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29th Annual Scientific Meeting of the American Pain Society, Baltimore, MD, May 6–8, 2010 Gabapentin Enacarbil Improves Pain Associated with Restless LegsSyndrome Daniel O. Lee,1 Ronald B. Ziman,2 A. Thomas Perkins,3 J. Steven Poceta,4 Arthur S. Walters,5 Ronald W. Barrett6
1Sleep Disorders Center, East Carolina Neurology, Inc., Greenville, NC; 2Northridge Neurological Center, Northridge, CA; 3Raleigh Neurology Associates, Raleigh, NC; 4Scripps Clinic, La Jolla, CA; 5Vanderbilt University, Nashville, TN; 6XenoPort, Inc., Santa Clara, CA
Introduction
All efficacy outcomes were performed on the modified intent-to-treat Figure 1. Mean (±2SE) change from baseline in average daily pain score
Figure 2. Proportion of subjects with A) ≥30% and B) ≥50% improvement in average daily pain score by visit (mITT population).
(mITT) population, which comprised all subjects in the safety (mITT population)
● Pain associated with Restless Legs Syndrome (RLS) is population who also had a baseline and at least one post-baseline A) Subjects with average daily pain scores >0 at baseline or at corresponding post-baseline visit
reported by approximately 60% of subjects, with 19% Efficacy outcomes were analyzed as change from baseline data using reporting pain as their most troublesome symptom.1 an ANCOVA model, adjusted for baseline score, pooled site and Gabapentin enacarbil (GEn) is a transported prodrug of treatment group; a treatment by pooled site interaction term was also gabapentin, absorbed throughout the large and small included in the model if significant (P<0.10), or responder outcomes intestine,2,3 that provides sustained, dose-proportional using a logistic regression model adjusted for pooled site and GEn, a non-dopaminergic treatment, has demonstrated Subgroup analyses of the proportion of responders with ≥30% or
≥50% improvement in average daily pain score from baseline were
PIVOT RLS II (XenoPort, Inc. protocol XP053; performed post hoc on those subjects with average daily pain scores ClinicalTrials.gov identifier NCT00365352) was a parallel ≥4 at baseline.
group, multicenter, 12-week, randomized, double-blind, placebo (PBO)-controlled study that assessed the efficacy and tolerability of GEn 600 mg and 1200 mg once daily in Week (LOCF)
Subjects
subjects with moderate-to-severe primary RLS.8 Secondary Overall, 325 subjects were randomized (GEn 1200 mg, n=113; GEn B) Subjects with average daily pain score ≥4 at baseline
endpoints assessing the efficacy of GEn 600 mg and PBO, subjects with pain score ≥4 at baseline (n=57) PBO, subjects with pain score ≥4 at baseline (n=57) 600 mg, n=115; PBO, n=97) and 279 subjects (GEn 1200 mg, n=98; GEn 600 mg, subjects with pain score ≥4 at baseline (n=59) GEn 600 mg, subjects with pain score ≥4 at baseline (n=59) 1200 mg in relieving pain associated with RLS are presented.
GEn 600 mg, n=104; PBO, n=77) completed the study. The mITT GEn 1200 mg, subjects with pain score ≥4 at baseline (n=62) GEn 1200 mg, subjects with pain score ≥4 at baseline (n=62) population comprised 321 subjects (GEn 1200 mg, n=111; GEn Subject demographics and baseline characteristics reflected a Study Design
population with moderate-to-severe primary RLS (Table 1).
Men and women (≥18 years) with RLS and International Restless
A total of 285/314 (91%) subjects reported RLS pain scores >0 at ≥15 at Visits 1 (baseline) and 2 (Day 1),
baseline or Week 12 LOCF, and 178/314 (57%) had average daily pain body mass index ≤34 kg/m2, and estimated creatinine clearance of
scores ≥4 at baseline.
≥60 mL/min were eligible.
Subjects were randomized 1:1:1 to receive GEn 1200 mg (2 x 600 mg Coprimary Endpoints
extended release tablets [600 mg on Days 1–3]), GEn 600 mg GEn 1200 mg significantly improved mean (SD) IRLS total score from (1 x 600 mg extended release tablet), or matching PBO once daily baseline to Week 12 LOCF compared with PBO (–13.0 [9.12] vs –9.8 Week (LOCF)
[7.69]; adjusted mean treatment difference [AMTD]: –3.5; 95% CI: ***P<0.0001, **P<0.001, *P<0.01, †P<0.05 vs PBO; ANCOVA with baseline average daily pain score as covariate and treatment and pooled site as main effects.
aSubjects with average daily pain scores >0 at baseline or at Week 12 LOCF (primary timepoint).
*P≤0.01 vs PBO; †P≤0.05. Logistic Regression model adjusted for pooled site and treatment.
Assessments
Significantly more GEn 1200 mg-treated subjects were considered Subjects recorded “pain associated with RLS symptoms” in the past CGI-I responders compared with PBO at Week 12 LOCF (77.5% vs 24 hours on an 11-point scale (0=no pain, 10=most intense pain 44.8%; adjusted odds ratio [AOR]: 4.3; 95% CI: 2.34, 7.86; P<0.0001).
imaginable) for 7 days prior to baseline and at each study visit at pain scores >0 at baseline or Week 12 LOCF (–2.5 [2.20] vs –1.7 [2.28]; Response of ≥50% Improvement in Average Daily
References
Weeks 2, 4, 8, and 12 (or the early termination visit). Average daily pain Secondary Endpoints
AMTD: –0.9; 95% CI: –1.4, –0.3; P=0.0029; Figure 1A) and subjects
Pain Scores
scores were calculated for each 7-day period.
with baseline scores ≥4 (–3.5 [2.19] vs –2.3 [2.34]; AMTD: –1.1; 95%
GEn 600 mg significantly improved mean (SD) IRLS total score from Allen RP, et al. Arch Intern Med 2005;165:1286–92.
CI: –1.9, –0.3; P=0.0084; Figure 1B).
Significantly more GEn 1200 mg-treated subjects reported a ≥50%
Cundy KC, et al. J Pharmacol Exp Ther 2004;311:315–23.
Coprimary efficacy endpoints (GEn 1200 mg compared with PBO at baseline compared with PBO at Week 12 LOCF (−13.8 [8.09] vs reduction from baseline in pain compared with PBO at Week 12 LOCF Cundy KC, et al. J Pharmacol Exp Ther 2004;311:324–33.
−9.8 [7.69]; AMTD: −4.3; 95% CI: –6.4, –2.3; P<0.0001).
Response of ≥30% Improvement in Average Daily
(60.0% vs 44.1%; P=0.0253); there was no significant treatment Cundy KC, et al. J Clin Pharmacol 2008;48:1378–88.
– mean change from baseline in IRLS total score Significantly more GEn 600 mg-treated subjects were CGI-I Lal R, et al. Clin Ther 2009;31:1776–86.
difference among subjects with average daily pain scores ≥4 at
– proportion of responders (rated as “much improved” or “very much responders compared with PBO at Week 12 LOCF (72.8% vs Pain Scores
Kushida CA, et al. Neurology 2009;72:439–46.
baseline (64.5% vs 50.9%; AOR: 1.8; 95% CI: 0.84, 3.72; P=0.1347; improved”) on the investigator-rated Clinical Global Impression– 44.8%; AOR: 3.3; 95% CI: 1.84, 5.99; P<0.0001).
Kushida CA, et al. Sleep 2009;32:159–68.
Significantly more GEn 1200 mg-treated subjects reported a ≥30%
Figure 2B).
Lee DO, et al. Mov Disord 2009;24:S443.
reduction from baseline in pain compared with PBO at Week 12 LOCF A greater proportion of GEn 600 mg-treated subjects reported a ≥50%
Reduction in Average Daily Pain Scores
(all subjects, 69.1% vs 51.6%; P=0.0117); there was no significant reduction from baseline in pain compared with PBO for all subjects – GEn 600 mg compared with PBO at Week 12 LOCF: GEn 1200 mg significantly reduced mean (SD) average daily pain treatment difference among subjects with average daily pain scores ≥4
(55.9% vs 44.1%; P=0.0997) and subjects with average daily pain • mean change from baseline in IRLS total score Acknowledgments
scores at Week 12 LOCF compared with PBO for subjects with at baseline (74.2% vs 61.4%; AOR: 1.8; 95% CI: 0.83, 4.02; P=0.1330; scores ≥4 at baseline (66.1% vs 50.9%; AOR: 1.9; 95% CI: 0.88, 4.07;
• proportion of responders on the investigator-rated CGI-I scale.
average daily pain scores >0 at baseline or Week 12 LOCF (–2.6 [2.43] Figure 2A).
This study was supported by XenoPort, Inc., Santa Clara, CA. The authors acknowledge Brian P=0.1023; Figure 2B), although these differences were not statistically
– GEn 1200 mg and GEn 600 mg compared with PBO at Week 12 vs –1.7 [2.28]; AMTD: –0.9; 95% CI: –1.5, –0.4; P=0.0015; Figure 1A)
Significantly more GEn 600 mg-treated subjects reported a ≥30%
Hunter, PhD (GlaxoSmithKline) for coordination, critical review, and editorial assistance, Daniel LOCF (for subgroups of subjects with average daily pain score >0 Bonzo, PhD (XenoPort, Inc.) for biometrics and data management, and Nicola Williams, MSc and subjects with baseline scores ≥4 (–3.5 [2.51] vs –2.3 [2.34]; AMTD:
reduction from baseline in pain compared with PBO at Week 12 LOCF (GlaxoSmithKline) for statistical support and interpretation of the data. Editorial support in and average daily pain score ≥4 baseline):
–1.1; 95% CI: –1.9, –0.3; P=0.0054; Figure 1B).
(all subjects, 67.6% vs 51.6%; P=0.0235 and; subjects with average Tolerability and Safety
the form of writing, drafting tables and figures, and collating author comments was • mean change from baseline in average daily RLS pain score GEn 600 mg significantly reduced mean (SD) average daily pain scores daily pain scores ≥4 at baseline, 81.4% vs 61.4%; AOR: 2.8; 95% CI:
provided by Nicola West, BSc (Hons) (Caudex Medical Ltd., Oxford, UK), funded by • proportion of responders with ≥30% or ≥50% improvement in
The two most commonly reported treatment-emergent AEs at Week 12 LOCF compared with PBO for subjects with average daily 1.20, 6.69; P=0.0178; Figure 2A).
GlaxoSmithKline. The authors also acknowledge the contributions of the following investigators: average daily pain score from baseline (subjects who withdrew (GEn 1200 mg, 600 mg, PBO) were dizziness (24%, 10%, 5%) Donald Ayres, MD; Eileen Brady, MD; David Chen, MD; John Cochran, MD; William Ellison, MD; from the study within 2 weeks of randomization and those who and somnolence (18%, 22%, 2%); the majority were mild or Ramedevi Gourineni, MD; Dennis Hill, MD; John Hudson, MD; David Kudrow, MD; Antoinette Table 1. Subject demographic and clinical characteristics at baseline (mITT population), by average daily pain score at baseline
Pragalos, MD; Marc Raphaelson, MD, PA; Albert Razzetti, MD; Paul Scheinberg, MD; had no pain [average daily pain score of 0] at both baseline and Baseline average daily pain score >0
Baseline average daily pain score ≥4
Markus Schmidt, MD, PhD; Susan Steen, MD; Stephen Thein, PhD; Alberto Vasquez, MD; Week 12 LOCF were counted as non-responders).
No clinically significant changes in vital signs, ECGs, or laboratory Jan Westerman, MD; David Winslow, MD.
GEn 600 mg
GEn 1200 mg
GEn 600 mg
GEn 1200 mg
Tolerability and Safety
Age, years
Proportion of women, n (%)
Conclusions
Disclosures
Treatment-emergent adverse events (AEs), clinical laboratoryparameters (hematology, serum chemistry, and urinalysis), vital signs, Race, White or Caucasian, n (%)
● GEn 600 mg and 1200 mg significantly improved RLS DOL has served on the RLS Scientific Advisory Board for GlaxoSmithKline. RBZ has received and electrocardiograms (ECGs) were evaluated.
Number of days with RLS in the past week
compensation for speaker services from GlaxoSmithKline, Novartis, Sanofi-Bristol Myers Squibb, symptoms (IRLS total score and CGI-I) and pain (mean Duration of RLS symptoms, years
Forest Pharmaceuticals, and UCB, and has received research funding from XenoPort, Inc., Statistical Analyses
Previously treated for RLS, n (%)
reduction and response of at least 30% improvement in GlaxoSmithKline, Pfizer, UCB, and Sepracor. ATP has received compensation for speaker services IRLS total score
from Cephalon, and has received research support from GlaxoSmithKline. JSP is on the speakers’ All safety data were summarized for the safety population, which average daily pain scores) associated with RLS compared Average daily RLS pain score
bureau for Cephalon, and has received research support from GlaxoSmithKline and Alexza comprised all subjects who received at least one dose (or portion with PBO, in subjects with moderate-to-severe primary RLS.
Pharmaceuticals. ASW has received compensation for speaker services for Boehringer Ingelheim.
All values are mean (SD) unless otherwise stated.
● GEn 600 mg and 1200 mg are generally well tolerated.
RWB is an employee of XenoPort, Inc.
Gabapentin enacarbil is an investigational compound

Source: http://ecnmri.com/articles/PainSociety2010.pdf