Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial

Abstract

Objective: To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design.

Methods: Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%.

Results: The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%-37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalin's overall safety profile was consistent with prior trials.

Conclusions: Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures.

Classification of evidence: This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy.

Trial registration: ClinicalTrials.gov NCT00524030.

Figure 1. Monotherapy study design and end-of-study options

*OL: open-label continuation of pregabalin; **Taper: gradual decrease of pregabalin while initiating new antiepileptic drugs (AEDs).

Figure 2. Patient disposition and study populations

*Includes patients meeting seizure-related exit criteria. For patients meeting exit criteria, the primary reason for discontinuation was recorded as “insufficient clinical response” unless the patient also experienced an adverse event (AE) requiring discontinuation at the same time, in which case the primary reason for discontinuation was reported as the AE. **Other reasons for discontinuation included loss to follow-up, no longer willing to participate, protocol violation, pregnancy, or other.

Figure 3. Seizure-related exit rates and comparison with 74% and 68% thresholds, and Kaplan-Meier plot for patients (efficacy evaluable population; n = 148) meeting seizure-related exit criteria during the double-blind treatment phase

The exit rate was calculated as (1 − Kaplan-Meier product limit estimate for survival function) × 100%. CI = confidence interval.