A Study of Oral Dosing of Gabapentin Enacarbil in Japanese Restless Legs Syndrome Patients

Study Overview
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Brief Summary
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The objective of this study was to assess the efficacy of once-daily oral administration of gabapentin enacarbil versus placebo, based on the change in International Restless Legs Syndrome Rating Scale (IRLS) score in participants with moderate-to-severe idiopathic restless legs syndrome. This study also assessed the safety of Gabapentin enacarbil.

Detailed Description
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After 1 week run in period with single-blind placebo, participants meeting the inclusion and none of the exclusion criteria were randomized to receive double-blind treatment with either gabapentin enacarbil 600 mg or placebo for 12 weeks treatment period. After then, single-blind placebo was given for 1 week for follow-up observation.

Official Title
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Gabapentin Enacarbil Post-marketing Clinical Study A Randomized, Double-blind, Placebo-controlled, Parallel-group Study in Subjects With Restless Legs Syndrome.

Conditions
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Restless Legs Syndrome (RLS)

Intervention / Treatment
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* Drug: Placebo
* Drug: Gabapentin enacarbil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has Restless Legs Syndrome (RLS), based on the International Restless Legs Syndrome Study Group (IRLSSG) Diagnostic Criteria. Subject has reported history of RLS symptoms for at least 15 days in the month prior to the first dosing; if on treatment, this frequency of symptoms was started before treatment. Subject with International Restless Legs Syndrome Rating Scale (IRLS) score ≥ 15. Subject has discontinued dopamine agonists, and/or gabapentin at least 1 week prior to the first dosing. Subject has discontinued other treatments for RLS at least 2 weeks prior to the first dosing. Female subject must either: Be of non-childbearing potential: Post-menopausal (defined as at least 1 year without any menses) prior to Screening, or documented surgically sterile Or, if of childbearing potential: Agree not to try to become pregnant during the study and for 28 days after the final study drug administration And have a negative urine pregnancy test at Screening And, if heterosexually active, agree to consistently use two forms of highly effective birth control starting at Screening and throughout the study period and for 28 days after the final study drug administration. Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 28 days after the final study drug administration. Female subject must not donate ova starting at Screening and throughout the study period, and for 28 days after the final study drug administration. Subject agrees not to participate in another interventional study while on treatment. Subject with a Body Mass Index of ≥ 18.5 and < 30. Subject with estimated creatinine clearance of ≥ 60 mL/min. Exclusion Criteria: Subject has a sleep disorder that may significantly affect the assessment of RLS. Subject has a history of RLS symptom augmentation or end-of-dose rebound with previous dopamine agonist treatment. Subject has neurologic disease or movement disorder. Subject has poorly controlled diabetes, iron deficiency anemia, or are currently taking any sedative/hypnotic. Subject has a history of suicide attempt within 6 months prior to informed consent. Subject has a high level of Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST). Subject is currently suffering from moderate or severe depression. Subject has a history of alcohol dependence or drug abuse, or subject had alcohol or drug abuse or dependence in the last 1 year. Subject is a shift worker, professional driver, or operator of dangerous machinery. Subject has clinically significant or unstable medical conditions. Subject has a history of hypersensitivity reaction to gabapentin. Subject has previously taken pregabalin, gabapentin enacarbil, or the study drug of Gabapentin enacarbil. Subject has participated in a clinical study for another investigational drug or medical device or post-marketing clinical study within 12 weeks (84 days) prior to the first dosing, or is currently participating in any of these studies.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo was administered orally once daily after the evening meal. | Drug: Placebo<br>* Oral administration<br>|
| Experimental: Gabapentin enacarbil<br>Gabapentin enacarbil was administered orally once daily after the evening meal. Participants with an estimated creatinine clearance of ≥ 60 mL/min to < 90 mL/min at the start of the run-in period were administrated gabapentin enacarbil 300 mg for 1 week followed by gabapentin enacarbil 600 mg for 11 weeks. | Drug: Gabapentin enacarbil<br>* Oral administration<br>* Other names: Regnite;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in International Restless Legs Syndrome Rating Scale (IRLS) Score at Week 12 | The IRLS consisted of 10-item scale for assessing severity of restless legs syndrome (RLS) with each item ranging from 0 (no symptoms) to 4 (very severe symptoms). The total IRLS score ranges from 0 to 40. Higher IRLS score indicated greater disease activity. Mixed Model of Repeated Measurements (MMRM) model with compound symmetry as a covariance structure was used. The explanatory variables of the model included treatment group, IRLS score at baseline, age category, estimated creatinine clearance category, time point, and interaction of treatment group and time point. | Baseline and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in IRLS Score at Each Time Point | ANCOVA model with the baseline value as a covariate was used. | Baseline and weeks 1, 2, 4, 6, 8, 10, 12 and EoT (week 12) | 
| Percentage of Participants With an Investigator-rated Clinical Global Impression (ICGI) Response | ICGI was assessed by 7-point ordinate scale. Participants who were Very much improved or Much improved were defined as responders. | EoT (week 12) | 
| Percentage of Participants With a Patient-rated Clinical Global Impression (PCGI) Response | PCGI was assessed by 7-point ordinate scale. Participants who were Very much improved or Much improved were defined as responders. | EoT (week 12) | 
| Change From Baseline in Pittsburgh Sleep Quality Index Total Score (PSQI) | The self-rated items of the PSQI generate seven component scores (range of subscale scores, 0-3). The sum of these seven component scores yielded one global score of subjective sleep quality (range, 0-21). Higher scores represent poorer subjective sleep. ANCOVA model with the baseline value as a covariate was used. | Baseline and EoT (week 12) | 
| Change From Baseline in Athens Insomnia Scale | Athens Insomnia Scale consisted of 8-item scale (range of subscale scores, 0-3). The scale range of Athens Insomnia was 0-24. Higher scores represent poorer sleep quality. ANCOVA model with the baseline value as a covariate was used. | Baseline and EoT (week 12) | 
| Change From Baseline in Restless Legs Syndrome (RLS) Pain Score | The scale range of RLS pain score was 0-10. Higher scores represent greater RLS pain intensity. ANCOVA model with the baseline value as a covariate was used. | Baseline and EoT (week 12) | 
| Change From Baseline in Health Status Score of EuroQol-5 Dimension-5 Level (EQ-5D-5L) | Health status was assessed by general visual analog scale (VAS). The VAS ranges from 0 (worst health status) and 100 (best health status). | Baseline and EoT (week 12) | 
| Number of Participants With Adverse Events | Treatment-emergent adverse events (TEAE) was defined as an adverse event (AE) with onset after the start of the run-in period. A drug-related TEAE was a TEAE with at least a possible relationship to the study drug as assessed by the investigator. Serious TEAE was an AE considered serious. | From first dose of study drug up to week 13 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Restless Legs Syndrome, ASP8825, Gabapentin enacarbil