Restless Legs Syndrome
Conditions
Keywords
gabapentin enacarbil, Horizant
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.
Interventions
DRUGGSK1838262 600 mg
Drug: GSK1838262 600 mg/day Comparison of 3 doses
DRUGGSK1838262 450 mg
Drug: GSK1838262 450 mg/day Comparison of 3 doses
DRUGGSK1838262 300 mg
Drug: GSK1838262 300 mg/day Comparison of 3 doses
DRUGGSK1838262 Placebo match
Drug; GSK1838262 placebo to match 600 mg, 450 mg, 300 mg doses
Sponsors
XenoPort, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | 12 Weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GSK1838262 600 mg Once-daily dose with food in the evening at approximately 5 PM | 119 |
| GSK1838262 450 mg Once-daily dose with food in the evening at approximately 5 PM | 112 |
| GSK1838262 300 mg Once-daily dose with food in the evening at approximately 5 PM | 111 |
| GSK1838262 Placebo Match Once-daily dose with food in the evening at approximately 5 PM | 117 |
| Total | 459 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 | 4 | 4 |
| Overall Study | Lack of Efficacy | 3 | 2 | 2 | 3 |
| Overall Study | Lost to Follow-up | 9 | 4 | 7 | 6 |
| Overall Study | Physician Decision | 3 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 6 | 10 | 12 | 5 |
| Overall Study | Withdrawal by Subject | 7 | 4 | 5 | 5 |
Baseline characteristics
| Characteristic | GSK1838262 600 mg | GSK1838262 450 mg | GSK1838262 300 mg | GSK1838262 Placebo Match | Total |
|---|---|---|---|---|---|
| Age, Continuous | 49.2 years STANDARD_DEVIATION 12.92 | 52.1 years STANDARD_DEVIATION 12.22 | 52.0 years STANDARD_DEVIATION 14.51 | 52.1 years STANDARD_DEVIATION 13.01 | 51.3 years STANDARD_DEVIATION 13.2 |
| IRLS Rating Scale Total Score, Continuous | 23.4 units on a scale STANDARD_DEVIATION 5.61 | 24.0 units on a scale STANDARD_DEVIATION 5.23 | 23.7 units on a scale STANDARD_DEVIATION 5.25 | 23.5 units on a scale STANDARD_DEVIATION 5.34 | 23.6 units on a scale STANDARD_DEVIATION 5.35 |
| Race/Ethnicity, Customized African American/African Heritage | 6 participants | 14 participants | 12 participants | 8 participants | 40 participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Unknown or not Reported | 0 participants | 0 participants | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 112 participants | 97 participants | 95 participants | 109 participants | 413 participants |
| Race/Ethnicity, Customized White & African American/African Heritage | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White & Asian | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 73 Participants | 69 Participants | 71 Participants | 64 Participants | 277 Participants |
| Sex: Female, Male Male | 46 Participants | 43 Participants | 40 Participants | 53 Participants | 182 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 55 / 122 | 56 / 123 | 33 / 121 | 46 / 121 |
| serious Total, serious adverse events | 1 / 122 | 0 / 123 | 2 / 121 | 1 / 121 |
Outcome results
Primary
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.
Time frame: Baseline, 12 weeks
Population: mITT (modified intent to treat) Population: The mITT population will include all randomly assigned subjects who received at least 1 dose (or any portion of a dose) of study medication as defined above for the Safety population, have a baseline IRLS Rating Scale total score, and have at least 1 on-treatment IRLS Rating Scale total score.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GSK1838262 600 mg | The Change From Baseline to the End of Treatment in the International Restless Legs Syndrome (IRLS) Rating Scale Score | -12.50 units on a scale | Standard Error 0.745 |
| GSK1838262 450 mg | The Change From Baseline to the End of Treatment in the International Restless Legs Syndrome (IRLS) Rating Scale Score | -12.54 units on a scale | Standard Error 0.764 |
| GSK1838262 300 mg | The Change From Baseline to the End of Treatment in the International Restless Legs Syndrome (IRLS) Rating Scale Score | -11.48 units on a scale | Standard Error 0.767 |
| GSK1838262 Placebo Match | The Change From Baseline to the End of Treatment in the International Restless Legs Syndrome (IRLS) Rating Scale Score | -9.93 units on a scale | Standard Error 0.753 |
Comparison: The null hypothesis for this study is that there is no difference between GEn and placebo in the change from Baseline to the end of treatment in the IRLS Rating Scale total score. All comparisons will be made at the two-sided 0.05 level of significance.p-value: 0.01495% CI: [-4.62, -0.52]ANCOVA
Comparison: The null hypothesis for this study is that there is no difference between GEn and placebo in the change from Baseline to the end of treatment in the IRLS Rating Scale total score. All comparisons will be made at the two-sided 0.05 level of significance.p-value: 0.01495% CI: [-4.68, -0.54]ANCOVA
Comparison: The null hypothesis for this study is that there is no difference between GEn and placebo in the change from Baseline to the end of treatment in the IRLS Rating Scale total score. All comparisons will be made at the two-sided 0.05 level of significance.p-value: 0.14495% CI: [-3.63, 0.53]ANCOVA
Primary
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.
Time frame: 12 weeks
Population: mITT (modified intent to treat) population: The mITT population will include all randomly assigned subjects who received at least 1 dose (or any portion of a dose) of study medication as defined above for the Safety population, have a baseline IRLS Rating Scale total score, and have at least 1 on-treatment IRLS Rating Scale total score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GSK1838262 600 mg | 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) | 67 percentage of participants |
| GSK1838262 450 mg | 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) | 67 percentage of participants |
| GSK1838262 300 mg | 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) | 68 percentage of participants |
| GSK1838262 Placebo Match | 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) | 50 percentage of participants |
Comparison: The null hypothesis for this study is that there is no difference between GEn and placebo in the proportion of subjects who are responders with much improved or very much improved on the investigator-rated CGI-I at the end of treatment.p-value: 0.00495% CI: [1.3, 3.95]Regression, Logistic
Comparison: The null hypothesis for this study is that there is no difference between GEn and placebo in the proportion of subjects who are responders with much improved or very much improved on the investigator-rated CGI-I at the end of treatment.p-value: 0.00795% CI: [1.23, 3.77]Regression, Logistic
Comparison: The null hypothesis for this study is that there is no difference between GEn and placebo in the proportion of subjects who are responders with much improved or very much improved on the investigator-rated CGI-I at the end of treatment.p-value: 0.00595% CI: [1.27, 3.94]Regression, Logistic
Secondary
The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment
Time frame: 12 Weeks
Population: mITT (modified intent to treat) Population: The mITT population will include all randomly assigned subjects who received at least 1 dose (or any portion of a dose) of study medication as defined above for the Safety population, have a baseline IRLS Rating Scale total score, and have at least 1 on-treatment IRLS Rating Scale total score.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GSK1838262 600 mg | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Responder | 67 percentage of participants |
| GSK1838262 600 mg | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Non-Responder | 33 percentage of participants |
| GSK1838262 450 mg | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Non-Responder | 33 percentage of participants |
| GSK1838262 450 mg | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Responder | 67 percentage of participants |
| GSK1838262 300 mg | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Responder | 68 percentage of participants |
| GSK1838262 300 mg | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Non-Responder | 32 percentage of participants |
| GSK1838262 Placebo Match | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Responder | 50 percentage of participants |
| GSK1838262 Placebo Match | The Dose-response Relationship for Investigator-rated CGI-I Scale at End of Treatment | Non-Responder | 50 percentage of participants |
p-value: 0.012Cochran-Armitage trend test
Secondary
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.
Time frame: Baseline, 12 Weeks
Population: mITT (modified intent to treat) Population: The mITT population will include all randomly assigned subjects who received at least 1 dose (or any portion of a dose) of study medication as defined above for the Safety population, have a baseline IRLS Rating Scale total score, and have at least 1 on-treatment IRLS Rating Scale total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| GSK1838262 600 mg | The Dose-response Relationship of Change From Baseline in IRLS Rating Scale Total Score at End of Treatment | -12.1 units on a scale | Standard Error 0.8 |
| GSK1838262 450 mg | The Dose-response Relationship of Change From Baseline in IRLS Rating Scale Total Score at End of Treatment | -12.7 units on a scale | Standard Error 0.82 |
| GSK1838262 300 mg | The Dose-response Relationship of Change From Baseline in IRLS Rating Scale Total Score at End of Treatment | -11.3 units on a scale | Standard Error 0.83 |
| GSK1838262 Placebo Match | The Dose-response Relationship of Change From Baseline in IRLS Rating Scale Total Score at End of Treatment | -9.8 units on a scale | Standard Error 0.8 |
Comparison: For the mean change from Baseline for IRLS Rating Scale total score at the EOT, the linear contrast test based on an analysis of variance with treatment effect was used to detect linear dose-response trends across increasing levels of GEn dosage.p-value: 0.022ANOVA
Comparison: Overall treatment effectp-value: 0.072ANOVA