Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study

Abstract

Objective: To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS).

Patients and methods: This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression-Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food. The primary end point was the proportion of patients experiencing relapse (worse scores on the IRLS and investigator-rated Clinical Global Impression of Change scale on 2 consecutive visits at least 1 week apart or withdrawal because of lack of efficacy) during the DB phase.

Results: A total of 221 of 327 patients completed the SB phase, 194 (96 in the gabapentin enacarbil group and 98 in the placebo group) were randomized to DB treatment, and 168 (84 in the gabapentin enacarbil group and 84 in the placebo group) completed the DB phase. A significantly smaller proportion of patients treated with gabapentin enacarbil (9/96 [9%]) experienced relapse compared with the placebo-treated patients (22/97 [23%]) (odds ratio, 0.353; 95% confidence interval, 0.2-0.8; P=.02). Somnolence and dizziness were the most common adverse events. One death occurred (unintentional choking during the SB phase) and was judged as being unrelated to the study drug. No clinically relevant changes were observed in laboratory values, in vital signs, or on electrocardiograms.

Conclusion: Gabapentin enacarbil, 1200 mg, maintained improvements in RLS symptoms compared with placebo and showed long-term tolerability in adults with moderate to severe primary RLS for up to 9 months of treatment.

Trial registration: ClinicalTrials.gov NCT00311363.

FIGURE 1.

Patient disposition. * Single-blind (SB) safety population defined as all patients who received at least 1 dose of SB study drug. † SB intent-to-treat (ITT) population defined as all patients who received at least 1 dose of SB study drug and for whom at least 1 SB visit, International Restless Legs Scale (IRLS) total score, and Clinical Global Impression–Improvement (CGI-I) assessment were available. ‡ Patients entering the randomized double-blind (DB) phase were responders who had an IRLS total score reduced by at least 6 points compared with baseline and an IRLS total score of less than 15 at week 24, who had a “much improved” or “very much improved” rating on the investigator-rated CGI-I at week 24, who were stable while taking 1200 mg of gabapentin enacarbil for at least 1 month before week 24, and who successfully completed the entire 24-week SB phase. § The DB safety population was defined as all patients who received at least 1 dose of DB study drug. // The DB ITT population was defined as all patients who received at least 1 dose of DB study drug and for whom at least 1 postrandomization visit IRLS total score and Clinical Global Impression of Change assessment were available.

FIGURE 2.

Time to relapse during double-blind treatment by week (double-blind intent-to-treat population). Log-rank test for treatment difference during week 24 to week 36 (P=.01). Relapse is defined as the worsening of restless legs syndrome symptoms (an increase of ≥6 points in the International Restless Legs Scale total score from double-blind baseline [week 24, randomization] to a score of ≥15 and a rating of “much worse” or “very much worse” on the investigator-rated Clinical Global Impression of Change on 2 consecutive visits ≥1 week apart) or withdrawal due to lack of efficacy during the double-blind phase.