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Clobazam and Aggression-Related Adverse Events in Pediatric Patients With Lennox-Gastaut Syndrome
Juliann M Paolicchi1, Gail Ross1, Deborah Lee2
1Weill Cornell Medical College, New York, New York.
Insights
Clobazam treatment for Lennox-Gastaut syndrome showed low, dose-dependent aggression rates. The drug effectively reduced drop seizures, regardless of behavioral history, in pediatric patients.
Area of Science:
- Neurology
- Pediatric Epilepsy
- Pharmacology
Background:
- Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy characterized by frequent drop seizures and intellectual disability.
- Patients with LGS often exhibit behavioral issues, including aggression, which may be exacerbated by benzodiazepine treatment like clobazam.
- The OV-1012 trial investigated the behavioral effects of clobazam in pediatric LGS patients.
Purpose of the Study:
- To assess the potential for clobazam to increase aggression or behavioral problems in pediatric patients with Lennox-Gastaut syndrome.
- To analyze the relationship between clobazam dosage and the occurrence and resolution of aggression-related adverse events.
- To evaluate the efficacy of clobazam in reducing drop seizures irrespective of behavioral history.
Main Methods:
- Phase 3, randomized, double-blind, parallel-group OV-1012 trial with baseline, titration, and maintenance periods.
- Analysis of 194 pediatric patients (2-18 years) with LGS, examining history of aggression and aggression-related adverse events.
- Child Behavior Checklist used to assess drug-related effects on behavior domains.
Main Results:
- Aggression-related adverse events were reported in 13.9% of patients, with similar rates in those with and without a history of aggression.
- In medium- and high-dose clobazam groups, aggression-related adverse effects emerged during titration, with most resolving by study end.
- No significant differences in behavior domains were observed between clobazam and placebo groups based on Child Behavior Checklist analysis.
Conclusions:
- Post hoc analyses suggest clobazam treatment for LGS is associated with low rates of aggression, which are dose-dependent.
- Clobazam demonstrated efficacy in reducing drop seizures in pediatric LGS patients, irrespective of their aggression experience.
- The findings support clobazam as a treatment option for LGS, with careful consideration of dosage regarding behavioral effects.
Background:
Lennox-Gastaut syndrome is an intractable epileptic encephalopathy marked by frequent drop seizures. Most patients develop moderate intellectual disability and behavioral problems, including hyperactivity, aggressiveness, insecurity, and autistic features. Treatment with benzodiazepines, including clobazam, may increase aggression/behavioral problems in patients with Lennox-Gastaut syndrome. Post hoc analyses of data from the OV-1012 trial assessed the potential for behavioral effects with clobazam treatment in pediatric (2 to 18 years) patients with Lennox-Gastaut syndrome.
Methods:
OV-1012 was a phase 3, randomized, double-blind, parallel-group trial comprising a 4-week baseline period, 3-week titration period, and a 12-week maintenance period. Data from 194 patients were analyzed for a history of aggression/behavioral problems, occurrence of aggression-related adverse events, and by assessment of potential drug-related effects on four behavior domains of the Child Behavior Checklist.
Results:
Twenty-nine aggression-related adverse events were reported for 27 (13.9%) patients. Similar percentages of clobazam-treated patients with and without a history of aggressive behavior experienced an aggression-related adverse event (16.7% versus 15.5%, respectively). In the medium- and high-dosage clobazam groups, onset of aggression-related adverse effects occurred within the 3-week titration period with 63.2% resolving by the end of the study. Aggression-related adverse event onset and resolution were similar for the low-dosage clobazam and placebo groups. Analysis of baseline to postbaseline T scores for the behavior domains of the Child Behavior Checklist indicated no significant differences between clobazam and placebo.
Conclusions:
Post hoc analyses indicate that the overall rate of aggression with clobazam treatment was low and dosage dependent. Clobazam treatment was effective in reducing drop seizures regardless of aggression experience.
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