PDF: Colbazam, Adjunct for LGS
(2015)Objective
Colbazam - To evaluate the short- and long-term efficacy and safety of clobazam as adjunctive treatment for Lennox–Gastaut syndrome across pediatric, adolescent, and adult age groups.
Study Summary
Intervention
Clobazam administered at low, medium, or high target doses (up to 1.0 mg/kg/day), followed by open-label extension with dose flexibility.
Inclusion Criteria
Patients aged 2–60 years with Lennox–Gastaut syndrome onset <11 years, ≥2 drop seizures during baseline, and on stable background AEDs.
Study Design
Arms: Placebo, Low-, Medium-, and High-Dose Clobazam in OV-1012; all received clobazam in OV-1004
Patients per Arm: OV-1012: 238 randomized; OV-1004: 267 enrolled
Outcome
Bottom Line
Post hoc analyses demonstrated that adjunctive clobazam was similarly effective and well-tolerated across all age groups (children ≥2 to <12 years, adolescents ≥12 to <17 years, and adults ≥17 years) for both short-term (OV-1012) and long-term (OV-1004) treatment of LGS. Efficacy was dose-dependent and sustained through Year 3, with no unexpected safety trends by age group.
Major Points
- Post hoc analysis of phase III trial OV-1012 and open-label extension OV-1004 stratified by age groups
- OV-1012: 238 randomized, 217 mITT population, 177 completed; Safety: 146 children, 40 adolescents, 52 adults
- OV-1004: 267 patients entered, 188 (70%) completed; 176 children, 45 adolescents, 46 adults
- Drop seizure reduction was similar across age groups and proportional to clobazam dose
- High-dose clobazam: drop seizure reduction 65% (children), 75% (adolescents), 82% (adults)
- ≥50% responder rates for drop seizures with high-dose: 77% children, 71% adolescents, 50% adults
- Long-term OLE: median seizure decreases sustained through Year 3 across all age groups
- Drop seizure reduction in OLE Year 3: 90% (children), 100% (adolescents), 80% (adults)
- Safety profile consistent across age groups with no unexpected trends
- Adults responded nearly as well as children despite longer duration of seizure disorder
Study Design
- Study Type
- Post hoc analyses of phase III randomized, double-blind, placebo-controlled trial (OV-1012) and open-label extension trial (OV-1004)
- Randomization
- Yes
- Blinding
- OV-1012: Double-blind; OV-1004: Open-label
- Sample Size
- 238
- Follow-up
- OV-1012: 4-week baseline + 3-week titration + 12-week maintenance; OV-1004: up to 6 years
- Countries
- United States, International
Primary Outcome
Definition: Mean percentage decrease in weekly drop-seizure rate during maintenance vs baseline, stratified by age group
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Children: +25%; Adolescents: -22%; Adults: +20% (increases indicate worsening) | Children: -22% to -65% (low to high dose); Adolescents: -36% to -75%; Adults: -39% to -82% | - |
Limitations & Criticisms
- Post hoc analysis rather than prospective age-stratified design
- Limited sample sizes in adolescent and adult subgroups preclude formal statistical comparisons
- Descriptive statistics only; no statistical tests comparing age groups
- Potential patient enrichment bias in OLE as only 6% withdrew for lack of efficacy
- Patients outside US discontinued OLE at 24 months per protocol, reducing long-term sample size
- Baseline seizure frequencies differed substantially between age groups (higher in children/adolescents)
- Different disease duration across age groups may confound comparisons
- Open-label extension lacks placebo control for long-term efficacy assessment
- Three Lundbeck employees among authors
- High SAE rate in OLE (42-48%) includes expected events for this severe population
Citation
Epilepsy Behav. 2015;46:221-226