Lennox-Gastaut Syndrome
Conditions
Keywords
Epilepsy, Seizures
Brief summary
To confirm that the combination therapy of rufinamide has superior efficacy compared to placebo in patients with Lennox-Gastaut syndrome.
Interventions
DRUGRufinamide (E2080)
Rufinamide tablets administered orally twice daily after breakfast and dinner. Treatment was divided into a Dose Titration Period (2 weeks) and a Dose Maintenance Period (10 weeks). As a general rule, the dose was increased by 1 step every 2 days until it reached the target maintenance dose determined by body weight at the start of the Observation Period. Target maintenance dose: 15.0 - 30.0 kg: 1000 mg/day (5 tablets each in the morning and evening) 30.1 - 50.0 kg: 1800 mg/day (4 tablets in the morning and 5 in the evening) 50.1 - 70.0 kg: 2400 mg/day (6 tablets each in the morning and evening) \>= 70.1 kg: 3200 mg/day (8 tablets each in the morning and evening)
DRUGPlacebo
Rufinamide Matching Placebo tablets administered orally twice daily after breakfast and dinner for a total of 12 weeks.
Sponsors
Eisai Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
4 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
1. Participants who are diagnosed as Lennox-Gastaut syndrome with tonic/atonic seizures and atypical absence seizures (A history of atypical absence seizures will also be incorporated). 2. Participants who had a slow spike-and-wave pattern in an electroencephalogram within 6 months prior to the enrollment for the Observation Period. 3. Participants who had at least a total of 90 seizures in the 28 days prior to the enrollment for the Observation Period. 4. Participants who have been on 1 - 3 anti-epileptic drugs from 28 days prior to the enrollment for the Observation Period and have not changed the type of the anti-epileptic drugs. 5. Participants who have not changed the type nor the dose or administration of the anti-epileptic drugs they are taking in the Observation Period.
Exclusion criteria
; 1. Participants who had a history of generalized tonic-clonic status epilepticus within baseline. 2. Participants who received drug therapy at least 4 times to be rescued from status epilepticus within baseline. 3. Participants who had a history of hypoxia which needed emergency resuscitation within 12 months prior to the Treatment Period. 4. Participants who were on a ketogenic diet or have received adrenocorticotropic hormone (ACTH) therapy or Vitamin B6 therapy within 6 months prior to the Treatment Period. 5. Participants who had a history of suicide attempt within the 1 year prior to the Treatment Period. 6. Participants who had a history of or has an allergy to triazole compound. 7. Participants who have clinically significant electrocardiogram abnormalities at baseline. 8. Participants who are pregnant, who may be pregnant, who are lactating or who wish to be pregnant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Tonic-Atonic Seizure Frequency From Baseline (Per 28 Days) | Baseline (28 day observational period) and End of Treatment (28 day treatment period) | The sum of the frequencies of tonic seizures and atonic seizures was defined as the tonic-atonic seizure frequency and the percent change in tonic-atonic seizure frequency per 28 days was assessed. The percent change in tonic-atonic seizure frequency was calculated using the tonic-atonic seizure frequency per 28 days of the Observation Period as the baseline and the tonic-atonic seizure frequency per 28 days of the Treatment Period as the post-treatment value. Percentage change in tonic - atonic seizure frequency was calculated as follows: \[100 x (post-treatment value - baseline)/ baseline\]. The frequency of epileptic seizures was recorded in the seizure diary by the recorder. Seizure frequency was counted based on the classification established by the International League Against Epilepsy (ILAE). The diary recorder monitored the participant and recorded the seizure diary in a consistent manner, and continued these practices throughout the study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Achieving a 50% Reduction in Tonic-atonic Seizure Frequency | 12 weeks | 50% Responder Rate in Tonic-Atonic Seizure Frequency was presented as the number of participants who achieved a 50% reduction in tonic-atonic seizure frequency. |
| Percent Change in Total Seizure Frequency (Per 28 Days) | Baseline (28 day observational period) and End of Treatment (28 day treatment period) | Percent change in the total seizure frequency (per 28 days) was calculated using the total seizure frequency per 28 days of the Observation Period as the baseline and the total seizure frequency per 28 days of the Treatment Period as the post-treatment value. Percentage change in total seizure frequency was calculated as follows: \[100 x (post-treatment value - baseline)/ baseline\]. |
| Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Baseline (28 day observational period) and End of Treatment (28 day treatment period) | Percent change in the frequency of seizures other than tonic-atonic seizures (per 28 days) was calculated using the total seizure frequency per 28 days of the Observation Period as the baseline and the total seizure frequency per 28 days of the Treatment Period as the post-treatment value. Percentage change in total seizure frequency was calculated as follows: \[100 x (post-treatment value - baseline)/ baseline\]. Seizures analyzed other than tonic-atonic seizures included: Partial seizure freq. (frequency), Absence seizure, Atyp. (atypical) absence seizure, Myoclonic seizure, Clonic seizure, Tonic seizure, Tonic-clonic seizure, Atonic seizure, & Uncla. (unclassified) epileptic seizure. The frequency of epileptic seizures was recorded in the diary by the recorder. Seizure frequency was counted based on the classification established by the International League Against Epilepsy (ILAE). The diary recorder monitored the participant and recorded the seizure diary in a consistent manner. |
| Clinical Global Impression of Change (CGIC) | Up to Week 12 of the treatment period | CGIC in participants with Lennox-Gastaut Syndrome (LGS) relative to placebo was presented as number of participants in each category at the final assessment (last observation carried forward \[LOCF\]) & at Week 12 of the Treatment Period. The investigator assessed the CGIC by comparing the participants' condition during the 4 weeks immediately before the completion (or discontinuation \[d/c\]) of the Treatment Period to his/her condition during the 4-week Observation Period (for participants who d/c'd the study during the Treatment Period, the CGIC was assessed by comparing the participant's condition from the start to discontinuation of the study treatment to his/her condition during the 4-week Observation Period). The CGIC was assessed according to the following 7-grade scale based on the frequency & severity of seizures, AEs, and overall conditions of daily life. Markedly improved, Improved, Slightly improved, Unchanged, Slightly worsened, Worsened, Markedly worsened. |
Countries
Japan
Participant flow
Pre-assignment details
Of n= 66 who started Observation Period, 7 discontinued from study. Primary reasons were deviation of the inclusion/ exclusion criteria (n=5), untoward event before study treatment (n=1) & other (n=1). Of 59 participants, 58 were included in full analysis set (FAS). 1 participant (E2080 group) was excluded due to inappropriate diagnosis of disease.
Participants by arm
| Arm | Count |
|---|---|
| Rufinamide (E2080) Rufinamide tablets administered orally twice daily after breakfast and dinner. Treatment was divided into a Dose Titration Period (2 weeks) and a Dose Maintenance Period (10 weeks). As a general rule, the dose was increased by 1 step every 2 days until it reached the target maintenance dose determined by body weight at the start of the Observation Period. Target maintenance dose: 15.0 - 30.0 kg: 1000 mg/day (5 tablets each in the morning and evening) 30.1 - 50.0 kg: 1800 mg/day (4 tablets in the morning and 5 in the evening) 50.1 - 70.0 kg: 2400 mg/day (6 tablets each in the morning and evening) \>= 70.1 kg: 3200 mg/day (8 tablets each in the morning and evening) | 28 |
| Placebo Rufinamide Matching Placebo tablets administered orally twice daily after breakfast and dinner for a total of 12 weeks. | 30 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
Baseline characteristics
| Characteristic | Rufinamide (E2080) | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 16.0 years STANDARD_DEVIATION 7.1 | 13.9 years STANDARD_DEVIATION 6.1 | 14.9 years STANDARD_DEVIATION 6.6 |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 22 Participants |
| Sex: Female, Male Male | 17 Participants | 19 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 29 | 21 / 30 |
| serious Total, serious adverse events | 1 / 29 | 1 / 30 |
Outcome results
Primary
Percent Change in Tonic-Atonic Seizure Frequency From Baseline (Per 28 Days)
The sum of the frequencies of tonic seizures and atonic seizures was defined as the tonic-atonic seizure frequency and the percent change in tonic-atonic seizure frequency per 28 days was assessed. The percent change in tonic-atonic seizure frequency was calculated using the tonic-atonic seizure frequency per 28 days of the Observation Period as the baseline and the tonic-atonic seizure frequency per 28 days of the Treatment Period as the post-treatment value. Percentage change in tonic - atonic seizure frequency was calculated as follows: \[100 x (post-treatment value - baseline)/ baseline\]. The frequency of epileptic seizures was recorded in the seizure diary by the recorder. Seizure frequency was counted based on the classification established by the International League Against Epilepsy (ILAE). The diary recorder monitored the participant and recorded the seizure diary in a consistent manner, and continued these practices throughout the study period.
Time frame: Baseline (28 day observational period) and End of Treatment (28 day treatment period)
Population: Full analysis set (FAS) is defined as participants who were registered for the Treatment Period and excludes those listed below.~Participants who did not meet the inclusion criterion related the target disease, participants who did not take the study drug, participants without any evaluable efficacy data after the start of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rufinamide (E2080) | Percent Change in Tonic-Atonic Seizure Frequency From Baseline (Per 28 Days) | -24.20 Percent Change |
| Placebo | Percent Change in Tonic-Atonic Seizure Frequency From Baseline (Per 28 Days) | -3.25 Percent Change |
p-value: 0.00390% CI: [-40.3, -11.8]Wilcoxon (Mann-Whitney)
Secondary
Clinical Global Impression of Change (CGIC)
CGIC in participants with Lennox-Gastaut Syndrome (LGS) relative to placebo was presented as number of participants in each category at the final assessment (last observation carried forward \[LOCF\]) & at Week 12 of the Treatment Period. The investigator assessed the CGIC by comparing the participants' condition during the 4 weeks immediately before the completion (or discontinuation \[d/c\]) of the Treatment Period to his/her condition during the 4-week Observation Period (for participants who d/c'd the study during the Treatment Period, the CGIC was assessed by comparing the participant's condition from the start to discontinuation of the study treatment to his/her condition during the 4-week Observation Period). The CGIC was assessed according to the following 7-grade scale based on the frequency & severity of seizures, AEs, and overall conditions of daily life. Markedly improved, Improved, Slightly improved, Unchanged, Slightly worsened, Worsened, Markedly worsened.
Time frame: Up to Week 12 of the treatment period
Population: Full analysis set (FAS) is defined as participants who were registered for the Treatment Period and excludes those listed below.~Participants who did not meet the inclusion criterion related the target disease, participants who did not take the study drug, participants without any evaluable efficacy data after the start of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Markedly improved (n=25, 29) | 0 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Improved (n=25, 29) | 9 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Markedly Worsened (n=25, 29) | 0 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Slightly Improved (n=25, 29) | 4 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Unchanged (n=25, 29) | 10 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Slightly Worsened (n=25, 29) | 1 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | Week 12: Worsened (n=25, 29) | 1 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Markedly Improved (n=28, 30) | 3 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Improved (n=28, 30) | 9 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Slightly Improved (n=28, 30) | 4 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Unchanged (n=28, 30) | 10 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Slightly Worsened (n=28, 30) | 1 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Worsened (n=28, 30) | 1 participants |
| Rufinamide (E2080) | Clinical Global Impression of Change (CGIC) | LOCF: Markedly Worsened (n=28, 30) | 0 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Unchanged (n=28, 30) | 19 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Markedly improved (n=25, 29) | 0 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Markedly Improved (n=28, 30) | 0 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Worsened (n=28, 30) | 1 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Improved (n=25, 29) | 0 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Improved (n=28, 30) | 0 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Slightly Improved (n=25, 29) | 9 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Slightly Worsened (n=28, 30) | 1 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Unchanged (n=25, 29) | 18 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Slightly Improved (n=28, 30) | 9 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Slightly Worsened (n=25, 29) | 1 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | LOCF: Markedly Worsened (n=28, 30) | 0 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Worsened (n=25, 29) | 1 participants |
| Placebo | Clinical Global Impression of Change (CGIC) | Week 12: Markedly Worsened (n=25, 29) | 0 participants |
Comparison: Analysis of Week 12 of the Treatment Periodp-value: 0.041Wilcoxon (Mann-Whitney)
Comparison: Analysis of final assessment (LOCF)p-value: 0.007Wilcoxon (Mann-Whitney)
Secondary
Number of Participants Achieving a 50% Reduction in Tonic-atonic Seizure Frequency
50% Responder Rate in Tonic-Atonic Seizure Frequency was presented as the number of participants who achieved a 50% reduction in tonic-atonic seizure frequency.
Time frame: 12 weeks
Population: Full analysis set (FAS) is defined as participants who were registered for the Treatment Period and excludes those listed below.~Participants who did not meet the inclusion criterion related the target disease, participants who did not take the study drug, participants without any evaluable efficacy data after the start of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rufinamide (E2080) | Number of Participants Achieving a 50% Reduction in Tonic-atonic Seizure Frequency | Yes (50% Reduction Achieved) | 7 Participants |
| Rufinamide (E2080) | Number of Participants Achieving a 50% Reduction in Tonic-atonic Seizure Frequency | No | 21 Participants |
| Placebo | Number of Participants Achieving a 50% Reduction in Tonic-atonic Seizure Frequency | No | 28 Participants |
| Placebo | Number of Participants Achieving a 50% Reduction in Tonic-atonic Seizure Frequency | Yes (50% Reduction Achieved) | 2 Participants |
p-value: 0.074Fisher's exact test
Secondary
Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days)
Percent change in the frequency of seizures other than tonic-atonic seizures (per 28 days) was calculated using the total seizure frequency per 28 days of the Observation Period as the baseline and the total seizure frequency per 28 days of the Treatment Period as the post-treatment value. Percentage change in total seizure frequency was calculated as follows: \[100 x (post-treatment value - baseline)/ baseline\]. Seizures analyzed other than tonic-atonic seizures included: Partial seizure freq. (frequency), Absence seizure, Atyp. (atypical) absence seizure, Myoclonic seizure, Clonic seizure, Tonic seizure, Tonic-clonic seizure, Atonic seizure, & Uncla. (unclassified) epileptic seizure. The frequency of epileptic seizures was recorded in the diary by the recorder. Seizure frequency was counted based on the classification established by the International League Against Epilepsy (ILAE). The diary recorder monitored the participant and recorded the seizure diary in a consistent manner.
Time frame: Baseline (28 day observational period) and End of Treatment (28 day treatment period)
Population: Full analysis set (FAS) is defined as participants who were registered for the Treatment Period and excludes those listed below.~Participants who did not meet the inclusion criterion related the target disease, participants who did not take the study drug, participants without any evaluable efficacy data after the start of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Atyp. Absence Seizure Freq. % Change (n=12,19) | -59.00 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Tonic Seizure Freq. % Change (n=28,28) | -24.20 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Absence Seizure Freq. % Change (n=1,0) | 3.40 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Tonic-clonic Seizure Freq. % Change (n=2,10) | -57.35 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Myoclonic Seizure Freq. % Change (n=10,10) | -52.35 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Atonic Seizure Freq. % Change (n=10,12) | -63.10 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Partial Seizure Freq. % Change (n=4,6) | -52.20 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Uncla. Epileptic Seizure Freq. % Change (n=1,0) | -88.70 Percent change |
| Rufinamide (E2080) | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Clonic Seizure Freq. % Change (n=1,0) | -81.20 Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Uncla. Epileptic Seizure Freq. % Change (n=1,0) | NA Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Partial Seizure Freq. % Change (n=4,6) | 4.5 Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Absence Seizure Freq. % Change (n=1,0) | NA Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Atyp. Absence Seizure Freq. % Change (n=12,19) | -21.10 Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Myoclonic Seizure Freq. % Change (n=10,10) | 6.60 Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Clonic Seizure Freq. % Change (n=1,0) | NA Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Tonic Seizure Freq. % Change (n=28,28) | -3.60 Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Tonic-clonic Seizure Freq. % Change (n=2,10) | 2.35 Percent change |
| Placebo | Percentage Change in the Frequency of Seizures Other Than Tonic-atonic Seizures (Per 28 Days) | Atonic Seizure Freq. % Change (n=10,12) | -6.10 Percent change |
Comparison: Analysis for Partial Seizure Frequencyp-value: 0.02590% CI: [-104.5, -17.3]Wilcoxon (Mann-Whitney)
Comparison: Analysis of atypical absence seizure frequencyp-value: 0.12890% CI: [-72, 0.9]Wilcoxon (Mann-Whitney)
Comparison: Analysis for myoclonic seizure frequencyp-value: 0.02190% CI: [-126.6, -15.4]Wilcoxon (Mann-Whitney)
Comparison: Analysis of tonic seizure frequencyp-value: 0.03190% CI: [-40.7, -5.6]Wilcoxon (Mann-Whitney)
Comparison: Analysis for Tonic-clonic seizure frequencyp-value: 0.10790% CI: [-464.7, 30.5]Wilcoxon (Mann-Whitney)
Comparison: Analysis of Atonic seizure frequencyp-value: 0.22190% CI: [-89.1, 10.8]Wilcoxon (Mann-Whitney)
Secondary
Percent Change in Total Seizure Frequency (Per 28 Days)
Percent change in the total seizure frequency (per 28 days) was calculated using the total seizure frequency per 28 days of the Observation Period as the baseline and the total seizure frequency per 28 days of the Treatment Period as the post-treatment value. Percentage change in total seizure frequency was calculated as follows: \[100 x (post-treatment value - baseline)/ baseline\].
Time frame: Baseline (28 day observational period) and End of Treatment (28 day treatment period)
Population: Full analysis set (FAS) is defined as participants who were registered for the Treatment Period and excludes those listed below.~Participants who did not meet the inclusion criterion related the target disease, participants who did not take the study drug, participants without any evaluable efficacy data after the start of study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rufinamide (E2080) | Percent Change in Total Seizure Frequency (Per 28 Days) | -32.90 Percent Change |
| Placebo | Percent Change in Total Seizure Frequency (Per 28 Days) | -3.05 Percent Change |
p-value: <0.00190% CI: [-47.1, -17]Wilcoxon (Mann-Whitney)