PDF: Colbazam, Adjunct for LGS
(2015)Objective
Clobazam - 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 at low (0.25 mg/kg/day, max 10 mg/day), medium (0.5 mg/kg/day, max 20 mg/day), or high (1.0 mg/kg/day, max 40 mg/day) target doses in OV-1012; open-label extension (OV-1004) with dose flexibility up to 2.0 mg/kg/day (max 80 mg/day).
Inclusion Criteria
Patients aged 2–60 years with Lennox–Gastaut syndrome onset before age 11, weight ≥12.5 kg, ≥2 drop seizures during a 4-week baseline, on stable dosages of 1–3 background AEDs (excluding benzodiazepines).
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 (safety: 146 children, 40 adolescents, 52 adults); OV-1004: 267 entered (176 children, 45 adolescents, 46 adults)
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 change was similar across age groups and proportional to clobazam dose
- High-dose clobazam mean % change in drop seizures: −65% (children), −75% (adolescents), −82% (adults) (negative = decrease)
- ≥50% responder rates for drop seizures with high-dose: 77% children, 71% adolescents, 88% adults
- Long-term OLE: median seizure changes sustained through Year 3 across all age groups
- OLE Year 3 median % change in drop seizures: −90% (children), −100% (adolescents), −70% (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 (patients outside the US discontinued at 24 months per protocol)
- Countries
- United States, International
Primary Outcome
Definition: Mean percentage change in weekly drop-seizure rate during maintenance vs baseline, stratified by age group (post hoc, descriptive; no formal statistical comparisons). Negative values indicate reduction; positive values indicate worsening. Paper phrases metric as 'mean percentage decrease' but Fig 1 y-axis plots 'Mean Change in Seizure Rate, %'.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Children: +25%; Adolescents: -22%; Adults: +20% (negative = decrease) | Children: -22% (low), -43% (medium), -65% (high); Adolescents: -36% (low), -67% (medium), -75% (high); Adults: -39% (low), -51% (medium), -82% (high) (negative = decrease) | - |
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