Pregabalin French
Year of Publication: 2003
Journal: Neurology
Link: https://doi.org/10.1212/01.WNL.0000068024.20285.65
PDF: https://www.neurology.org/doi/pdf/10.121...068024.20285.65
PDF: Clinical Question
Does adjunctive pregabalin reduce seizure frequency in a dose-dependent manner in patients with refractory partial seizures?
Study Overview
Objective
To evaluate the dose-response efficacy and safety of adjunctive pregabalin for refractory partial seizures.
Study Summary
- Seizure-frequency reduction rose with dose: 34% (150 mg), 44% (300 mg), and 54% (600 mg) vs 7% with placebo (all p≤0.0001); 50 mg was no better than placebo
- ≥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
Patients per Arm
Placebo: 100, 50 mg: 88, 150 mg: 86, 300 mg: 90, 600 mg: 89
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
Design
Study Type: Phase 3 multicenter randomized double-blind placebo-controlled parallel-group dose-ranging study
Randomization: 1
Blinding: Double-blind
Follow-up Duration: 12-week treatment (after 8-week baseline)
Sample Size: 453
Analyzed: 453
Analysis: ITT with LOCF; ANOVA with step-down comparisons vs placebo; Cochran-Mantel-Haenszel
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| N | 100 | 353 |
| Age mean | 39.5 | ~38 |
| Female | 48% | ~52% |
| Median seizures/28d | 9.5 | ~9 |
| Epilepsy duration | 24 y | ~25 y |
| 2+ AEDs | 72% | ~70% |
Arms
| Field | Control | Pregabalin 50 mg/d | Pregabalin 150 mg/d | Pregabalin 300 mg/d | Pregabalin 600 mg/d |
|---|---|---|---|---|---|
| N | 100 | 88 | 86 | 90 | 89 |
| Intervention | Placebo BID, no titration | Pregabalin 25 mg BID (total 50 mg/d), no titration | Pregabalin 75 mg BID (total 150 mg/d), no titration | Pregabalin 150 mg BID (total 300 mg/d), no titration | Pregabalin 300 mg BID (total 600 mg/d), no titration |
| Duration | 12 weeks | 12 weeks | 12 weeks | 12 weeks | 12 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Percent reduction in partial-seizure frequency from baseline to week 12 (via RRatio) | Primary | 7% reduction (placebo) | 12% (50 mg), 34% (150 mg), 44% (300 mg), 54% (600 mg) | Linear dose-response | p≤0.0001 for 150, 300, 600 mg vs placebo; 50 mg not significant |
| Responder rate (≥50% reduction) | Secondary | 14% | 15%, 31%, 40%, 51% | p≤0.006 for 150, 300, 600 mg | |
| Dose-response trend (RRatio) | Secondary | Reference | Monotonic | p≤0.0001 linear trend | |
| Dose-response trend (responder rate) | Secondary | Reference | Monotonic | p≤0.001 linear trend | |
| Placebo-corrected responder rate success | Secondary | Reference | 17.4% (150 mg) to 36.6% (600 mg) | Compares favorably with other new AEDs | |
| Reduction in seizures with secondary generalization | Secondary | Minimal change | Reduced at 300, 600 mg | Consistent with primary | |
| Any AE | Adverse | 74% | 67%, 71%, 84%, 89% across doses | Dose-related rise | |
| Dizziness | Adverse | 9% | 9%, 16%, 31%, 43% | Clear dose-response | |
| Somnolence | Adverse | 11% | 10%, 17%, 18%, 28% | Dose-related | |
| Ataxia | Adverse | 3% | 3%, 11%, 10%, 15% | Dose-related | |
| Weight gain | Adverse | 0% | 1%, 2%, 7%, 12% | Dose-related | |
| Blurred vision (amblyopia) | Adverse | 5% | 3%, 4%, 8%, 10% | Modest increase | |
| Headache | Adverse | 13% | 7%, 9%, 6%, 6% | No pregabalin signal | |
| Discontinuation for AE | Adverse | 5% | 7%, 1%, 14%, 24% | Steep at 600 mg | |
| Serious AE | Adverse | Uncommon | Uncommon | No safety signal beyond CNS AEs |
Subgroup Analysis
Efficacy consistent across seizure subtypes (simple partial, complex partial, secondarily generalized). Patients on 3 concomitant AEDs responded similarly to those on 1-2. No signal for cognitive adverse events ('thinking abnormal' 2-8% with no dose relationship). Most discontinuations due to dizziness occurred in first 2 weeks, supporting a potential for slower titration in clinical practice.
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
Funding
Pfizer Inc. (manufacturer of pregabalin/Lyrica)
Based on: Pregabalin French (Neurology, 2003)
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