Epilepsy, Epilepsy, Generalized, Seizures
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of clobazam as adjunctive therapy in the treatment of seizures which lead to drop attacks (drop seizures) in subjects 2 to 30 years of age with Lennox-Gastaut Syndrome (LGS). Subjects will be enrolled at approximately 10 investigational sites in the U.S. for up to 15 weeks. Subjects will be randomly assigned to either a low dose or a high dose. The study will include a baseline period, a titration period and a maintenance period. After the maintenance period, subjects will either continue into an open-label extension study or enter the taper period with a final visit 1 week after the last dose.
Detailed description
LGS poses a significant treatment challenge. While antiepileptic medications are the mainstay of treatment, no one antiepileptic drug (AED) provides satisfactory relief for all or most patients with LGS and a combination of treatments is often required. Many patients with LGS are refractory to standard AED treatment. More effective and better tolerated treatment options are needed for this population of medically intractable epilepsy patients. Clobazam is unique in that it is the only non-1, 4-benzodiazepine used in the treatment of epilepsy.
Interventions
5 to 10 mg/day with doses in the morning and at bedtime; orally
5 to 40 mg/day with doses in the morning and at bedtime; orally
Sponsors
Lundbeck LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 30 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Subject must have been \<11 years of age at the onset of LGS * Subject must have LGS * Subject must be on at least 1 stable dose AED * Parent or caregiver must be able to keep an accurate seizure diary Key
Exclusion criteria
* Etiology of subject's seizures is a progressive neurologic disease. Subjects with tuberous sclerosis will not be excluded from study participation * Subject has had an episode of status epilepticus within 12 weeks of baseline * Subject has had an anoxic episode requiring resuscitation within 1 year of screening * Subject has had a clinically significant history of an allergic reaction or significant sensitivity to benzodiazepines * Subject is taking more than 3 concurrent AEDs. Note: Vagal Nerve Stimulation (VNS) or ketogenic diet is allowed and each will be counted as one of the three allowed AEDs * If the subject is on the ketogenic diet, has been for less than 4 weeks prior to screening or suffers from frequent stooling * If the subject has a VNS, the settings have not been stable for at least 4 weeks prior to screening * Subject has taken corticotropins in the 6 months prior to screening * Subject is currently taking long-term systemic steroids (excluding inhaled medication for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception will be made of prophylactic medication, for example, for urinary tract infections or asthma * If the subject is taking felbamate, has been taking it for less than 1 year prior to screening or previous treatment with felbamate resulted in withdrawal due to liver or bone marrow adverse events
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Reduction in Number of Drop Seizures. | 4-week baseline period and 4-week maintenance period | Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal. |
| A Comparison of the High Dose Group to Low Dose Group of the Percent Reduction in Number of Drop Seizures. | 4-week baseline period and the 4-week maintenance period | Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | 4-week baseline period and 4-week maintenance period | Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal. |
| Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Week 3 | The parent/caregiver was asked to rate the patient's overall change in symptoms and overall change in seizure activity and Quality of Life since the beginning of clobazam treatment by checking very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Clobazam Low Dose 5 to 10 mg/day with doses in the morning and at bedtime; orally | 32 |
| Clobazam High Dose 5 to 40 mg/day with doses in the morning and at bedtime; orally | 36 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 5 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Clobazam Low Dose | Clobazam High Dose | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 30 Participants | 33 Participants | 63 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 5 Participants |
| Age Continuous | 9.18 years STANDARD_DEVIATION 5.37 | 8.51 years STANDARD_DEVIATION 5.14 | 8.82 years STANDARD_DEVIATION 5.22 |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Male | 19 Participants | 23 Participants | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 27 / 32 | 31 / 36 |
| serious Total, serious adverse events | 1 / 32 | 3 / 36 |
Outcome results
Primary
A Comparison of the High Dose Group to Low Dose Group of the Percent Reduction in Number of Drop Seizures.
Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.
Time frame: 4-week baseline period and the 4-week maintenance period
Population: MITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clobazam Low Dose | A Comparison of the High Dose Group to Low Dose Group of the Percent Reduction in Number of Drop Seizures. | 29 Percent Reduction |
| Clobazam High Dose | A Comparison of the High Dose Group to Low Dose Group of the Percent Reduction in Number of Drop Seizures. | 93 Percent Reduction |
p-value: <0.00011-sided Wilcoxon Rank-Sum Test
Primary
Percent Reduction in Number of Drop Seizures.
Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.
Time frame: 4-week baseline period and 4-week maintenance period
Population: Modified Intention-to-Treat (MITT) populations consist of all randomized patients who received study medication and who have both a baseline and post-baseline measurement and have at least one measurement during the maintenance period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clobazam Low Dose | Percent Reduction in Number of Drop Seizures. | 10.1 Percent Reduction | Standard Deviation 122.3 |
| Clobazam High Dose | Percent Reduction in Number of Drop Seizures. | 85.2 Percent Reduction | Standard Deviation 17.1 |
p-value: <0.01821-sided Wilcoxon signed rank test
p-value: 0.00011-sided Wilcoxon signed rank test
Secondary
Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms.
The parent/caregiver was asked to rate the patient's overall change in symptoms and overall change in seizure activity and Quality of Life since the beginning of clobazam treatment by checking very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse.
Time frame: Week 3
Population: MITT population, baseline evaluations compared to Week 3 evaluations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Improved | 9 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Worse | 0 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Improved | 7 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Worse | 1 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | No Change | 3 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Worse | 0 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Improved | 9 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Worse | 0 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Improved | 15 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Improved | 15 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Improved | 1 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | No Change | 0 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Worse | 1 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Worse | 0 participants |
Secondary
Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms.
The parent/caregiver was asked to rate the patient's overall change in symptoms and overall change in seizure activity and Quality of Life since the beginning of clobazam treatment by checking very much improved, much improved, minimally improved, no change, minimally worse, much worse, or very much worse.
Time frame: Week 7
Population: MITT population, baseline evaluations compared to Week 7 evaluations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Improved | 10 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Worse | 1 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Improved | 6 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Worse | 0 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | No Change | 5 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Worse | 0 participants |
| Clobazam Low Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Improved | 6 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Worse | 0 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Very Much Improved | 16 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Improved | 11 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Improved | 1 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | No Change | 0 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Minimally Worse | 1 participants |
| Clobazam High Dose | Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. | Much Worse | 0 participants |
Secondary
Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures.
Number of drop seizures (average per week) was obtained from seizure diaries. The average drop in seizures per week for patients who did not complete the maintenance period was calculated based on the time from the beginning of the maintenance period to date of withdrawal.
Time frame: 4-week baseline period and 4-week maintenance period
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Clobazam Low Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | ≥ 25% reduction | 18 Percent of participants |
| Clobazam Low Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | ≥ 50% reduction | 12 Percent of participants |
| Clobazam Low Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | ≥ 75% reduction | 7 Percent of participants |
| Clobazam Low Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | 100% reduction | 2 Percent of participants |
| Clobazam High Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | 100% reduction | 8 Percent of participants |
| Clobazam High Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | ≥ 25% reduction | 32 Percent of participants |
| Clobazam High Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | ≥ 75% reduction | 23 Percent of participants |
| Clobazam High Dose | Percent of Patients Considered Treatment Responders Defined as Those With a >= 25%, >= 50%, >= 75%, and 100% Reduction in Drop Seizures. | ≥ 50% reduction | 30 Percent of participants |