MINNEAPOLIS—The prodrug gabapentin enacarbil improves sleep, daytime function, and symptoms of restless legs syndrome (RLS), according to two pooled analyses presented at the 28th Annual Meeting of the Associated Professional Sleep Societies. A dose of 600 mg/day provides significant improvement to patients with moderate to severe primary RLS, but a dose of 1,200 mg/day may be more effective for patients with severe primary RLS. The most frequent adverse events associated with gabapentin enacarbil are somnolence and dizziness.

Pooled Analyses of Three Clinical Trials
In both analyses, Mansoor Ahmed, MD, Medical Director of the Cleveland Sleep Research Center, and colleagues analyzed pooled data from three 12-week, randomized, placebo-controlled, double-blind trials of gabapentin enacarbil. Adult participants in the studies were diagnosed with RLS according to International RLS Study Group criteria. Patients had RLS symptoms for 15 or more days during the month before screening. Eligible participants had an IRLS Rating Scale total score of 15 or higher and documented symptoms of RLS for four or more days of the seven-day baseline period.

Patients discontinued RLS treatment two or more weeks before baseline. In all studies, participants responded to the IRLS Rating Scale at baseline and at 12 weeks. In one study, participants responded to the Post-Sleep Questionnaire (PSQ) at week 12.

Dr. Ahmed and colleagues pooled data for adult patients receiving placebo, 600 mg/day of gabapentin enacarbil, or 1,200 mg/day of gabapentin enacarbil. The researchers included all patients who received at least one dose of gabapentin enacarbil in their safety analysis. They used a modified intent-to-treat population for the efficacy analyses. The researchers analyzed treatment effects with a mixed model for repeated measures and Cochran–Mantel–Haenszel row mean scores testing. In addition, Dr. Ahmed and colleagues assessed correlations between IRLS Rating Scale items and two relevant PSQ items with Spearman’s rank correlation coefficient.

Reduced Symptom Severity in Moderate to Severe RLS
An analysis of data for patients with moderate to severe primary RLS included 161 individuals who received 600 mg/day of gabapentin enacarbil, 266 participants who received 1,200 mg/day of gabapentin enacarbil, and 244 participants who received placebo. The mean age of these patients was approximately 49, and mean IRLS Rating Scale score was approximately 23. About 60% of participants were female. The researchers observed no demographic differences between treatment groups.

The mean change in total IRLS Rating Scale score from baseline to week 12 was –14.2 for patients receiving 600 mg/day of gabapentin enacarbil, –13.8 for patients receiving 1,200 mg/day of gabapentin enacarbil, and –9.9 for placebo. Both doses significantly improved least squares mean treatment differences for the total IRLS Rating Scale score and for individual items on the IRLS Rating Scale, compared with placebo. In addition, the prodrug significantly improved mean changes from baseline to each week for the majority of IRLS Rating Scale items, including severity of sleep disturbance, daytime tiredness, and severity of mood disturbance.

The researchers made correlations between IRLS Rating Scale items and two items from the PSQ: overall sleep quality and ability to function. Most correlation coefficients showed strong or moderate positive correlations. The correlation indicates that the IRLS Rating Scale and PSQ complement each other as subjective measures of RLS symptoms, said the authors. “Correlative findings suggest a possible relationship between RLS symptom severity and sleep quality,” they added.

Higher Dose Had Larger Treatment Effects
In a second pooled analysis, Dr. Ahmed and colleagues examined data from the same three trials, but only for patients with severe primary RLS, which was defined as a baseline IRLS Rating Scale total score of 24 or greater. The researchers used the same methods of data analysis for this study as for the abovementioned study.

This analysis included 110 patients who received placebo, 80 patients who took 600 mg/day of gabapentin enacarbil, and 119 patients who took 1,200 mg/day of gabapentin enacarbil. Patients’ mean age was approximately 49, and about 65% of the population was female. Participants’ mean IRLS Rating Scale total score was 27.7. Demographic characteristics were similar among all treatment groups.

The least squares mean change from baseline to week 12 in total IRLS Rating Scale score was –16.3 for patients taking 600 mg/day of gabapentin enacarbil, –18.0 for patients taking 1,200 mg/day of gabapentin enacarbil, and –12.3 for patients taking placebo. Both doses of the prodrug significantly improved the least squares mean treatment difference in total IRLS Rating Scale score, compared with placebo.

The 600-mg/day dose of gabapentin enacarbil significantly improved least squares mean treatment differences for most IRLS Rating Scale items at week 12, compared with placebo, except for RLS severity overall. In contrast, the 1,200-mg/day dose of gabapentin enacarbil significantly improved least squares mean treatment differences for all IRLS Rating Scale items at week 12, compared with placebo. The researchers saw no significant least squares mean treatment differences between the two doses for any IRLS Rating Scale item at week 12.

Patients receiving 600 mg/day of gabapentin enacarbil had significant improvement from baseline to week 12 on all PSQ items, compared with placebo, except for overall quality of sleep. Patients taking 1,200 mg/day of gabapentin enacarbil had significant improvement on all PSQ items from baseline to week 12, compared with placebo.

—Erik Greb

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