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

Phase 4

Completed

Conditions: Restless Legs Syndrome

Interventions: Drug: GSK1838262 300 mg
Drug: GSK1838262 600 mg
Drug: GSK1838262 450 mg
Drug: GSK1838262 Placebo match

Registration Number: NCT01668667

Lead Sponsor: XenoPort, Inc.

Brief Summary: 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).

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 501

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK1838262 300 mg	GSK1838262 300 mg	Once-daily dose with food in the evening at approximately 5 PM
GSK1838262 600 mg	GSK1838262 600 mg	Once-daily dose with food in the evening at approximately 5 PM
GSK1838262 450 mg	GSK1838262 450 mg	Once-daily dose with food in the evening at approximately 5 PM
GSK1838262 placebo match	GSK1838262 Placebo match	Once-daily dose with food in the evening at approximately 5 PM

Primary Outcome Measures

Name	Time	Method
The Change From Baseline to the End of Treatment in the International Restless Legs Syndrome (IRLS) Rating Scale Score	Baseline, 12 weeks	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)	12 weeks	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.

Secondary Outcome Measures

Name	Time	Method
The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment	12 Weeks
The Dose-response Relationship of Change From Baseline in IRLS Rating Scale Total Score at End of Treatment	Baseline, 12 Weeks	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.