Epilepsy, Partial
Conditions
Keywords
epilepsy, lamotrigine, Lamictal, monotherapy
Brief summary
This study is being conducted to determine the effectiveness of a lower monotherapy dose of lamotrigine than that currently approved.
Detailed description
The study consists of a Treatment phase, where efficacy is determined and a Continuation phase for extended safety information. The Continuation phase is open to all Treatment phase participants and those who did not qualify for treatment because of an insufficient number of seizures during the Baseline phase.
Interventions
DRUGlamotrigine, 300 mg/day
300 mg/day
DRUGlamotrigine, 250 mg/day
250 mg/day
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or Female ≥13 years of age * Have a confident diagnosis of epilepsy with partial seizures for at least 24 weeks prior to the Baseline Phase * Have a documented history of partial seizures such that the investigator must judge that the subject is likely to have at least 4 partial seizures during the 8-week Baseline Phase. * Have experienced at least 4 partial seizures (i.e., simple or complex partial seizures with or without secondary generalization) during an 8-week (i.e., 56 days) prospective Baseline Phase with at least one partial seizure occurring during each 4-week (i.e., 28-day) period. * NOTE: With prior authorization from GlaxoSmithKline (GSK), retrospective data may take the place of up to the first 4 weeks (i.e., first 28 days) of the Baseline Phase for subjects providing reliable documentation of the following: 1. A complete daily seizure diary that includes the number, and type (i.e., simple or complex partial seizures with or without secondary generalization), of seizures experienced each day for up to 28 consecutive days immediately prior to the prospective Baseline Phase 2. Stability of prescribed dosages of background antiepileptic drug (AED) 3. Compliance with background AED All subjects permitted to use retrospective baseline data must complete a minimum of four weeks (i.e., 28 days) of the prospective Baseline Phase. The retrospective plus the prospective Baseline Phases must equal the 56 consecutive days prior to the start of dosing with study drug. * be currently receiving AED monotherapy treatment with a stable regimen of a non-enzyme inducing AED for at least four weeks prior to starting the Baseline Phase. * be able and willing to maintain an accurate, complete, written daily seizure diary, or has a parent/caregiver who is able and willing to maintain and accurate, complete, written daily seizure diary for the entire duration of the study. * be able to comply with the dosing of study drugs, background AED, and all study procedures. * understand and sign written informed consent, or will have a parent or a legally authorized representative who has done so, prior to the performance of any study assessments * if female, and of childbearing potential 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 2 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. 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. NOTE: A pharmacokinetic interaction has been observed between lamotrigine (LTG) and estrogen-based oral contraceptives. Therefore, the use of hormonal therapy (e.g., for contraception or hormone replacement therapy) is not allowed.
Exclusion criteria
* Exhibits any primary generalized seizures (e.g., absence, myoclonic primary generalized tonic-clonic seizures). * Has had status epilepticus within the 24 weeks prior to, or during, the Baseline Phase. * Is taking an enzyme-inducing AED (EIAED - e.g. carbamazepine, phenytoin, phenobarbital, primidone) or is taking more than 1 background AED. * Is currently taking lamotrigine (LTG) or has previously had an adequate trial of LTG. * Is currently taking felbamate * Is using hormone therapy * Is abusing alcohol and/or other substances * 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 as specified in Section 8.1.2 * Is currently following the ketogenic diet. * Is using vagal nerve stimulation * Is planning surgery to control seizures during the study. * Is pregnant, breastfeeding, or planning to become pregnant during the study or within the three weeks after the last dose of study drug. * Is suffering from acute or progressive neurological disease, severe psychiatric disease or severe mental abnormality that is 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Percentage of Participants in the 300 mg/Day Dose Group Who Prematurely Discontinued the Study Between Study Visit 5 (Approximately Week 7) and Visit 9 (End of the Treatment Phase) | From Study Visit 5 through Visit 9 of the Treatment Phase (approximately Week 7 through Week 23) | The percentage of participants prematurely discontinuing the study was calculated as the number of participants who discontinued the study divided by the number who reached Visit 5 minus major protocol violators. The Control group is composed of data from other similar studies and is not part of this study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Discontinuation in the Treatment Phase | From Study Visit 5 through Visit 9 of the Treatment phase (approximately Week 7 through Week 23) | Time (days) until the participant discontinued the study |
| Percentage of Participants Meeting Escape Criteria in the Treatment Phase | Study Visit 5 through Visit 9 of the Treatment phase (approximately Week 7 through Week 23) | The percentage of participants meeting Escape Criteria was calculated as the number of participants who met an Escape Criterion divided by the number who had reached Visit 5 minus major protocol violators. Escape Criteria are: (1) doubling of average monthly seizure frequency; (2) doubling of the highest consecutive 2-day seizure total; (3) occurrence of a new, more severe seizure type; or (4) worsening of generalized tonic-clonic seizures. |
| Percent Change From Baseline in Weekly Seizure Frequency Between Study Visits 3 (Start of Dosing) and 9 (End of the Treatment Phase) | Baseline and Study Visit 3 through Visit 9 of the Treatment phase (Treatment Week 0 through Week 23) | Change from Baseline was measured as the number of seizures at Visits 3 through 9 minus the number of seizures at Baseline. The number of partial seizures during treatment divided by the number of weeks of treatment was compared to the weekly seizure frequency during Baseline. A positive number equals a reduction in seizure frequency. |
| The Percentage of Participants in the 250 mg/Day Dose Group Who Prematurely Discontinued the Study Between Study Visit 5 (Approximately Week 7) and Visit 9 (End of the Treatment Phase) | From Study Visit 5 through Visit 9 of the Treatment phase (approximately Week 7 through Week 23) | The percentage of participants prematurely discontinuing the study was calculated as the number of participants who discontinued the study divided by the number who had reached Visit 5 minus major protocol violators. The Control group was composed of data from other similar studies and is not part of this study. |
| Percent Change From Baseline in the Average Seizure Frequency Measured at the End of Participation in the Continuation Phase | Baseline and start of Continuation phase through Week 24 or end of participation in the Continuation phase | Change from baseline was calculated as the average seizure frequency at the end of the Continuation Phase minus the average seizure frequency at Baseline. The number of seizures during the Continuation phase divided by the number of weeks was compared to the number of seizures at Baseline. A positive number indicates a reduction in seizure frequency. |
| The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | Baseline and entire Continuation phase (24 Weeks) | Change in seizure frequency was calculated as the average seizure frequency during the Continuation Phase minus the seizure frequency at Baseline. |
| Number of Seizure-free Participants During the Last 12 Weeks of Treatment of the Treatment Phase | The last 12 weeks of treatment of the Treatment phase (Monotherapy phase - approximately Week 11 through Week 23) | The number of participants who had no seizures during the treatment period was calculated. The last 12 weeks of treatment were either Weeks 11-22 or 12-23 depending on which background AED was being withdrawn |
Countries
Argentina, Chile, Costa Rica, Puerto Rico, Russia, South Korea, Ukraine, United States
Participant flow
Recruitment details
All participants in the Treatment phase and all Baseline Failure participants are eligible to enter the Continuation phase. The Continuation phase is for long-term safety exposure to lamotrigine extended release (LTG XR) at 300 mg/day; it is not a cross-over phase.
Pre-assignment details
The number of participants (par.) starting the Continuation phase (CP) does not equal the number completing the Treatment phase (TP), as 1) the CP was optional, 2) not everyone from the TP was eligible to enter the CP, and 3) par. who failed to qualify for the TP (Baseline Failures) were allowed to enter the CP. All par. start the TP at 300 mg/day.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Phase: LTG XR, 300 mg LTG XR, 300 mg/day in the Treatment phase | 112 |
| Treatment Phase: LTG XR, 250 mg LTG XR, 250 mg/day in the Treatment phase | 111 |
| Total | 223 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Continuation Phase | Adverse Event | 2 | 0 | 1 |
| Continuation Phase | Lack of Efficacy | 5 | 0 | 0 |
| Continuation Phase | Lost to Follow-up | 2 | 0 | 1 |
| Continuation Phase | Protocol Violation | 1 | 0 | 1 |
| Continuation Phase | Ran Out of Drug Due to Travel | 1 | 0 | 0 |
| Continuation Phase | Scheduling Error | 1 | 0 | 0 |
| Continuation Phase | Site Closed by Sponsor | 8 | 0 | 0 |
| Continuation Phase | Withdrawal by Subject | 4 | 0 | 0 |
| Double-Blind (DB) Treatment Phase | Adverse Event | 4 | 10 | 0 |
| Double-Blind (DB) Treatment Phase | Lack of Efficacy | 6 | 7 | 0 |
| Double-Blind (DB) Treatment Phase | Lost to Follow-up | 0 | 4 | 0 |
| Double-Blind (DB) Treatment Phase | Pregnancy | 0 | 1 | 0 |
| Double-Blind (DB) Treatment Phase | Protocol Violation | 0 | 4 | 0 |
| Double-Blind (DB) Treatment Phase | Withdrawal by Subject | 9 | 8 | 0 |
Baseline characteristics
| Characteristic | Treatment Phase: LTG XR, 300 mg | Treatment Phase: LTG XR, 250 mg | Total |
|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 14.3 | 32.9 years STANDARD_DEVIATION 12.6 | 33.4 years STANDARD_DEVIATION 13.5 |
| Gender Female | 56 Participants | 66 Participants | 122 Participants |
| Gender Male | 56 Participants | 45 Participants | 101 Participants |
| Number of participants taking indicated concurrent antiepileptic drug at study entry Levetiracetam | 11 participants | 13 participants | 24 participants |
| Number of participants taking indicated concurrent antiepileptic drug at study entry Oxcarbazepine | 12 participants | 12 participants | 24 participants |
| Number of participants taking indicated concurrent antiepileptic drug at study entry Pregabalin | 1 participants | 1 participants | 2 participants |
| Number of participants taking indicated concurrent antiepileptic drug at study entry Topiramate | 12 participants | 10 participants | 22 participants |
| Number of participants taking indicated concurrent antiepileptic drug at study entry Valproate | 73 participants | 70 participants | 143 participants |
| Number of participants taking indicated concurrent antiepileptic drug at study entry Zonisamide | 3 participants | 5 participants | 8 participants |
| Race/Ethnicity, Customized African American | 5 participants | 4 participants | 9 participants |
| Race/Ethnicity, Customized Arabic/North African | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Asian | 11 participants | 11 participants | 22 participants |
| Race/Ethnicity, Customized Asian - Central/South Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian - East Asian | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 96 participants | 94 participants | 190 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 44 / 112 | 52 / 111 | 47 / 184 | 4 / 11 |
| serious Total, serious adverse events | 3 / 112 | 5 / 111 | 3 / 184 | 1 / 11 |
Outcome results
Primary
The Percentage of Participants in the 300 mg/Day Dose Group Who Prematurely Discontinued the Study Between Study Visit 5 (Approximately Week 7) and Visit 9 (End of the Treatment Phase)
The percentage of participants prematurely discontinuing the study was calculated as the number of participants who discontinued the study divided by the number who reached Visit 5 minus major protocol violators. The Control group is composed of data from other similar studies and is not part of this study.
Time frame: From Study Visit 5 through Visit 9 of the Treatment Phase (approximately Week 7 through Week 23)
Population: All randomized participants in the 300 mg/day dose group who began withdrawal of background antiepileptic drug (AED) (Visit 5) minus any major protocol violators
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | The Percentage of Participants in the 300 mg/Day Dose Group Who Prematurely Discontinued the Study Between Study Visit 5 (Approximately Week 7) and Visit 9 (End of the Treatment Phase) | 12 percentage of participants |
Secondary
Number of Seizure-free Participants During the Last 12 Weeks of Treatment of the Treatment Phase
The number of participants who had no seizures during the treatment period was calculated. The last 12 weeks of treatment were either Weeks 11-22 or 12-23 depending on which background AED was being withdrawn
Time frame: The last 12 weeks of treatment of the Treatment phase (Monotherapy phase - approximately Week 11 through Week 23)
Population: All randomized participants who began withdrawal of background AED (Visit 5) minus any major protocol violators
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | Number of Seizure-free Participants During the Last 12 Weeks of Treatment of the Treatment Phase | 22 participants |
| LTG XR, 250 mg | Number of Seizure-free Participants During the Last 12 Weeks of Treatment of the Treatment Phase | 8 participants |
Secondary
Percentage of Participants Meeting Escape Criteria in the Treatment Phase
The percentage of participants meeting Escape Criteria was calculated as the number of participants who met an Escape Criterion divided by the number who had reached Visit 5 minus major protocol violators. Escape Criteria are: (1) doubling of average monthly seizure frequency; (2) doubling of the highest consecutive 2-day seizure total; (3) occurrence of a new, more severe seizure type; or (4) worsening of generalized tonic-clonic seizures.
Time frame: Study Visit 5 through Visit 9 of the Treatment phase (approximately Week 7 through Week 23)
Population: All randomized participants who began withdrawal of background AED (Visit 5) minus any major protocol violators
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | Percentage of Participants Meeting Escape Criteria in the Treatment Phase | 4 percentage of participants |
| LTG XR, 250 mg | Percentage of Participants Meeting Escape Criteria in the Treatment Phase | 6 percentage of participants |
Secondary
Percent Change From Baseline in the Average Seizure Frequency Measured at the End of Participation in the Continuation Phase
Change from baseline was calculated as the average seizure frequency at the end of the Continuation Phase minus the average seizure frequency at Baseline. The number of seizures during the Continuation phase divided by the number of weeks was compared to the number of seizures at Baseline. A positive number indicates a reduction in seizure frequency.
Time frame: Baseline and start of Continuation phase through Week 24 or end of participation in the Continuation phase
Population: All participants who began the Continuation Phase
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | Percent Change From Baseline in the Average Seizure Frequency Measured at the End of Participation in the Continuation Phase | 72.2 percent change in seizures |
| LTG XR, 250 mg | Percent Change From Baseline in the Average Seizure Frequency Measured at the End of Participation in the Continuation Phase | 68.8 percent change in seizures |
Secondary
Percent Change From Baseline in Weekly Seizure Frequency Between Study Visits 3 (Start of Dosing) and 9 (End of the Treatment Phase)
Change from Baseline was measured as the number of seizures at Visits 3 through 9 minus the number of seizures at Baseline. The number of partial seizures during treatment divided by the number of weeks of treatment was compared to the weekly seizure frequency during Baseline. A positive number equals a reduction in seizure frequency.
Time frame: Baseline and Study Visit 3 through Visit 9 of the Treatment phase (Treatment Week 0 through Week 23)
Population: All randomized participants who began withdrawal of background AED (Visit 5) minus any major protocol violators
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | Percent Change From Baseline in Weekly Seizure Frequency Between Study Visits 3 (Start of Dosing) and 9 (End of the Treatment Phase) | 54.8 percent change in seizures |
| LTG XR, 250 mg | Percent Change From Baseline in Weekly Seizure Frequency Between Study Visits 3 (Start of Dosing) and 9 (End of the Treatment Phase) | 52.2 percent change in seizures |
Secondary
The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks)
Change in seizure frequency was calculated as the average seizure frequency during the Continuation Phase minus the seizure frequency at Baseline.
Time frame: Baseline and entire Continuation phase (24 Weeks)
Population: All participants who entered the Continuation Phase
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 50% reduction in seizures | 137 participants |
| Lamotrigine Extended-release (LTG XR), 300 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | 100% reduction in seizures | 38 participants |
| Lamotrigine Extended-release (LTG XR), 300 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 75% reduction in seizures | 85 participants |
| Lamotrigine Extended-release (LTG XR), 300 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 50% increase in seizures | 6 participants |
| Lamotrigine Extended-release (LTG XR), 300 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 25% reduction in seizures | 169 participants |
| LTG XR, 250 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 50% increase in seizures | 3 participants |
| LTG XR, 250 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 25% reduction in seizures | 7 participants |
| LTG XR, 250 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 50% reduction in seizures | 6 participants |
| LTG XR, 250 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | At least a 75% reduction in seizures | 3 participants |
| LTG XR, 250 mg | The Number of Participants With at Least the Specified Change in Seizure Frequency, Compared to Baseline, at the End of Participation in the Continuation Phase (Maximum of 24 Weeks) | 100% reduction in seizures | 2 participants |
Secondary
The Percentage of Participants in the 250 mg/Day Dose Group Who Prematurely Discontinued the Study Between Study Visit 5 (Approximately Week 7) and Visit 9 (End of the Treatment Phase)
The percentage of participants prematurely discontinuing the study was calculated as the number of participants who discontinued the study divided by the number who had reached Visit 5 minus major protocol violators. The Control group was composed of data from other similar studies and is not part of this study.
Time frame: From Study Visit 5 through Visit 9 of the Treatment phase (approximately Week 7 through Week 23)
Population: All randomized participants in the 250 mg/day dose group who began withdrawal of background AED (Visit 5) minus any major protocol violators
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | The Percentage of Participants in the 250 mg/Day Dose Group Who Prematurely Discontinued the Study Between Study Visit 5 (Approximately Week 7) and Visit 9 (End of the Treatment Phase) | 16 percentage of participants |
Secondary
Time to Discontinuation in the Treatment Phase
Time (days) until the participant discontinued the study
Time frame: From Study Visit 5 through Visit 9 of the Treatment phase (approximately Week 7 through Week 23)
Population: Intent-to-Treat (ITT) Population: All participants who were randomized and began dosing with study drug
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lamotrigine Extended-release (LTG XR), 300 mg | Time to Discontinuation in the Treatment Phase | 147.3 Days | Standard Deviation 31.5 |
| LTG XR, 250 mg | Time to Discontinuation in the Treatment Phase | 133.2 Days | Standard Deviation 45.6 |