Dose-Response and Pharmacokinetics of Gabapentin Enacarbil (GEn [XP13512 / GSK1838262]) in Restless Legs Syndrome

Study Overview
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Brief Summary
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The objective of the study was to generate the data necessary to determine the gabapentin exposure produced by 4 dose levels of GEn (600 mg, 1200 mg, 1800 mg, and 2400 mg) or placebo, and the corresponding relief of symptoms in subjects with Restless Legs Syndrome (RLS).

Detailed Description
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This was a multicenter, randomized, double blind, placebo controlled, parallel group study, comparing 4 doses of GEn (XP13512) with placebo given once daily to subjects with RLS. Eligible subjects were randomized in equal numbers into 1 of 5 treatment groups (GEn 600 mg, 1200 mg, 1800 mg, or 2400 mg or placebo) for 12 weeks of treatment. Data from this study will be utilized as part of a larger pharmacokinetic (PK) pharmacodynamic (PD) analysis of data from several studies (XP084/RXP111495) that are part of the GEn RLS clinical development program. Safety and tolerability were also assessed.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Dose-Response Study to Assess the Efficacy, Safety, and Pharmacokinetics of XP13512 (GSK1838262) in Patients With Restless Legs Syndrome

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: GEn (XP13512/GSK1838262)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women at least 18 years of age RLS, based on the IRLSSG Diagnostic Criteria History of RLS symptoms occurring at least 15 nights in the month prior to Screening or, if on RLS treatment, this frequency of symptoms must have been applicable prior to start of treatment Documented RLS symptoms for at least 4 of the 7 consecutive evenings/nights Total RLS severity score of 15 or greater on the IRLS Rating Scale If taking dopamine agonists, gabapentin, or other treatments for RLS (e.g., opioids, benzodiazepines) medications must have been discontinued at least 2 weeks prior to Screening; 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; Body Mass Index (BMI) of 34 or below estimated creatinine clearance of at least 60 mL/min Exclusion Criteria: a sleep disorder (e.g., sleep apnea) that may significantly 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 (e.g., diabetic neuropathy, Parkinson's disease, multiple sclerosis, dyskinesias, and dystonias); other clinically significant or unstable medical condition or conditions which could affect RLS treatment efficacy assessments serum ferritin level below 20 ng/mL currently suffering from moderate or severe depression using the Diagnostic and Statistical Manual of Mental Disorders and Treatment IV (DSM IV TR)

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GEn (XP13512/GSK1838262) 600 mg<br>GEn (XP13512/GSK1838262) 600 mg | Drug: GEn (XP13512/GSK1838262)<br>* Double-Blind Treatment Phase: 600 mg GEn (XP13512) orally, once daily for 3 days followed by 600 or 1200 mg on days 4-6, followed by 600 or 1200 or 1800 mg on days 7-9, followed by 600 or 1200 or 1800 or 2400 mg on days 10-84. Double-Blind Taper Phase: 600 or 1200 or 1800 mg GEn (XP13512) orally, once daily on days 85-86, followed by 600 mg or 1200 mg on days 87-88, followed by 600 mg on days 89-91<br>* Other names: GSK1838262;|
| Experimental: GEn (XP13512/GSK1838262) 1200 mg<br>GEn (XP13512/GSK1838262) 1200 mg | Drug: GEn (XP13512/GSK1838262)<br>* Double-Blind Treatment Phase: 600 mg GEn (XP13512) orally, once daily for 3 days followed by 600 or 1200 mg on days 4-6, followed by 600 or 1200 or 1800 mg on days 7-9, followed by 600 or 1200 or 1800 or 2400 mg on days 10-84. Double-Blind Taper Phase: 600 or 1200 or 1800 mg GEn (XP13512) orally, once daily on days 85-86, followed by 600 mg or 1200 mg on days 87-88, followed by 600 mg on days 89-91<br>* Other names: GSK1838262;|
| Experimental: GEn (XP13512/GSK1838262) 1800 mg<br>GEn (XP13512/GSK1838262) 1800 mg | Drug: GEn (XP13512/GSK1838262)<br>* Double-Blind Treatment Phase: 600 mg GEn (XP13512) orally, once daily for 3 days followed by 600 or 1200 mg on days 4-6, followed by 600 or 1200 or 1800 mg on days 7-9, followed by 600 or 1200 or 1800 or 2400 mg on days 10-84. Double-Blind Taper Phase: 600 or 1200 or 1800 mg GEn (XP13512) orally, once daily on days 85-86, followed by 600 mg or 1200 mg on days 87-88, followed by 600 mg on days 89-91<br>* Other names: GSK1838262;|
| Experimental: GEn (XP13512/GSK1838262) 2400 mg<br>GEn (XP13512/GSK1838262) 2400 mg | Drug: GEn (XP13512/GSK1838262)<br>* Double-Blind Treatment Phase: 600 mg GEn (XP13512) orally, once daily for 3 days followed by 600 or 1200 mg on days 4-6, followed by 600 or 1200 or 1800 mg on days 7-9, followed by 600 or 1200 or 1800 or 2400 mg on days 10-84. Double-Blind Taper Phase: 600 or 1200 or 1800 mg GEn (XP13512) orally, once daily on days 85-86, followed by 600 mg or 1200 mg on days 87-88, followed by 600 mg on days 89-91<br>* Other names: GSK1838262;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Css, Max and Css, Min | Css, max is defined as the maximum or peak concentration of a drug observed after multiple administration, at steady state. Css, max is one of the parameters of particular use in estimating the bioavailability of drugs, by measuring the total amount of drug absorbed. Css, min is defined as the minimum concentration of a drug observed after its administration, in steady state. ng, nanograms; PK, pharmacokinetic; W, week; BLQ, below limit of quantitation. | Weeks 4 and 12 | 
| Mean Tmax and T1/2 | Tmax is defined as the time to the maximum or peak concentration of a drug observed after multiple administration. T1/2 is defined as the time to when half of the total amount of a particular substance is eliminated from the body. | Weeks 4 and 12 | 
| Mean AUCss | The area under the plot of plasma concentration of drug against time after drug administration is defined as the area under the curve (AUC). The AUCss is the area under the curve during the steady-state period. The AUCss is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. AUCss used concentration data from 0 to 24 hours at steady-state for Weeks 4 and 12. | Weeks 4 and 12 |