PDF: Rufinamide LGS
(2008)Objective
Rufinamide (adjunctive) — to evaluate efficacy and safety for treatment of seizures associated with Lennox-Gastaut syndrome.
Study Summary
• Reduction in tonic-atonic drop seizures was dramatic: 42.5% reduction (rufinamide) vs 1.4% increase (placebo); p<0.0001.
• Seizure severity improvement and ≥50% responder rates for both total and drop seizures favored rufinamide.
• Drop seizures are particularly debilitating in LGS; rufinamide's effect on this subtype is clinically meaningful.
• Common AEs: somnolence (24%) and vomiting (22%); mostly mild-to-moderate, manageable.
• Established rufinamide as an effective adjunct for LGS; FDA-approved in 2008 and a European orphan drug for this rare encephalopathy.
Intervention
Rufinamide adjunctive therapy titrated to target dose (45 mg/kg/d, max 3200 mg/d) vs placebo; 84-day treatment after 28-day baseline.
Inclusion Criteria
Patients 4–30 years with Lennox-Gastaut syndrome: ≥90 seizures in preceding month, multiple seizure types including tonic-atonic, and slow spike-and-wave EEG pattern.
Study Design
Arms: Rufinamide vs Placebo
Patients per Arm: Rufinamide 74; Placebo 64 (N=138 randomized; 139 eligible, 138 analyzed)
Outcome
• Key: Median % change in tonic-atonic (drop) seizure frequency — -42.5% vs +1.4%; p<0.0001
• Seizure severity rating improvement favored rufinamide (p=0.0041)
• 50% responder rate for total seizures: higher with rufinamide (p=0.0045)
• 50% responder rate for tonic-atonic seizures: higher with rufinamide (p=0.002)
• Common AEs: somnolence 24.3% (rufinamide) vs 12.5% (placebo); vomiting 21.6% vs 6.3%
Clinical Question
Is adjunctive rufinamide effective for Lennox-Gastaut syndrome, particularly for drop seizures?
Bottom Line
In patients aged 4–30 years with Lennox-Gastaut syndrome, adjunctive rufinamide reduced median total seizure frequency by 32.7% vs 11.7% with placebo (p=0.0015) and dramatically reduced tonic-atonic (drop) seizures by 42.5% vs a 1.4% increase on placebo (p<0.0001) over 84 days. Established rufinamide as an effective adjunctive treatment for drop seizures in LGS.
Major Points
- Phase 3 multicenter randomized double-blind placebo-controlled adjunctive trial
- 139 patients aged 4-30 with LGS (multiple seizure types, slow spike-wave EEG, ≥90 seizures in past month) randomized; 138 analyzed
- Rufinamide 74 vs placebo 64 (patients continued their existing AEDs)
- Rufinamide titrated to 45 mg/kg/d (max 3200 mg/d) over 14 days, then 84-day maintenance
- Primary endpoint: median % change in total seizure frequency per 28 days during maintenance
- Key secondary: median % change in tonic-atonic (drop) seizure frequency
- Median total seizure reduction: -32.7% (rufinamide) vs -11.7% (placebo); p=0.0015
- Drop seizures: -42.5% (rufinamide) vs +1.4% (placebo); p<0.0001 — a dramatic effect
- Seizure severity rating (investigator global improvement) favored rufinamide (p=0.0041)
- 50% responder rate total seizures: higher with rufinamide (p=0.0045)
- 50% responder rate for tonic-atonic seizures: higher with rufinamide (p=0.002)
- Common AEs: somnolence (24.3% vs 12.5%), vomiting (21.6% vs 6.3%)
- Discontinuation due to AEs: similar overall between arms
- Led to FDA approval of rufinamide in 2008 for adjunctive treatment of LGS seizures (age 1+)
- EU orphan drug designation for LGS
- Particularly valued for its effect on drop seizures, which are a major cause of injury in LGS
Study Design
- Study Type
- Phase 3 multicenter randomized double-blind placebo-controlled parallel-group adjunctive trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 139
- Follow-up
- 14-day titration + 84-day maintenance (98 days total)
- Centers
- Multicenter, international
Primary Outcome
Definition: Median percent change in total seizure frequency per 28 days during 84-day maintenance
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -11.7% (placebo) | -32.7% (rufinamide) | - | p=0.0015 |
Limitations & Criticisms
- Short 84-day maintenance period does not assess durability
- Open-label extension data needed to evaluate long-term efficacy and tolerability
- Rare but serious hypersensitivity syndrome (DRESS) has been described with rufinamide post-marketing
- QT shortening effect requires caution in patients with Brugada syndrome or on QT-shortening drugs
- AE profile (somnolence, vomiting) can limit titration and tolerability
- No direct comparisons with other LGS drugs (clobazam, cannabidiol, fenfluramine) in same trial
Citation
Neurology 2008;70(21):1950-1958