Clobazam in Patients With Lennox-Gastaut Syndrome

Study Overview
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Brief Summary
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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 patients 2 to 60 years of age with Lennox-Gastaut Syndrome (LGS). Patients will be enrolled at approximately 65 sites in the U.S. and ex-US for up to 23 weeks. Patients will be randomly assigned to either a low, medium or high dose, or placebo. The study will include a baseline period, a titration period and a maintenance period. After the maintenance period, patients 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
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LGS poses a significant treatment challenge. No single antiepileptic drug (AED) provides satisfactory relief for all or most patients with LGS and a combination of treatments is often required. Even with combination therapy, many LGS patients show resistance to treatment. Adjunctive therapy with newer anticonvulsant medications has demonstrated efficacy for some patients, although polytherapy and high medication doses are often associated with unfavorable adverse event profiles. More effective and better-tolerated treatment options are needed for this population of medically intractable epilepsy patients. Clobazam may provide an improved safety profile compared to other AEDs currently approved for the treatment of LGS and may have less hypotonia and drooling effects than other benzodiazepines.

Official Title
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Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Clobazam in Patients With Lennox-Gastaut Syndrome

Conditions
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Epilepsy, Epilepsy, Generalized, Seizures

Intervention / Treatment
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* Drug: Clobazam Low Dose
* Drug: Clobazam Medium Dose
* Drug: Clobazam High Dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have been <11 years of age at the onset of LGS. Patient must have LGS. Patient must be on at least 1 AED. Parent or caregiver must be able to keep an accurate seizure diary. Exclusion Criteria: Etiology of patient's seizures is a progressive neurologic disease. Patients with tuberous sclerosis will not be excluded from study participation, unless there is a progressive tumor. Patient has had an episode of status epilepticus within 12 weeks of baseline. Patient has had an anoxic episode requiring resuscitation within 6 months of screening. Patient has a clinically significant history of an allergic reaction or significant sensitivity to benzodiazepines. Patient is taking more than 3 concurrent AEDs. Patient has been on the ketogenic diet for less than 30 days prior to screening or suffers from frequent stooling. If the patient has a Vagal Nerve Stimulator (VNS), the settings have not been stable for at least 30 days prior to screening. Patient has taken corticotropins in the 6 months prior to screening. Patient is currently taking long-term systemic steroids (excluding inhaled mediation for asthma treatment) or any other daily medication known to exacerbate epilepsy. An exception will be made of prophylactic medication, for example, for idiopathic nephrotic syndrome or asthma. If the patient is taking felbamate, has been taking it for less than 1 year prior to screening. Other protocol-defined inclusion and exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clobazam Low Dose<br> | Drug: Clobazam Low Dose<br>* 0.25 mg/kg/day; tablets; orally; for 15-18 weeks<br>* Other names: Onfi™;|
| Experimental: Clobazam Medium Dose<br> | Drug: Clobazam Medium Dose<br>* 0.5 mg/kg/day; tablets; orally; for 15-18 weeks<br>* Other names: Onfi™;|
| Experimental: Clobazam High Dose<br> | Drug: Clobazam High Dose<br>* 1.0 mg/kg/day; tablets; orally; for 15-18 weeks<br>* Other names: Onfi™;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* tablets; orally; daily for 15-18 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Reduction in Number of Drop Seizures (12-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. | 4-week baseline period and 12-week maintenance period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Reduction in Number of Drop Seizures (First 4 Weeks of the 12-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. | 4-week baseline period and the first 4 weeks of the 12-week maintenance period | 
| Percent Reduction in Number of Drop Seizures (Middle 4 Weeks of the 12-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. | 4-week baseline period and the middle 4 weeks of the 12-week maintenance period | 
| Percent Reduction in Number of Drop Seizures (Last 4 Weeks of the 12-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. | 4-week baseline period and the last 4 weeks of the 12-week maintenance period | 
| Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (12-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. | 4-week baseline period and the 12-week maintenance period | 
| Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (First 4 Weeks of the 12-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. | 4-week baseline period and the first 4 weeks of the 12-week maintenance period | 
| Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (Middle 4 Weeks of the 12-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. | 4-week baseline period and the middle 4 weeks of the 12-week maintenance period | 
| Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (Last 4 Weeks of the 12-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. | 4-week baseline period and the last 4 weeks of the 12-week maintenance period | 
| Tolerance | Study responders who have ≥50% reduction in their drop seizure rate during the first 4 or first 8 weeks of maintenance compared to the 4 week baseline period. | 4-week baseline period and first 4/first 8 weeks of the maintenance period | 
| Investigator Global Evaluations of the Patient's Overall Change in Symptoms. | The physician 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. | Week 15 | 
| 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. | Week 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy, Lennox-Gastaut Syndrome, Drop seizures, Clobazam