LTG vs CBZ
(1995)Objective
To compare lamotrigine with carbamazepine as initial monotherapy for newly diagnosed epilepsy.
Study Summary
• Lamotrigine was significantly better tolerated, with higher study completion (65% vs 51%, p=0.018) and fewer withdrawals for adverse events (15% vs 27%)
• Time to treatment failure was significantly longer with lamotrigine
Intervention
Lamotrigine (target 100-200 mg/day) vs carbamazepine (target 400-800 mg/day) monotherapy; N=260
Inclusion Criteria
Age ≥4 years, newly diagnosed epilepsy requiring monotherapy, ≥2 unprovoked seizures in the previous year.
Study Design
Arms: Lamotrigine vs Carbamazepine (control)
Patients per Arm: Total N=260 randomized 1:1; 151 completed 48 weeks
Outcome
• Study completion: LTG 65% vs CBZ 51% (p=0.018), HR 1.57 (95% CI 1.07-2.31)
• Withdrawal for adverse events: LTG 15% vs CBZ 27%
• Somnolence LTG 12% vs CBZ 22% (p<0.05); time to treatment failure longer 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