LTG vs CBZ
(1995)Objective
To compare the efficacy and tolerability of lamotrigine versus carbamazepine as initial monotherapy for newly diagnosed epilepsy
Study Summary
• Key AE differences: somnolence 12% vs 22% (p<0.05); rash leading to withdrawal 9% vs 13%; established lamotrigine as first-line alternative to carbamazepine for newly diagnosed epilepsy
Intervention
Lamotrigine (target 100-200 mg/day, max 400 mg) vs carbamazepine (target 400-800 mg/day) monotherapy
Inclusion Criteria
Age 12-65, newly diagnosed epilepsy (partial or GTCS), >=2 unprovoked seizures, previously untreated, appropriate for monotherapy
Study Design
Arms: Lamotrigine vs Carbamazepine
Patients per Arm: Lamotrigine: 131, Carbamazepine: 129
Outcome
• Tolerability: Study completion LTG 65% vs CBZ 51% (p=0.018, HR 1.57, 95% CI 1.07-2.31); AE withdrawal LTG 15% vs CBZ 27%
• AEs: somnolence LTG 12% vs CBZ 22% (p<0.05); rash withdrawal LTG 9% vs CBZ 13%; less dizziness, nausea, diplopia with LTG
Bottom Line
Lamotrigine and carbamazepine had equivalent efficacy as initial monotherapy for newly diagnosed epilepsy (39% vs 38% seizure-free during last 24 weeks). However, lamotrigine was significantly better tolerated with higher study completion rates (65% vs 51%, p=0.018) and fewer withdrawals due to adverse events (15% vs 27%). This trial helped establish lamotrigine as a first-line option for newly diagnosed epilepsy.
Major Points
- Equal efficacy: seizure-free during last 24 weeks — LTG 39% vs CBZ 38% (P=NS).
- LTG better tolerated: time to withdrawal significantly longer (P=0.001); fewer adverse effects.
- Treatment failure due to adverse events: LTG 10% vs CBZ 22%.
- Treatment failure due to lack of seizure control: LTG 16% vs CBZ 12% (P=NS).
- 260 patients randomized. 1:1 LTG vs CBZ monotherapy. 37 UK centers.
- Target doses: LTG 200 mg/day, CBZ 600 mg/day (slow titration).
- Landmark trial establishing LTG as viable alternative to CBZ for newly diagnosed epilepsy.
- Led to SANAD I/II which further compared first-line monotherapy options.
- Double-blind, randomized. Published NEJM 1998 (Brodie et al.).
- CBZ advantages: faster onset of action. LTG advantages: fewer cognitive/sedation side effects.
Study Design
- Study Type
- Multicenter, double-blind, randomized, parallel-group comparison
- Randomization
- Yes
- Blinding
- Double-blind (identical-appearing tablets)
- Sample Size
- 260
- Follow-up
- 48 weeks
- Centers
- 8
- Countries
- United Kingdom
Primary Outcome
Definition: Seizure-free during last 24 weeks of treatment
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| CBZ: 38% | LTG: 39% | - | Not significant |
Limitations & Criticisms
- Industry-sponsored by lamotrigine manufacturer (GlaxoWellcome), potential bias
- High dropout rate: only 151/260 (58%) completed the 48-week trial
- Short trial duration (48 weeks) for a lifelong treatment
- Relatively small sample for a non-inferiority/equivalence comparison
- No placebo arm
- Carbamazepine dose titration may have been too rapid, inflating its early AE rate
- Predominantly UK white population with limited ethnic diversity
Citation
Brodie MJ et al. Lancet. 1995;345(8948):476-479. DOI: 10.1016/S0140-6736(95)90581-2