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Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

ABSTRACT: Gabapentin enacarbil is a prodrug of the anticonvulsant gabapentin. The efficacy and safety of gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (RLS) has been evaluated in several clinical trials in the United States and Japan. Although most clinical trials assessed gabapentin enacarbil at doses greater than 600 mg/day and demonstrated the overall safety and efficacy (defined as improvements in the coprimary endpoints of the international RLS rating scale [IRLS] total score and Clinical Global Impression-Improvement response), the US Food and Drug Administration approved the 600 mg once-daily dosage because doses higher than 600 mg/day were considered to provide no additional benefits and were associated with higher rates of adverse events, such as somnolence and dizziness. Nonetheless, the results of clinical trials and post hoc meta-analyses have indicated that the 1,200 mg once-daily dosage was the most validated gabapentin enacarbil treatment for not only subjective RLS symptoms but also severe sleep disturbance associated with RLS. A Japanese dose-finding study showed that 900 mg/day, the intermediate dose between 600 and 1,200 mg, failed to show a significant improvement in IRLS total score, probably because many of the patients who discontinued treatment did so early, suggesting that a half-landing dose may cause more adverse effects than favorable ones in some RLS patients early in the treatment. Gabapentin enacarbil may have two distinct therapeutic doses for the treatment of RLS: 600 mg/day or lower doses for the treatment of subjective RLS symptoms and 1,200 mg/day or higher doses for the treatment of both subjective RLS symptoms and associated problems such as severe sleep disturbances.

SUBMITTER: Kume A

PROVIDER: S-EPMC3921090 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

Kume Akito A

Neuropsychiatric disease and treatment 20140203

Gabapentin enacarbil is a prodrug of the anticonvulsant gabapentin. The efficacy and safety of gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (RLS) has been evaluated in several clinical trials in the United States and Japan. Although most clinical trials assessed gabapentin enacarbil at doses greater than 600 mg/day and demonstrated the overall safety and efficacy (defined as improvements in the coprimary endpoints of the international RLS rating sca ...[more]

PMID: 24523590

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Project description:BACKGROUND:Dopamine agonists (DAs) are a first-line therapy for moderate-to-severe restless legs syndrome (RLS), but these treatments may lead to complications, such as augmentation and impulse control disorders, requiring switching to another therapeutic class. Here we assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with moderate-to-severe primary RLS, with or without prior DA exposure. METHODS:Data from 3 trials were pooled. Patients were identified as DA-naive or DA-exposed, based on prior treatment with ropinirole, pramipexole, rotigotine, or pergolide mesylate, and the dopamine precursor levodopa. Details on prior treatment duration and dose were unavailable. Patients with a history of augmentation were excluded. Within DA-naive/DA-exposed patients we investigated the co-primary end points from the pivotal trials: mean change from baseline to week 12 in International RLS (IRLS) Rating Scale total score and proportion of responders ("much"/"very much" improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety was also assessed. RESULTS:671 patients were randomized (DA-naive: placebo, n?=?194; GEn 600 mg, n?=?131; GEn 1200 mg, n?=?214; DA-exposed: placebo, n?=?50; GEn 600 mg, n?=?30; GEn 1200 mg, n?=?52). Across treatment arms, no significant differences between DA-naive and DA-exposed subgroups in IRLS Rating Scale total score change from baseline at any visit were seen, except week 1 in the placebo group (-6.1 DA-naive vs -3.4 DA-exposed, P?=?.020). No significant differences in the odds of CGI-I response at week 12 between DA-naive vs DA-exposed patients in any treatment group were seen; however, with placebo there was a nonsignificant trend toward fewer responders among DA-exposed (34.0%) vs DA-naive (44.3%) patients. Both GEn doses significantly improved the IRLS Rating Scale total score change from baseline and CGI-I response vs placebo, regardless of prior DA exposure. The most common treatment-emergent adverse events were dizziness and somnolence. CONCLUSIONS:Prior DA exposure had no significant effect on efficacy or tolerability of GEn (600 or 1200 mg) in this pooled analysis of adults with moderate-to-severe primary RLS. These data support the use of GEn in DA-exposed and DA-naive patients. TRIAL REGISTRATION:ClinicalTrials.gov NCT00298623, NCT00365352, and NCT01332305.

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

Dataset Information

Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

Publications

Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

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