Epilepsy
Conditions
Brief summary
This is a multi-center, uncontrolled, open-label study conducted in Japan and South Korea to evaluate the efficacy and safety of lamotrigine monotherapy in subjects with newly diagnosed epilepsy and those with recurrent epilepsy (currently untreated). The study is composed of baseline, escalation phase, maintenance phase, taper phase and post study examination. During the escalation phase, the investigational product is administered orally at 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks and finally 100 mg/day for 2 weeks. During the maintenance phase, 200 mg/day is administered orally for 24 weeks. However, the dose can be decreased to 100 mg/day if there are safety concerns. Also, if it is confirmed that the seizures cannot be controlled at the dose of 200 mg/day, the dose can be gradually increased up to 400 mg/day by 50-100 mg/day at intervals of at least 1 week. As a rule, lamotrigine should be administered once daily (in the evening), but the dose exceeding 200 mg/day can be administered in two divided doses (in the morning and evening). After the completion of maintenance phase, Japanese subjects who have responded to lamotrigine without tolerability issues are eligible to enter an extension phase of the study if indicated, until either approval of this indication (monotherapy in epilepsy) or after 24 months after LSLV (Last Subject's Last Visit) of the maintenance phase, whichever is sooner.
Interventions
DRUGLamictal
No comparison.
Sponsors
GlaxoSmithKline
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Target disease: Subjects with newly diagnosed epilepsy or recurrent epilepsy which is untreated, having the following seizure types as classified by the International Classification of Seizures. * Partial seizures (with or without secondarily generalisation) * Generalized tonic-clonic seizures without focal onset, with or without myoclonus but without other generalized seizure type(s). 2. Subjects have a confident diagnosis of epilepsy uncomplicated by pseudoseizures (psychogenic nonepileptic seizures). 3. Subjects have had at least 2 seizures in the previous 6 months with at least 1 seizure in the previous 3 months. 4. Age: ≥16 years (at the time of obtaining consent) 5. Outpatients 6. Subjects are able to write a seizure diary. 7. Subjects understand and sign written informed consent. If a subject is under 20 years at the time of obtaining consent, a subject and a legally acceptable representative (e.g., a parent or a custodian) sign written consent to participate in this study. 8. Gender: Male or female If female, and of childbearing potential, be using an acceptable form of birth control. 9. 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. 10. Subjects are able to comply with dosing of investigational products and all study procedures.
Exclusion criteria
1. Subjects having seizure types other than partial seizure or generalized tonic clonic seizures with or without myoclonus. Subjects having status epilepticus within the 6 months prior to the start of study treatment. 2. Subjects with a history of treatment with AEDs (≥2 weeks) during 6 months before the start of treatment with the investigational product. 3. Subjects with a history of treatment with lamotrigine. 4. Subjects with a history of rash associated with other AED treatment. 5. Subjects with a history of substance (including alcohol and drugs) dependence within 12 months before the start of investigational product or abuse within 1 month before the start of investigational product according to DSM-IV-TR. 6. 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. 7. Subjects with a severe psychiatric disorder which affects the procedure of study or drug assessment. 8. Subjects with an acute or progressive neurological disorder or an organic disease. 9. Subjects with any clinically significant chronic cardiac, renal, or hepatic medical condition. Any patient with these conditions are excluded from the study even if these conditions are being controlled with chronic therapy. 10. 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). 11. Female subjects who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study. 12. Subjects taking inducers of lamotrigine glucuronidation (i.e., rifampicin, lopinavir/ritonavir), atazanavir/ritonavir, risperidone, oral contraceptives or hormone drug which includes estrogen. 13. Subjects having participated in other clinical study within 3 months before the start of investigational product. 14. 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. 15. Subjects whom the investigator or subinvestigator considers ineligible for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study) | Weeks 7 to 30 | Participants were considered to be seizure free if they did not report any seizures during the Maintenance Phase. Seizure types are defined as: ALL=any type of seizure; A: simple partial seizures, B: complex partial seizures; C: partial seizures evolving to secondary generation seizures; D5: tonic-clonic seizures. Simple partial seizures are seizures that affect only a small region of the brain, often the temporal lobes or hippocampi. Complex partial seizures are epileptic seizures that are associated with bilateral cerebral hemisphere involvement and cause impairment of awareness or responsiveness. Partial seizures evolving to secondary generation seizures are seizures that start as partial seizures, then spread to include the entire brain. Tonic-clonic seizures are a type of generalized seizure that affects the entire brain. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases) | up to Week 30 | Time to withdrawal is defined as the time from the start of treatment until withdrawal from the study. Seizure types are defined as: ALL=any type of seizure; A: simple partial seizures, B: complex partial seizures; C: partial seizures evolving to secondary generation seizures; D5: tonic-clonic seizures. Simple partial seizures are seizures which affect only a small region of the brain, often the temporal lobes or hippocampi. Simple partial seizures are seizures that affect only a small region of the brain, often the temporal lobes or hippocampi. Complex partial seizures are epileptic seizures that are associated with bilateral cerebral hemisphere involvement and cause impairment of awareness or responsiveness. Partial seizures evolving to secondary generation seizures are seizures that start as partial seizures, then spread to include the entire brain. Tonic-clonic seizures are a type of generalized seizure that affects the entire brain. |
| Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type) | Weeks 7 to 30 | The time to the first seizure in the Maintenance Phase is measured at the time the first seizure occurred in the Maintenance Phase. Seizure types are defined as: ALL=any type of seizure; A: simple partial seizures, B: complex partial seizures; C: partial seizures evolving to secondary generation seizures; D5: tonic-clonic seizures. Simple partial seizures are seizures that affect only a small region of the brain, often the temporal lobes or hippocampi. Complex partial seizures are epileptic seizures that are associated with bilateral cerebral hemisphere involvement and cause impairment of awareness or responsiveness. Partial seizures evolving to secondary generation seizures are seizures that start as partial seizures, then spread to include the entire brain. Tonic-clonic seizures are a type of generalized seizure that affects the entire brain. |
Countries
Japan, South Korea
Participant flow
Recruitment details
A total of 70 participants were enrolled; 3 participants were screened but withdrew from the study before prescription of the first investigational product (67), and only 65 of the participants received at least one dose of the investigational product which comprised the safety population.
Pre-assignment details
The study consisted of a 6-week Escalation Phase, a 24-week Maintenance Phase (MP), a \>=2-week Taper Phase, and a post-study examination conducted within 1-4 weeks after the last dose of lamotrigine. In Japan only, the Extension Phase was conducted until either approval for this indication or after 24 months after Last Subject Last Visit in the MP.
Participants by arm
| Arm | Count |
|---|---|
| Lamotrigine In the EP, lamotrigine 25 milligrams per day (mg/day) was orally administered once daily (QD; in the evening \[PM\]) as the initial dose from Week (W) 1 to W2. As a fixed dose escalation, lamotrigine 50 mg/day was orally administered QD (in the PM) from W3 to W4; 100 mg/day was administered from W5 to W6. In the MP, lamotrigine 200 mg/day was orally administered QD (in the PM) from W7 to W30. The dose could have been decreased to 100 mg/day per safety concerns. Per investigator discretion, the investigational product was discontinued if safety concerns remained. If the 200 mg/day dose did not control seizures, the dose could have been increased up to 400 mg/day by 50-100 mg/day at \>=1-week intervals. A dose \>200 mg/day could have been administered in 2 divided doses (in the morning and PM). In the ExP, lamotrigine was administered at 100-400 mg/day based on seizure status/safety. If a dose \<100 or \>400 mg/day was judged to be necessary, the participant was withdrawn from the study. | 65 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 18 |
| Overall Study | Lack of Efficacy | 7 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Protocol-defined Stopping Criteria | 2 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Lamotrigine |
|---|---|
| Age, Continuous | 37.3 Years STANDARD_DEVIATION 20.2 |
| Race/Ethnicity, Customized Asian - East Asian Heritage | 26 participants |
| Race/Ethnicity, Customized Asian - Japanese Heritage | 39 participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 65 |
| serious Total, serious adverse events | 8 / 65 |
Outcome results
Primary
Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study)
Participants were considered to be seizure free if they did not report any seizures during the Maintenance Phase. Seizure types are defined as: ALL=any type of seizure; A: simple partial seizures, B: complex partial seizures; C: partial seizures evolving to secondary generation seizures; D5: tonic-clonic seizures. Simple partial seizures are seizures that affect only a small region of the brain, often the temporal lobes or hippocampi. Complex partial seizures are epileptic seizures that are associated with bilateral cerebral hemisphere involvement and cause impairment of awareness or responsiveness. Partial seizures evolving to secondary generation seizures are seizures that start as partial seizures, then spread to include the entire brain. Tonic-clonic seizures are a type of generalized seizure that affects the entire brain.
Time frame: Weeks 7 to 30
Population: Full Analysis Set (FAS): all participants in the Safety Population (SP) who provided at least one set of efficacy data after the first dosing of investigational product. The SP is comprised of all participants who had taken at least one dose of investigational product. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lamotrigine | Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study) | All, n=65 | 28 participants |
| Lamotrigine | Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study) | A+B+C, n=55 | 22 participants |
| Lamotrigine | Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study) | A+B, n=42 | 17 participants |
| Lamotrigine | Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study) | C, n=33 | 23 participants |
| Lamotrigine | Number of Participants Who Were Seizure Free in the Maintenance Phase (Across Seizure Types and by Seizure Type Within 6 Months Prior to the Start of the Study) | D5, n=10 | 8 participants |
95% CI: [30.85, 55.96]
95% CI: [27.02, 54.09]
95% CI: [25.63, 56.72]
95% CI: [51.29, 84.41]
95% CI: [44.39, 97.48]
Secondary
Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type)
The time to the first seizure in the Maintenance Phase is measured at the time the first seizure occurred in the Maintenance Phase. Seizure types are defined as: ALL=any type of seizure; A: simple partial seizures, B: complex partial seizures; C: partial seizures evolving to secondary generation seizures; D5: tonic-clonic seizures. Simple partial seizures are seizures that affect only a small region of the brain, often the temporal lobes or hippocampi. Complex partial seizures are epileptic seizures that are associated with bilateral cerebral hemisphere involvement and cause impairment of awareness or responsiveness. Partial seizures evolving to secondary generation seizures are seizures that start as partial seizures, then spread to include the entire brain. Tonic-clonic seizures are a type of generalized seizure that affects the entire brain.
Time frame: Weeks 7 to 30
Population: FAS. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lamotrigine | Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type) | All, n=52 | 103.0 Days | Standard Error 9.43 |
| Lamotrigine | Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type) | A+B+C, n=44 | 100.4 Days | Standard Error 10.44 |
| Lamotrigine | Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type) | A+B, n=34 | 94.2 Days | Standard Error 12.22 |
| Lamotrigine | Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type) | C, n=29 | 113.3 Days | Standard Error 12.06 |
| Lamotrigine | Time to the First Seizure in the Maintenance Phase (Across Seizure Types and by Seizure Type) | D5, n=8 | NA Days | — |
Secondary
Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases)
Time to withdrawal is defined as the time from the start of treatment until withdrawal from the study. Seizure types are defined as: ALL=any type of seizure; A: simple partial seizures, B: complex partial seizures; C: partial seizures evolving to secondary generation seizures; D5: tonic-clonic seizures. Simple partial seizures are seizures which affect only a small region of the brain, often the temporal lobes or hippocampi. Simple partial seizures are seizures that affect only a small region of the brain, often the temporal lobes or hippocampi. Complex partial seizures are epileptic seizures that are associated with bilateral cerebral hemisphere involvement and cause impairment of awareness or responsiveness. Partial seizures evolving to secondary generation seizures are seizures that start as partial seizures, then spread to include the entire brain. Tonic-clonic seizures are a type of generalized seizure that affects the entire brain.
Time frame: up to Week 30
Population: FAS. Only those participants available at the specified time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lamotrigine | Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases) | All, n=65 | 150.0 Days | Standard Error 8.99 |
| Lamotrigine | Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases) | A+B+C, n=55 | 148.4 Days | Standard Error 9.72 |
| Lamotrigine | Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases) | A+B, n=42 | 147.9 Days | Standard Error 10.72 |
| Lamotrigine | Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases) | C, n=33 | 168.0 Days | Standard Error 10.91 |
| Lamotrigine | Time to Withdrawal/Dropout From the Study (Across Seizure Types and by Seizure Type in Past 6 Months in the Escalation and Maintenance Phases) | D5, n=10 | 14.6 Days | Standard Error 0.54 |