Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

Figures & data

Table 1 Published Phase II and III clinical trials for gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome

Trial	Design	Setting	Duration	Participants	Dosage of GEn	Primary endpoints	Results	Adverse events
XP021 Kushida et al^Citation50	Randomized, DB, PC, crossover	9 US sites	14 days	38 (22 women, 34 white)	1,800 mg/day	IRLS score	Greater reduction in IRLS(P<0.000l)	Somnolence: 30.6% GEn, 2.8% placebo Dizziness: 27.8% GEn, 5.6% placebo
XP045 Walters et al^Citation51	Randomized, DB, PC	14 US sites	14 days	95 (59 women, 93 white)	600 mg/day, 1,200 mg/day	IRLS score for GEn 1,200 mg/day	Greater reduction in IRLS with GEn 1,200 mg/day (P<0.0001); no difference with GEn 600 mg/day	Somnolence: 36% GEn 1,200 mg, 14% GEn 600 mg, 15% placebo Dizziness: 18% GEn 1,200 mg, 14% GEn 600 mg, 3% placebo
XP081 Lal et al^Citation43	Randomized, DB, PC	21 US sites	12 weeks	217 (139 women, 208 white)	600 mg/day, 1,200 mg/day, 1,800 mg/day, 2,400 mg/day	NA	Dose-proportional exposure of gabapentin to GEn dose	Somnolence: 51 % GEn 2,400 mg, 26% GEn 1,800 mg, 24% GEn 1,200 mg, 15% GEn 600 mg, 5% placebo Dizziness: 40% GEn 2,400 mg, 26% GEn 1,800 mg, 22% GEn 1,200 mg, 21% GEn 600 mg, 2% placebo
XP052 PIVOT RLS-I Kushida et al^Citation52	Randomized, DB, PC	22 US sites	12 weeks	222 (132 women, 214 white)	1,200 mg/day	IRLS score and CGI-I score	Greater reduction in IRLS (P=0.0003) and more treatment responders by CGI-I (P<0.000l)	Somnolence: 27% GEn, 7% placebo Dizziness: 20% GEn, 5% placebo
XP053 PIVOT RLS-II Lee et al^Citation53	Randomized, DB, PC	28 US sites	12 weeks	325(189 women, 304 white)	600 mg/day, 1,200 mg/day	IRLS score and CGI-I score for GEn 1,200 mg/day	Greater reduction in IRLS (P=0.0015) and more treatment responders by CGI-I (P<0.000l) with GEn 1,200 mg/day; greater reduction in IRLS (P=0.0001) and more treatment responders by CGI-I (P<0.000l) with GEn 600 mg/day	Somnolence: 18.0% GEn 1,200 mg, 21.7% GEn 600 mg, 2.1% placebo Dizziness: 24.3% GEn 1,200 mg, 10.4% GEn 600 mg, 5.2% placebo
XP060 PIVOT RLS maintenance Bogan et al^Citation54	Randomized, DB, PC	27 US sites	24 weeks SB phase 12 weeks DB phase	194 (114 women, 184 white)	1,200 mg/day	Proportion of patients with RLS relapse during DB phase	Less relapse with GEn versus placebo (9% versus 23%; P=0.02)	SB phase: Somnolence: 29.8% Dizziness: 22.1 % DB phase: Somnolence: 3% GEn, 1% placebo Dizziness: 2% GEn, 1% placebo
XP055 Ellenbogen et al^Citation55	Open-label, extension	67 US sites	52 weeks	573 (336 women, 552 white)	1,200 mg/day	NA	GEn was generally safe and well tolerated and improved RLS symptoms for up to 64 weeks	Somnolence: 19.7% Dizziness: 11.5%
RXP110908 Winkelman et al^Citation56	Randomized, DB, PC, crossover	23 US sites	4 weeks	131 with significant sleep disturbance (76 women, 120 white)	1,200 mg/day	WTDS	Greater reduction in WTDS (−26.00 min; P<0.000l)	Somnolence: 13% GEn, 2% placebo Dizziness: 20% GEn, 2% placebo
CL-OOO5 Inoue et al^Citation60	Open-label	Japanese sites	52 weeks	181 (93 women, all Asian)	1,200 mg/day	NA	GEn improved RLS symptoms in Japanese patients with an accepted safety profile	Somnolence: 41.2% (prevalence 37.4% at 0–4 weeks to 13.7% at week 52) Dizziness: 46.2% (prevalence 42.3% at 0–4 weeks to 9.2% at week 52)
CL-0003 Inoue et al^Citation61	Randomized, DB, PC	Japanese sites	12 weeks	469 (211 women, all Asian)	600 mg/day, 900 mg/day, 1,200 mg/day	IRLS score for GEn 1,200 mg/day	Greater reduction in IRLS with GEn 1,200 mg/day (P=0.011) No difference with GEn 600 or 900 mg/day (when excluding patients who discontinued the study because of adverse events: greater reduction in IRLS with GEn 600 mg/day [P=0.012], 900 mg/day [P=0.024] and 1,200 mg/day [P=0.006])	Somnolence: 32.5% GEn 1,200 mg, 26.9% GEn 900 mg, 19.2% GEn 600 mg, 17.2% placebo Dizziness: 28.9% GEn 1,200 mg, 25.2% GEn 900 mg, 25.0% GEn 600 mg, 6.9% placebo

Abbreviations: GEn, gabapentin enacarbil; DB, double-blind; PC, placebo-controlled; IRLS, International Restless Legs Syndrome rating scale; CGI-I, Clinical Global Impression-Improvement; RLS, restless legs syndrome; NA, not applicable; SB, single-blind; WTDS, wake time during sleep.

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