title: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00298623, NCT00365352, and NCT01332305.
authors.affiliation: University of Texas Health Science Center at Houston, 6410 Fannin Street, Suite 1010, Houston, TX 77030 USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Ondo
authors.affiliation: University of California Irvine Movement Disorders Program, 100 Irvine Hall, Irvine, CA 92697 USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Hermanowicz
authors.affiliation: Sleep Research Institute, Alberto Alcocer 19, 28036 Madrid, Spain.
authors.forename: Diego García
authors.initials: DG
authors.lastname: Borreguero
authors.affiliation: Summit Analytical, LLC, 2422 Stout Street, Denver, CO 80205 USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Jaros
authors.affiliation: XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051 USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.affiliation: XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051 USA.
authors.forename: Gwendoline
authors.initials: G
authors.lastname: Shang
keywords: Augmentation; Clinical global impression–improvement; Dopamine agonist; Gabapentin enacarbil; International restless legs syndrome rating scale; Restless legs syndrome