Clobazam in Patients With Lennox-Gastaut Syndrome

• Sponsor: Lundbeck LLC
• Information provided by (Responsible Party): Lundbeck LLC

Study Description

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 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.

Condition or disease	Intervention/treatment	Phase
Epilepsy; Epilepsy, Generalized; Seizures	Drug: Clobazam Low Dose; Drug: Clobazam Medium Dose; Drug: Clobazam High Dose; Drug: Placebo	Phase 3

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	238 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Primary Purpose:	Treatment
Official Title:	Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Clobazam in Patients With Lennox-Gastaut Syndrome
Study Start Date :	August 2007
Actual Primary Completion Date :	December 2009
Actual Study Completion Date :	April 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Clobazam Low Dose	Drug: Clobazam Low Dose; 0.25 mg/kg/day; tablets; orally; for 15-18 weeks; Other Name: Onfi™
Experimental: Clobazam Medium Dose	Drug: Clobazam Medium Dose; 0.5 mg/kg/day; tablets; orally; for 15-18 weeks; Other Name: Onfi™
Experimental: Clobazam High Dose	Drug: Clobazam High Dose; 1.0 mg/kg/day; tablets; orally; for 15-18 weeks; Other Name: Onfi™
Placebo Comparator: Placebo	Drug: Placebo; tablets; orally; daily for 15-18 weeks

Outcome Measures

Primary Outcome Measures :

1. Percent Reduction in Number of Drop Seizures (12-week Maintenance Period). [ Time Frame: 4-week baseline period and 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.

Secondary Outcome Measures :

1. Percent Reduction in Number of Drop Seizures (First 4 Weeks of the 12-week Maintenance Period). [ Time Frame: 4-week baseline period and the 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.
2. Percent Reduction in Number of Drop Seizures (Middle 4 Weeks of the 12-week Maintenance Period). [ Time Frame: 4-week baseline period and the 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.
3. Percent Reduction in Number of Drop Seizures (Last 4 Weeks of the 12-week Maintenance Period). [ Time Frame: 4-week baseline period and the 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. Percent of Patients Considered Treatment Responders Defined as Those With a >=25%, >=50%, >=75%, 100% Reduction in Drop Seizures (12-week Maintenance Period). [ Time Frame: 4-week baseline period and 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.
5. 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). [ Time Frame: 4-week baseline period and the 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.
6. 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). [ Time Frame: 4-week baseline period and the 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.
7. 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). [ Time Frame: 4-week baseline period and the 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.
8. Tolerance [ Time Frame: 4-week baseline period and first 4/first 8 weeks of the maintenance period ]
   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.
9. Investigator Global Evaluations of the Patient's Overall Change in Symptoms. [ Time Frame: Week 15 ]
   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".
10. Parent/Caregiver Global Evaluations of the Patient's Overall Change in Symptoms. [ Time Frame: Week 15 ]
    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".

Eligibility Criteria

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Ages Eligible for Study:	2 Years to 60 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Sponsors and Collaborators

Lundbeck LLC

Investigators

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Study Director:	Email contact via H. Lundbeck A/S	LundbeckClinicalTrials@lundbeck.com

More Information

Publications of Results:

Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA; OV-1012 Study Investigators. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011 Oct 11;77(15):1473-81. doi: 10.1212/WNL.0b013e318232de76. Epub 2011 Sep 28.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gidal BE, Wechsler RT, Sankar R, Montouris GD, White HS, Cloyd JC, Kane MC, Peng G, Tworek DM, Shen V, Isojarvi J. Deconstructing tolerance with clobazam: Post hoc analyses from an open-label extension study. Neurology. 2016 Oct 25;87(17):1806-1812. Epub 2016 Sep 28.

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Responsible Party:	Lundbeck LLC
ClinicalTrials.gov Identifier:	NCT00518713 History of Changes
Other Study ID Numbers:	13110A; OV1012 ( Other Identifier: Former study ID )
First Posted:	August 21, 2007
Results First Posted:	February 9, 2012
Last Update Posted:	February 9, 2012
Last Verified:	January 2012

Keywords provided by Lundbeck LLC:

Epilepsy; Lennox-Gastaut Syndrome; Drop seizures; Clobazam

Additional relevant MeSH terms:

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Epilepsy; Seizures; Lennox Gastaut Syndrome; Epilepsy, Generalized; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Epileptic Syndromes; Genetic Diseases, Inborn; Clobazam	Anticonvulsants; Anti-Anxiety Agents; Tranquilizing Agents; Central Nervous System Depressants; Physiological Effects of Drugs; Psychotropic Drugs; GABA-A Receptor Agonists; GABA Agonists; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action