PDF: Pregabalin French
(2003)Objective
To evaluate the dose-response efficacy and safety of adjunctive pregabalin for refractory partial seizures.
Study Summary
• ≥50% responder rates were 31%, 40%, and 51% vs 14% with placebo (p≤0.006 for 150/300/600 mg)
• Dose-related CNS adverse events (dizziness, somnolence, ataxia) and discontinuations increased with dose, peaking at 600 mg/day
Intervention
Adjunctive pregabalin 50, 150, 300, or 600 mg/day (BID, no titration) vs placebo, added to 1-3 AEDs; N=453
Inclusion Criteria
Age 12-70 years with refractory partial seizures on 1-3 AEDs (8-week baseline; 12-week treatment).
Study Design
Arms: Placebo vs Pregabalin 50 vs 150 vs 300 vs 600 mg/day
Patients per Arm: Placebo: 100, 50 mg: 88, 150 mg: 86, 300 mg: 90, 600 mg: 89
Outcome
• ≥50% responder rate: 14%, 15%, 31%, 40%, 51% (p≤0.006 for 150/300/600 mg)
• Significant linear dose-response for both efficacy measures
• Dose-related AEs (dizziness up to 43%); discontinuation for AE 5%, 7%, 1%, 14%, 24% across arms
Bottom Line
In 453 patients with refractory partial seizures despite 1-3 AEDs, adjunctive pregabalin 150, 300, and 600 mg/day produced 34%, 44%, and 54% seizure-frequency reductions vs 7% with placebo (all p≤0.0001). Responder rates (≥50% reduction): 31%, 40%, 51% vs 14% placebo. Dose-related CNS AEs (dizziness, somnolence, ataxia) and discontinuations (5%, 7%, 1%, 14%, 24%) rose with dose. Established pregabalin's dose-response relationship and supported FDA approval (2005) for adjunctive partial-onset seizures.
Major Points
- Phase 3 multicenter randomized double-blind placebo-controlled dose-ranging study at 76 US/Canada centers (French 2003, Neurology)
- N=453 ITT adolescents/adults 12-70 with refractory partial seizures on 1-3 AEDs
- 5 arms: placebo, pregabalin 50, 150, 300, 600 mg/day (BID, no titration) after 8-week baseline, 12-week treatment
- Primary measure: seizure frequency reduction (RRatio method) and responder rate
- Seizure reduction: 7% (placebo), 12% (50 mg), 34% (150 mg), 44% (300 mg), 54% (600 mg); p≤0.0001 for 150/300/600 mg
- 50 mg/day not better than placebo — subtherapeutic
- Responder rate (≥50% reduction): 14%, 15%, 31%, 40%, 51% across arms; p≤0.006 for 150/300/600 mg
- Linear dose-response trend significant for both RRatio and responder rate
- Dose-related CNS AEs: dizziness 9-43%, somnolence 11-28%, ataxia 3-15%, weight gain 0-12%
- Discontinuation for AE: 5%, 7%, 1%, 14%, 24% — steep increase at 600 mg/day
- No-titration design inflated early AE rate; clinical practice uses slower titration
- Supported 2005 FDA approval of pregabalin (Lyrica) for adjunctive partial-onset seizures
Study Design
- Study Type
- Phase 3 multicenter randomized double-blind placebo-controlled parallel-group dose-ranging study
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 453
- Follow-up
- 12-week treatment (after 8-week baseline)
Primary Outcome
Definition: Percent reduction in partial-seizure frequency from baseline to week 12 (via RRatio)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 7% reduction (placebo) | 12% (50 mg), 34% (150 mg), 44% (300 mg), 54% (600 mg) | - (Not tabulated individually; ANOVA-based) | p≤0.0001 for 150, 300, 600 mg vs placebo; 50 mg not significant |
Limitations & Criticisms
- Only 12-week treatment period — long-term efficacy and tolerance not addressed
- No-titration design inflated early AE rate and discontinuations at 600 mg; clinical practice uses slower titration
- 50-mg arm clearly ineffective, confirming this as a subtherapeutic dose — useful but unnecessary subgroup
- Refractory population on average 25 years of epilepsy and 10+ seizures/month — results may not fully translate to newly treated or earlier-stage patients
- Dose-related weight gain signal (mean 2.28 kg at 600 mg) not fully explored — later recognized as clinically important
- Suicidal ideation/behavior risk (later AED class warning 2008) not specifically assessed