5%)
Scarlet fever	1/20 (5%)
Varicella	2/20 (10%)
Adenovirus infection	1/20 (5%)
Folliculitis	1/20 (5%)
Otitis media acute	1/20 (5%)
Rhinitis	1/20 (5%)
Sinusitis	1/20 (5%)
Conjunctivitis	2/20 (10%)
Injury, poisoning and procedural complications
Fracture	1/20 (5%)
Arthropod bite	1/20 (5%)
Arthropod sting	3/20 (15%)
Chillblains	1/20 (5%)
Skin abrasion	1/20 (5%)
Hand fracture	1/20 (5%)
Investigations
Alanine aminotransferase increased	1/20 (5%)
Aspartate aminotransferase increased	1/20 (5%)
Metabolism and nutrition disorders
Decreased appetite	1/20 (5%)
Dehydration	1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	1/20 (5%)
Nervous system disorders
Headache	4/20 (20%)
Psychomotor hyperactivity	1/20 (5%)
Febrile convulsion	1/20 (5%)
Renal and urinary disorders
Proteinuria	1/20 (5%)
Hematuria	1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/20 (5%)
Epistaxis	1/20 (5%)
Skin and subcutaneous tissue disorders
Rash	6/20 (30%)
Drug eruption	2/20 (10%)
Dermatitis atopic	1/20 (5%)
Eczema	2/20 (10%)
Acne	1/20 (5%)
Dry skin	1/20 (5%)
Urticaria	1/20 (5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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.