Gabapentin Enacarbil (GSK1838262) Adult Restless Leg Syndrome (RLS) Post Marketing Commitment Study (CONCORD)

Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, Parallel-Group Study to Compare the Efficacy, Tolerability, and Safety of 3 Doses of Gabapentin Enacarbil (GSK1838262) With Placebo in Treatment of Moderate-to-Severe Primary RLS

Gabapentin enacarbil (GEn; GSK1838262; HORIZANT), at a dose of 600 mg/day, is currently approved in the United States for the treatment of adults with moderate-to-severe primary Restless Legs Syndrome (RLS). The aim of this study is to compare the efficacy, tolerability, and safety of GEn at lower doses (450 and 300 mg/day) as well as the already approved dose of 600 mg/day versus placebo for the treatment of subjects with moderate to severe primary RLS. This study is being conducted as a post-marketing commitment (PMC) as a condition of the approval of HORIZANT tablets (NDA 022399).

This is a Phase IV randomized, double-blind, placebo-controlled, fixed-dose, parallel group study to assess the efficacy, tolerability, and safety of 3 doses of GEn (600, 450, and 300 mg/day) compared with placebo in the treatment of subjects with moderate-to-severe primary RLS. The study will include 9 visits over approximately 14 weeks for eligible subjects including a 1-week Screening Period, a 12-week Treatment Period, and a 1 week Follow up Period. Screening will occur within 1 week of the first scheduled dose of study medication. The total duration of the study, from the first subject enrolled to the last subject completed will be approximately 2 years. Eligible subjects (at least 18 years of age) must have: a diagnosis of RLS according to the IRLSSG Diagnostic Criteria a history of RLS symptoms for at least 15 nights in the prior month or, if on treatment, this frequency of symptoms before treatment was started documented RLS symptoms for at least 4 of the 7 consecutive evenings/nights during the Screening Period, and a total RLS severity score of at least 15 on the International Restless Legs Syndrome (IRLS) Rating Scale at the screening and baseline visits Approximately 498 subjects will be enrolled, randomly assigned to treatment groups, and receive study medication once daily for 12 weeks. Subjects will be randomly assigned to receive 1 of the 4 following treatment groups in a ratio of 1:1:1:1: GEn 600 mg/day GEn 450 mg/day GEn 300 mg/day Matching placebo Subjects will be instructed to take their study medication once daily with food in the evening at approximately 5 PM. Each tablet must be swallowed whole and not divided, crushed, or chewed. Each subject, regardless of treatment assignment, will take 3 tablets of study medication (1 tablet from Bottle A, 1 tablet from Bottle B, and 1 tablet from Bottle C) once daily continuing through the end of the Treatment Period (Week 12). Subjects will return to the study site for a follow-up visit (Visit 9, Week 13) approximately 1 week after the last dose of study medication. Each subject's participation in the study will be approximately 14 weeks unless they withdraw early from the study. For subjects who complete the study, Visit 9 (which can occur between Day 86 and 92) will be considered their end-of-study visit.

The Change From Baseline to the End of Treatment in the International Restless Legs Syndrome (IRLS) Rating Scale Score

International Restless Legs Syndrome Rating Scale: Very severe=31-40, Severe=21-30, Moderate=11-20, Mild=1-10, None=0. Change from Baseline = LOCF value at current visit - value at Baseline (the last nonmissing assessment before the first dose of study medication). A negative treatment difference indicates a benefit relative to placebo. The change from baseline data is analyzed using an ANCOVA model with treatment and pooled site as the main effects and the baseline IRLS Rating Scale total score as a covariate.

The Proportion of Subjects at the End of Treatment Who Are Responders With Either "Much Improved" or "Very Much Improved" on the Investigator-rated Clinical Global Impression of Improvement (CGI-I)

Clinical Global Impression - Improvement Scale (CGI-I): 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved), 2 (much improved), on the scale. Higher score = more affected. Number of subjects responding to treatment at Week 12 with respect to dose level. CGI-I Responders = subjects who reported CGI-I scores of very much improved or much improved.

The Dose-response Relationship of Change From Baseline in IRLS Rating Scale Total Score at End of Treatment

International Restless Legs Syndrome Rating Scale: Very severe=31-40, Severe=21-30, Moderate=11-20, Mild=1-10, None=0. This model only includes treatment in the model. Least squares mean is used for analysis.

Inclusion Criteria: Men or women 18 years of age or older History of RLS symptoms for at least 15 nights/month Documented RLS symptoms, using the 7-day RLS Symptom Record, for at least 4 of the 7 consecutive evenings/nights during the night Total RLS severity score of 15 or greater on the International RLS (IRLS) Rating Scale at Visit 1 and at Visit 2 Discontinuation of dopamine agonists and/or gabapentin , or other treatments for RLS (e.g. opioids, benzodiazepines) at least 2 weeks prior to Baseline If taking any prescription medication, therapy must have been stabilized for at least 3 months prior to Screening with no anticipated changes for the duration of the study Female subjects are eligible if of non-childbearing potential or not lactating, has a negative pregnancy, and agrees to use a highly effective method for avoiding pregnancy Body mass index of 34 or below Estimated creatinine clearance of ≥60 mL/min Provides written consent in accordance with all applicable regulatory requirements Exclusion Criteria: History of a sleep disorder that may affect the assessment of RLS History of RLS symptom augmentation or end-of-dose rebound with previous dopamine agonist treatment Neurologic disease or movement disorder Other medical conditions or drug therapy that could affect RLS efficacy assessments or may present a safety concern Have clinically significant or unstable medical conditions Have active suicidal plan/intent or has had active suicidal thoughts in the past 6 months; has a history of suicide attempt