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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

Clinical Question

Does adjunctive pregabalin reduce seizure frequency in a dose-dependent manner in patients with refractory partial seizures?

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	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)	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)

Content summarized and formatted by NeuroTrials.ai.

Pregabalin French

(2003)

Objective

Pregabalin 50, 150, 300, or 600 mg/day as adjunctive therapy — to establish the dose-response efficacy, tolerability, and safety of pregabalin without dose titration in refractory partial-onset seizures.

Study Summary

• Pregabalin 150, 300, 600 mg/day reduced seizures 34%, 44%, 54% vs 7% placebo (all p≤0.0001); 50 mg/day 12% was not better than placebo.
• Responder rate (≥50% seizure reduction): 31%, 40%, 51% vs 14% placebo (p≤0.006); dose-response linear.
• Twice-daily dosing without titration was effective and generally tolerated despite higher early AE rates.
• CNS AEs (dizziness, somnolence, ataxia) were dose-related; weight gain appeared at higher doses.
• Discontinuation for AEs: 5% (placebo), 7%, 1%, 14%, 24% across placebo to 600 mg/day — steepest at 600 mg.
• Established pregabalin as an effective adjunctive AED for partial seizures with a clear dose-response, supporting 2005 FDA approval.

Intervention

Pregabalin 50, 150, 300, or 600 mg/day administered twice-daily without dose titration, or placebo, as adjunctive therapy to existing 1-3 AEDs for 12 weeks after an 8-week baseline.

Inclusion Criteria

Adolescents/adults 12-70 years with refractory partial seizures, ≥3 partial seizures in the month before screening and ≥6 in the 8-week baseline, on 1-3 stable AEDs, CrCl >60 mL/min.

Study Design

Arms: Placebo vs Pregabalin 50, 150, 300, 600 mg/day (all BID, no titration)

Patients per Arm: Placebo 100; 50 mg 88; 150 mg 86; 300 mg 90; 600 mg 89 (N=453 ITT)

Outcome

• Primary: Seizure frequency reduction — 7% (placebo), 12% (50 mg), 34% (150 mg), 44% (300 mg), 54% (600 mg); p≤0.0001 for 150, 300, 600 mg vs placebo
• Responder rate (≥50% reduction): 14%, 15%, 31%, 40%, 51% across doses; p≤0.006 for 150, 300, 600 mg
• Dose-response linear trend significant for both RRatio and responder rate (p≤0.001)
• AE discontinuation: 5%, 7%, 1%, 14%, 24% across dose groups — substantially higher at 600 mg
• Dizziness (9-43%), somnolence (11-28%), ataxia (3-15%), weight gain (0-12%) rose with dose

Bottom Line

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

Citation

View Original Publication →

Pregabalin French

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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