PDF: Rufinamide LGS
(2008)Objective
To evaluate adjunctive rufinamide for generalized seizures associated with Lennox-Gastaut syndrome.
Study Summary
• Tonic-atonic (drop) seizures dropped 42.5% with rufinamide vs a 1.4% increase with placebo (p<0.0001)
• Investigator global improvement and ≥50% responder rates favored rufinamide; most common AEs were somnolence and vomiting
Intervention
Adjunctive rufinamide titrated to 45 mg/kg/day (max 3200 mg/day) vs placebo, added to 1-3 AEDs; N=138 analyzed
Inclusion Criteria
Age 4-30 years with LGS, ≥3 seizure types including tonic-atonic (drop) seizures, slow spike-and-wave EEG, ≥90 seizures in the 28-day baseline.
Study Design
Arms: Rufinamide vs Placebo (control)
Patients per Arm: Rufinamide: 74, Placebo: 64
Outcome
• Tonic-atonic (drop) seizures: -42.5% vs +1.4%, p<0.0001
• ≥50% responder rate higher for total seizures (p=0.0045) and drop seizures (p=0.002)
• AEs: somnolence 24.3% vs 12.5%, 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