title: Dose response of Gabapentin Enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies.
abstract: BACKGROUND
  The efficacy and tolerability of gabapentin enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg.
  
  
  OBJECTIVE
  The objective of this study was to evaluate key efficacy and safety outcomes in subjects with RLS treated with once-daily gabapentin enacarbil 600 mg, 1200 mg, 1800 mg and 2400 mg, providing supportive evidence of the efficacy of gabapentin enacarbil 600 mg compared with higher doses and placebo.
  
  
  METHODS
  Integrated post hoc analysis of three 12-week, randomized, double-blind, placebo-controlled trials in subjects with RLS.
  
  
  METHODS
  The three studies were carried out at multiple centres in the US.
  
  
  METHODS
  In total, 760 subjects were included in the pooled analysis (placebo, n = 245; gabapentin enacarbil 600 mg, n = 163; gabapentin enacarbil 1200 mg, n = 269; gabapentin enacarbil 1800 mg, n = 38; gabapentin enacarbil 2400 mg, n = 45).
  
  
  METHODS
  In all studies, gabapentin enacarbil or placebo was administered once daily at approximately 5 p.m. with food. Gabapentin enacarbil was initiated at a dose of 600 mg with subsequent titration in 600 mg increments every 3 days up to the randomized dose.
  
  
  METHODS
  The efficacy endpoints analysed for the purpose of this integrated analysis were change from baseline in International Restless Legs Scale (IRLS) total score and the proportion of responders (subjects rated as 'much' or 'very much' improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety endpoints assessed were the incidence of treatment-emergent adverse events (AEs) and serious AEs.
  
  
  RESULTS
  Gabapentin enacarbil 600 mg significantly improved IRLS total score compared with placebo (adjusted mean [standard error] change in IRLS total score from baseline to week 12 last observation carried forward: -13.6 [0.71] vs -9.3 [0.55]; adjusted mean treatment difference: -4.3; 95% CI -6.01, -2.52; p < 0.0001). A significantly higher proportion of subjects was rated as responders on the investigator-rated CGI-I scale with gabapentin enacarbil 600 mg compared with placebo (70.2% vs 42.2%; adjusted odds ratio 3.1; 95% CI 1.96, 4.89; p < 0.0001). Similar treatment benefits were seen with both efficacy endpoints for the three higher doses. The AEs reported most frequently were somnolence and dizziness; there was a dose-response relationship to these AEs. No new or unexpected safety issues were identified by this integrated analysis.
  
  
  CONCLUSIONS
  The lowest dose of gabapentin enacarbil evaluated (600 mg) significantly improved RLS symptoms compared with placebo. The safety profile was consistent with that described previously in the literature.
authors: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors: Susan A
authors: SA
authors: VanMeter
authors: Sarah T
authors: ST
authors: Kavanagh
authors: Samantha
authors: S
authors: Warren
authors: Ronald W
authors: RW
authors: Barrett
mesh_terms: D002219:Carbamates / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D023381:Endpoint Determination; D005260:Female; D018682:GABA Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D017060:Patient Satisfaction; D010919:Placebos; D016032:Randomized Controlled Trials as Topic; D012148:Restless Legs Syndrome / Q000175:diagnosis / Q000188:drug therapy*; D012720:Severity of Illness Index; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C493250:1-(((alpha-isobutanoyloxyethoxy)carbonyl)aminomethyl)-1-cyclohexaneacetic acid; D002219:Carbamates; D018682:GABA Agents; D010919:Placebos; D005680:gamma-Aminobutyric Acid