Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials

Abstract

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.

Keywords: Augmentation; Clinical global impression–improvement; Dopamine agonist; Gabapentin enacarbil; International restless legs syndrome rating scale; Restless legs syndrome.

Figures

Figure 1

IRLS Rating Scale total score change from baseline in DA-naive vs DA-exposed patients (week 12). Change from baseline reported as the LS mean change from baseline. DA, dopamine agonist; Diff, mean treatment difference between DA-naive and DA-exposed treatment groups; GEn, gabapentin enacarbil; IRLS, International Restless Legs Syndrome; LS, least squares; SE, standard error.

Figure 2

IRLS Rating Scale total score changes from baseline by visit in DA-naive (A) and DA-exposed (B) patients. MMRM analysis. Change from baseline reported as the LS mean change from baseline. Within the placebo group, there were no statistically significant differences in change in IRLS Rating Scale total score from baseline between the DA-naive vs DA-exposed patients in any treatment arm at any of the visits, except at week 1. Within the GEn 600-mg and GEn 1200-mg groups, there were no statistically significant differences in change in IRLS Rating Scale total score from baseline between the DA-naive vs DA-exposed patients in any treatment arm at any of the visits. DA, dopamine agonist; GEn, gabapentin enacarbil; IRLS, International Restless Legs Scale; LS, least squares; MMRM, mixed-effect model for repeated measures; W, week.

Figure 3

Percentage of responders on the investigator-rated CGI-I in DA-naive vs DA-exposed patients (week 12). Response on the CGI-I was defined as “much” or “very much” improved at week 12. CGI-I, Clinical Global Impression–Improvement; CI, confidence interval; DA, dopamine agonist; GEn, gabapentin enacarbil; OR, odds ratio.