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).

Study Overview

• Status: Completed
• Conditions: Restless Legs Syndrome
• Intervention / Treatment: Drug: GSK1838262 600 mg; Drug: GSK1838262 450 mg; Drug: GSK1838262 300 mg; Drug: GSK1838262 Placebo match

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.

• Study Type: Interventional
• Enrollment (Actual): 501
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85020
      • GSK Investigational Site
    • Phoenix, Arizona, United States, 85050
      • GSK Investigational Site
    • Tucson, Arizona, United States, 85704
      • GSK Investigational Site
  • Arkansas
    • Little Rock, Arkansas, United States, 72211
      • GSK Investigational Site
  • California
    • Santa Monica, California, United States, 90404
      • GSK Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • GSK Investigational Site
    • Denver, Colorado, United States, 80239
      • GSK Investigational Site
  • Florida
    • DeLand, Florida, United States, 32720
      • GSK Investigational Site
    • Tampa, Florida, United States, 33609
      • GSK Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • GSK Investigational Site
    • Woodstock, Georgia, United States, 30189
      • GSK Investigational Site
  • Kansas
    • Lenexa, Kansas, United States, 66214
      • GSK Investigational Site
    • Topeka, Kansas, United States, 66606
      • GSK Investigational Site
  • Kentucky
    • Crestview Hills, Kentucky, United States, 41017
      • GSK Investigational Site
    • Louisville, Kentucky, United States, 40217
      • GSK Investigational Site
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • GSK Investigational Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • GSK Investigational Site
  • Michigan
    • Bingham Farms, Michigan, United States, 48025
      • GSK Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68134
      • GSK Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • GSK Investigational Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • GSK Investigational Site
  • North Carolina
    • Hickory, North Carolina, United States, 28601
      • GSK Investigational Site
    • Raleigh, North Carolina, United States, 27612
      • GSK Investigational Site
    • Winston-Salem, North Carolina, United States, 27103
      • GSK Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45255
      • GSK Investigational Site
    • Cleveland, Ohio, United States, 44130
      • GSK Investigational Site
    • Middleburg Heights, Ohio, United States, 44130
      • GSK Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • GSK Investigational Site
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • GSK Investigational Site
    • Lafayette Hill, Pennsylvania, United States, 19444
      • GSK Investigational Site
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • GSK Investigational Site
  • South Carolina
    • Columbia, South Carolina, United States, 29201
      • GSK Investigational Site
    • Greer, South Carolina, United States, 29651
      • GSK Investigational Site
    • Mount Pleasant, South Carolina, United States, 29464
      • GSK Investigational Site
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • GSK Investigational Site
  • Texas
    • Austin, Texas, United States, 78731
      • GSK Investigational Site
    • Fort Worth, Texas, United States, 76135
      • GSK Investigational Site
    • San Angelo, Texas, United States, 76904
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78229
      • GSK Investigational Site
    • San Antonio, Texas, United States, 78205
      • GSK Investigational Site
  • Utah
    • Murray, Utah, United States, 84123
      • GSK Investigational Site
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: GSK1838262 600 mg; Once-daily dose with food in the evening at approximately 5 PM	Drug: GSK1838262 600 mg; Drug: GSK1838262 600 mg/day Comparison of 3 doses; Other Names: XP13512; Horizant; gabapentin enacarbil GEn
Active Comparator: GSK1838262 450 mg; Once-daily dose with food in the evening at approximately 5 PM	Drug: GSK1838262 450 mg; Drug: GSK1838262 450 mg/day Comparison of 3 doses; Other Names: XP13512; Horizant; gabapentin enacarbil GEn
Active Comparator: GSK1838262 300 mg; Once-daily dose with food in the evening at approximately 5 PM	Drug: GSK1838262 300 mg; Drug: GSK1838262 300 mg/day Comparison of 3 doses; Other Names: XP13512; Horizant; gabapentin enacarbil GEn
Placebo Comparator: GSK1838262 placebo match; Once-daily dose with food in the evening at approximately 5 PM	Drug: GSK1838262 Placebo match; Drug; GSK1838262 placebo to match 600 mg, 450 mg, 300 mg doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 12 weeks
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.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 12 Weeks
The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment		12 Weeks

Collaborators and Investigators

• Sponsor: XenoPort, Inc.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: June 14, 2012
• First Submitted That Met QC Criteria: August 16, 2012
• First Posted (Estimate): August 20, 2012

Study Record Updates

• Last Update Posted (Actual): May 24, 2021
• Last Update Submitted That Met QC Criteria: April 30, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: gabapentin enacarbil; Horizant
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Dyskinesias; Psychomotor Disorders; Parasomnias; Syndrome; Psychomotor Agitation; Restless Legs Syndrome; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Anti-Anxiety Agents; Anticonvulsants; Antimanic Agents; Gabapentin
• Other Study ID Numbers: 114025