A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome

Abstract

Study objective: To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS).

Methods: This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events.

Results: 325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: -3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo-treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg).

Conclusions: GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated.

Trial registration: ClinicalTrials.gov NCT00365352.

Keywords: GSK1838262; Gabapentin enacarbil; PIVOT RLS II; XP13512; restless legs syndrome.

Figures

Figure 1

Subject disposition a2 subjects were ineligible for study entry due to failed entry criteria at baseline. b1 subject withdrawn due to an adverse event of somnolence. c8 subjects withdrawn due to adverse events of depression (n = 2), hypotension (n = 1), vertigo (n = 1), decreased libido (n = 1), joint sprain (n = 1), sedation (n = 1), and nausea and dizziness (n = 1). d6 subjects withdrawn due to adverse events of somnolence (n = 1), fatigue and somnolence (n = 1), increased platelet count (n = 1), dizziness (n = 1), sedation (n = 1), and hypertension (n = 1). e6 subjects withdrawn due to adverse events of palpitations and chest discomfort (n = 1), mood swings (n = 1), headache (n = 1), pruritis (n = 1), joint swelling (n = 1), and sleep apnea syndrome (n = 1). mITT, modified intent-to-treat.

Figure 2

Mean (SD) change from baseline in IRLS total score by visit (mITT population) Adjusted mean treatment difference GEn compared with placebo at Week 12 LOCF: Co-primary endpoint: GEn 1200 mg, −3.5 (95% CI: −5.6, −1.3; p = 0.0015); Secondary endpoint: GEn 600 mg, −4.3 (95% CI: −6.4, −2.3; p

Figure 3

Proportion of responders (much or very much improved) on the investigator-rated CGI-I by visit (mITT population) Adjusted odds ratios for GEn compared with placebo at Week 12 LOCF: Co-primary endpoint: GEn 1200 mg, 4.3 (95% CI: 2.34, 7.86; p aObserved case. ***p < 0.0001; **p < 0.001; *p < 0.01; †p < 0.05 compared with placebo. CI, confidence interval; CGI-I, Clinical Global Impression–Improvement scale; GEn, gabapentin enacarbil; LOCF, last observation carried forward; mITT, modified intent-to-treat.

Figure 4

Proportion of subjects free of RLS symptoms over 24 hours, beginning at 8 am (mITT Population) Median time to onset of RLS symptoms over 24 hours Baselinea: 5.5 hours (95% CI: 4.0, 7.5) Week 12: GEn 1200 mg, 13.8 h (95% CI: 11.5, 17.0), GEn 600 mg, 13.5 h (95% CI: 12.5, 16.5), Placebo, 12.8 h (95% CI: 9.5, 15.0) aCombined treatment groups. CI, confidence interval; GEn, gabapentin enacarbil; mITT, modified intent-to-treat.

Figure 5

Proportion of subjects reporting no RLS symptoms at Baseline and Week 12 (mITT Population) Assessed during the 24 hours prior to baseline and Week 12 visits. aCombined treatment groups. GEn, gabapentin enacarbil; mITT, modified intent-to-treat.

Figure 6

Mean (SD) change from baseline in daily (a) wake time after sleep onset and (b) total sleep time on the PghSD by visit (mITT Population) (a) Adjusted mean treatment difference, GEn compared with placebo at Week 12 LOCF: GEn 1200 mg, –9.8 (95% CI: –15.5, –4.2; p = 0.0007); GEn 600 mg, –7.6 (95% CI: –13.3, –2.0; p = 0.0081). **p < 0.001; *p < 0.01; †p < 0.05. (b) Adjusted mean treatment difference, GEn compared with placebo at Week 12 LOCF: GEn 1200 mg, 0.2 (95% CI: −0.1, 0.6; p = 0.1161); GEn 600 mg, 0.1 (95% CI: −0.2, 0.4; p = 0.6778). *p < 0.01; †p < 0.05. CI, confidence interval; GEn, gabapentin enacarbil; LOCF, last observation carried forward; mITT, modified intent-to-treat; PghSD, Pittsburgh Sleep Diary; SD, standard deviation.

Figure 7

Mean (SD) change from baseline in domains of the MOS Sleep Scalea by visit (mITT Population) Adjusted mean treatment difference GEn compared with placebo at Week 12 LOCF: GEn 1200 mg: Sleep disturbance, –13.4 (95% CI: –18.5, –8.2; p †p < 0.05. aScale 0–100, except for sleep quantity; decreases in daytime somnolence and sleep disturbance, and increases in sleep adequacy and quantity represent improvements. CI, confidence interval; GEn, gabapentin enacarbil; LOCF, last observation carried forward; mITT, modified intent-to-treat; MOS, Medical Outcomes Study; SD, standard deviation.

Figure S1

24-hour RLS symptom diary

Figure S1

24-hour RLS symptom diary

Figure S2

Sudden Onset of Sleep questionnaire