Simulated Driving Study in Restless Legs Syndrome

Study Overview
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Brief Summary
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This study was a multi center, randomized, double blind, active and placebo controlled, parallel group study to assess simulated driving performance in XP13512 treated subjects with Restless Legs Syndrome (RLS). Eligible subjects were randomized to receive a once daily dose of placebo (2 groups), XP13512 1200 mg, or XP13512 1800 mg for 16 days. On Day 16, one of the placebo groups also received one 50 mg dose of diphenhydramine (DPH) to assess the effects of an agent known to have sedative properties, while the other 3 groups received a DPH placebo.

Detailed Description
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This study was a multicenter, randomized, double blind, active and placebo controlled, parallel group study. Eligible subjects were randomized in a 1:1:1:1 ratio to 1 of the following 4 treatment groups: A) XP13512 Placebo + Diphenhydramine Placebo (Pbo) B) XP13512 1200 mg/day + Diphenhydramine Placebo (1200 mg) C) XP13512 1800 mg/day + Diphenhydramine Placebo (1800 mg) D) XP13512 Placebo + 50 mg Diphenhydramine (Pbo/DPH)

Official Title
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A Randomized, Double Blind, Active- and Placebo-Controlled, Parallel Group Safety Study Assessing Simulated Driving Performance in XP13512-(GSK1838262) Treated Patients With Restless Legs Syndrome

Conditions
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Restless Legs Syndrome

Intervention / Treatment
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* Drug: XP13512
* Drug: Diphenhydramine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women who were 21 through 65 years of age and fluent in English; Subjects with RLS, based on the IRLSSG Diagnostic Criteria; Currently a licensed and experienced driver who has driven an average of 3 or more times/week for the past 3 years; Able to successfully complete the 5 minute practice simulated driving test at Screening; History of RLS symptoms at least 15 nights in the prior month or, if on treatment, this frequency of symptoms before treatment was started; Total RLS severity score of 15 or greater on the IRLS Rating Scale; Documented RLS symptoms for at least 4 of the 7 consecutive evenings/nights Discontinuation of treatments for RLS (e.g., opioids, benzodiazepines, dopamine agonists and/or gabapentin) at least 2 weeks prior to Screening; - Body Mass Index of 34 or below; Estimated creatinine clearance of at least 60 mL/min; Agreed to maintain abstinence from alcohol and smoking throughout the entire study period; Agreed to maintain abstinence from caffeine from midnight of the day prior to and until the end of each Visit (Visits 2 to 4). Exclusion Criteria: A sleep disorder (e.g., sleep apnea) other than RLS that may significantly affect the assessment of RLS; Current use of a sleeping medication or sedating medication; Current use of CNS stimulants; Neurologic disease or movement disorder; Other medical conditions which could affect RLS assessments; Significant medical history that may impair psychomotor coordination; Subjects who had clinically significant or unstable medical conditions; Serum ferritin level below 20 ng/mL; Subjects currently suffering from moderate or severe depression using the Diagnostic and Statistical Manual of Mental Disorders and Treatment IV (DSM IV TR); Subjects with a history of substance abuse (alcohol or drugs) or substance dependence within 12 months prior to enrollment; Shift workers or subjects who were not on normal day/night sleep cycles; Subjects who had smoked an average of greater than one half pack of cigarettes (or nicotine equivalent) per day within 30 days of the Screening Visit; Subjects who had consumed an average of >5 cups (i.e., 40 ounces) of caffeinated beverages per day within 20 days of the Screening Visit; Subjects with a history of allergy to gabapentin, diphenhydramine, or XP13512 excipients

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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 |
| --- | --- |
| Placebo Comparator: Placebo<br>XP13512 Placebo + Diphenhydramine Placebo | Drug: Placebo<br>* XP13512 placebo once daily for 16 days<br>|
| Experimental: XP13512 1200 mg<br>XP13512 1200 mg/day + Diphenhydramine Placebo | Drug: XP13512<br>* XP13512 once daily for 16 days<br>* Other names: Gabapentin Enacarbil (GEn);|
| Experimental: XP13512 1800 mg<br>XP13512 1800 mg/day + Diphenhydramine Placebo | Drug: XP13512<br>* XP13512 once daily for 16 days<br>* Other names: Gabapentin Enacarbil (GEn);|
| Active Comparator: Placebo + Diphenhydramine<br>XP13512 Placebo + 50 mg Diphenhydramine | Drug: Diphenhydramine<br>* one 50 mg dose of diphenhydramine (DPH) on day 16<br>Drug: Placebo<br>* XP13512 placebo once daily for 16 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Day -1) in Overall Lane Position Variability (LPV) on Day 16 (Tmax) | Lane position variability (LPV) was defined as the standard deviation of lane position, and was measured from the center line of the 26 foot wide 2-lane paved road to the center of the vehicle. Change from baseline in overall LPV was calculated as the Day 16 mean LPV over the 1-hour drive minus the Baseline mean LPV over the 1-hour drive. The Day 16 measurement is at the time of maximum concentration (Tmax) for both GEn and DPH. | Baseline (Day -1) and Day 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Day -1) to Day 14 (Evening) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in Overall Lane Position Variability (LPV) | Lane position variability (LPV) was defined as the standard deviation of lane position, and was measured from the center line of the 26 foot wide 2-lane paved road to the center of the vehicle. Change from baseline in overall LPV was calculated as the Day 14 (in the evening) or Day 15 (in the morning after GEn dosed at 5 PM) mean LPV over the 1-hour drive minus the Baseline (Day -1 or Day 1) mean LPV over the 1-hour drive. | Baseline (Days -1 and 1) and Days 14 and 15 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in Overall Average Lane Position | Lane position was measured from the center line of the 26 foot wide 2-lane paved road to the center of the vehicle. Change from baseline in overall average lane position was calculated as the Day 14 (in the evening), 15 (in the morning after GEn dosed at 5 PM), or 16 (assessment at Tmax of GEn and DPH) mean lane position over the 1-hour drive minus the Baseline (Days -1 and 1) mean lane position over the 1-hour drive. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in Overall Speed Variability | Speed variability was defined as the standard deviation of the speed (measured in miles per hour). Participants were instructed to maintain a speed of 55 miles per hour during the test drive. Change from baseline in overall speed variability was calculated as the Day 14 (in the evening), 15 (in the morning), or 16 (at Tmax of GEn and DPH) mean speed variability over the 1-hour drive minus the Baseline (Days -1 and 1) mean speed variability over the 1-hour drive. | Baseline (Day -1) and Days 14 and 16; baseline (Day 1) and Day 15 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in Overall Average Speed | Participants were instructed to maintain a speed of 55 miles per hour during the driving assessment. Change from baseline in overall average speed was calculated as the Day 14 (in the evening), 15 (in the morning), or 16 (at Tmax of GEn and DPH) mean speed over the 1-hour drive minus the Baseline (Days -1 and 1) mean speed over the 1-hour drive. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Number of Participants With the Indicated Number of Simulated Crashes on Days 14 (Evening), 15 (Morning After Dose), and 16 (Tmax) | A simulated crash was defined as a collision with an oncoming car or obstacle (e.g., tree) or when the distance to the center line was greater than 18 feet on either side of the road. | Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in Brake Reaction Time | Brake reaction time was assessed as the time it took for each participant to move their foot off the accelerator and onto the brake pedal after the appearance of a stop sign on the simulation screen. Change from baseline was calculated as the Day 14, 15, or 16 mean reaction time minus the Baseline (Days -1 and 1) mean reaction time. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in the Alertness Visual Analog Scale (VAS) Score | Alertness VAS was completed immediately before and after each simulated driving assessment. Participants indicated their alertness by marking a vertical line on a horizontal scale anchored by responses extremely sleepy and extremely alert. VAS score was determined by measuring the distance in millimeters (mm) from the left hand end of the line to the point the participant marked. Scores ranged from 0-100 mm, with higher scores indicating more alertness and lower scores indicating more sleepiness. Change score was calculated as the Day 14, 15, or 16 VAS score minus the Baseline VAS score. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) in the Epworth Sleepiness Scale (ESS) Total Score | The Epworth Sleepiness Scale (ESS) is a questionnaire designed to evaluate daytime sleepiness. Participants were asked to rate how likely they were to doze or fall asleep during 8 activities on a scale of 0 (would never do) to 3 (high chance of dozing). The total score ranges from 0-24, with a score greater than 10 representing excessive daytime sleepiness (an increased chance of dozing). Change from baseline was calculated as the Day 14 total score minus the Baseline total score. | Baseline (Day -1) and Day 14 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Composite Score | The BAC was designed as a comprehensive measure of cognitive function, including 6 individual tests: Verbal Memory Recall, Digit Sequencing, Token Motor Task, Verbal Fluency, Symbol Coding, and Tower of London. The composite/total BAC score is calculated by scoring each individual test, comparing each score to a healthy control sample (matched for sex and age category) to create z-scores, summing the z-scores, and rescaling the sum. The composite score range is -2127.8 to 1878.8, with higher scores indicating better cognition. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Scaled Verbal Memory Test Score | Participants were presented with 15 words and asked to recall as many as possible; the procedure was repeated 5 times. The total number of words recalled correctly across the 5 administrations of the list was the participant's Verbal Memory Recall score (range: 0-75). The scaled test score was calculated as ((BAC component raw test score - healthy control sample test mean)/healthy control sample test standard deviation); a healthy control sample was matched to the participant's sex and age category. The scaled test score range is -7.37 to 4.86; higher scaled scores indicate better cognition. | Baseline (Days -1and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Scaled Digit Sequencing Score (DSS) | Participants (par.) were presented with sets of numbers of increasing length and asked to tell the experimenter the numbers in order from lowest to highest. The task has 7 levels; the first level had 2 digits in the set (e.g., 5, 2); the second level had 3 digits in the set, etc. The number of times the par. correctly arranged the numbers was recorded as the score for each level. The DSS is the sum of the 7 level scores (range: 0-28). The scaled test score was calculated as indicated for the Verbal Memory Test and ranges from -6.68 to 2.73; higher scaled scores indicate better cognition. | Baseline (Days -1and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Scaled Token Motor Task Test Score | Participants were given 100 plastic tokens and asked to place them in a container, 2 at a time, as quickly as possible for 60 seconds. The number of tokens correctly placed in the container was the Token Motor Task score (range: 0-100). The BAC was conducted prior to each simulated driving test. The Token Motor Task scaled test score was calculated as indicated for the Verbal Memory Test. Change from baseline was calculated as the Day composite score minus the Baseline composite score. The scaled test score range is -6.95 to 3.35, with higher scaled scores indicating better cognition. | Baseline (Days -1and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Scaled Verbal Fluency Test Score | Verbal Fluency included one semantic fluency and two letter fluency tasks. Participants were given 60 seconds to name as many words as possible within a given semantic category (supermarket items), and in two separate trials, participants were given 60 seconds to generate as many words as possible that began with a given letter. The total number of words from all of the 3 trials was the Verbal Fluency score (range: 0-150). The scaled test score was calculated as indicated for the Verbal Memory Test. The scaled test score range is -5 to 10.83; higher scaled scores indicate better cognition. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Scaled Symbol Coding Test Score | Participants were given a list of numbers (numerals 1-9) that were each associated with a unique symbol. Participants decoded a list of 110 symbols as quickly as possible in 90 seconds. The total number of symbols correctly decoded was the Symbol Coding Score (range: 0-110). The Symbol Coding scaled test score was calculated as indicated for the Verbal Memory Test. Change from baseline was calculated as the Day composite score minus the Baseline composite score. The scaled test score range is -7 to 10.08, with higher scaled scores indicating better cognition. | Baseline (Days -1and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Brief Assessment of Cognition (BAC) Scaled Tower of London (TOL) Score | Participants (par.) were asked to look at 2 pictures simultaneously; each picture showed 3 different colored balls arranged on 3 pegs. Par. were to estimate the number of times the balls in 1 picture would have to be moved to make the arrangement of balls identical to that of the second picture. Par. were allowed 20 seconds to respond to each pair of pictures. The number of correct items was the TOL Score (range: 0-22). The TOL scaled test score was calculated as indicated for the Verbal Memory Test. The scaled test score range is -7.53 to 2.76; higher scaled scores indicate better cognition. | Baseline (Days -1and 1) and Days 14, 15, and 16 | 
| Mean Change From Baseline (Day -1) at Day 14 in the International Restless Legs Syndrome (IRLS) Rating Scale Total Score | The IRLS Rating scale is a measure of RLS disease severity and reflects the participant-reported assessment of primary sensory and motor features and associated sleep problems in RLS. Items are included that assess the impact of symptoms on participants' mood, daily life, and activities. The total score ranges from 0-40 points, with 40 being the most severe. The scale assesses symptoms over the week prior to measurement. | Baseline (Day -1) and Day 14 | 
| Number of Participants in Each Category of the Investigator-Rated Clinician Global Impression of Improvement (CGI-I) Scale at Day 14 | The CGI scale is a widely used tool designed to allow clinicians to rate the severity of illness and the change of the disease severity over time based on a seven-point rating scale, with a score of 1 being very much improved and a score of 7 being very much worse compared to baseline. | Day 14 | 
| Number of Participants Who Responded to Treatment Based on Scores on the Investigator-Rated CGI-I at Day 14 | The investigator-rated CGI-I is a clinician-rated assessment designed to allow clinicians to rate the change of their participant's disease severity over time based on a seven-point scale, with a score of 1 being very much improved, and a score of 7 being very much worse compared to baseline. For this endpoint, response was defined as a rating of very much improved or much improved (score of 1 or 2 on the scale) compared to baseline. | Day 14 | 
| Number of Participants in Each Category of the Participant-Rated Clinician Global Impression of Improvement (CGI-I) Scale at Day 14 | The participant-rated CGI-I scale is a self-rated assessment designed to allow participants to rate the change of their disease severity over time based on a seven-point scale, with a score of 1 being very much improved and a score of 7 being very much worse. | Day 14 | 
| Number of Participants Who Responded to Treatment Based on Scores on the Participant-Rated CGI-I at Day 14 | The participant-rated CGI-I is a self-rated assessment designed to allow participants to rate the change of their disease severity over time based on a seven-point scale, with a score of 1 being very much improved, and a score of 7 being very much worse. Response was defined as a rating of very much improved or much improved (score of 1 or 2 on the scale). | Day 14 | 
| Median Time to Onset of a Participant's First RLS Symptoms Using the 24-hour RLS Symptom Record at Day 14 | The 24-Hour RLS Record is a diary in which participants report the presence and severity of RLS symptoms (none, mild, moderate, or severe) for a 24-hour period, in 30-min increments beginning at 8AM on the day prior to the visit. For Arms 2 and 3, upper limits of the confidence intervals are not available, as they are beyond the 24-hour time frame. | Day 14 | 
| Percentage of Participants With no Reported RLS Symptoms During the 24-hour RLS Record at Day 14 | The 24-Hour RLS Record is a diary in which participants report the presence and severity of RLS symptoms (none, mild, moderate, or severe) for a 24-hour period, in 30-min increments beginning at 8AM on the day prior to the visit. | Day 14 | 
| Number of Participants With no Reported RLS Symptoms During Each of the 4-hour Periods From the 24-hour RLS Record at Day 14 | The 24-Hour RLS Record is a diary in which participants report the presence and severity of RLS symptoms (none, mild, moderate, or severe) for a 24-hour period, in 30-minute increments. The period was divided into 7 four-hour intervals (8 AM to 12 PM, 12 PM to 4 PM, 4 PM to 8 PM, 6 PM to 10 PM, 8 PM to 12 Midnight, Midnight to 4 AM, and 4 AM to 8 AM). | Day 14 | 
| Number of Participants With the Indicated Post Sleep Questionnaire (PSQ) Responses at Day 14 | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. | Day 14 | 
| Mean Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) on the Pittsburgh Sleep Diary (PghSD) Sleep Onset Items | The PghSD assessed participant's previous night's sleep. Change from baseline was calculated as the Day 14 (in the evening), 15 (in the morning), and 16 (at Tmax of GEn and DPH) value minus the Baseline (Days -1 and 1) value. Latency to sleep onset (time to fall asleep) and wake time after sleep onset are expressed in minutes. | Baseline (Days -1and 1) and Days 14, 15, and 16 | 
| Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in the Pittsburgh Sleep Diary (PghSD) Total Sleep Time Item | The PghSD assessed a participant's previous night's sleep. Change from baseline was calculated as the Day 14 (in the evening), 15 (in the morning after dose), and 16 (at Tmax)value minus the Baseline (Days -1 and 1) value. Total sleep time is expressed in hours. | Baseline (Days -1 and 1) and Days 14, 15, and 16 | 
| Mean Change From Baseline (Day -1) to Day 14 (Evening) and Day 16 (at Tmax) and Change From Baseline (Day 1) to Day 15 (Morning After Dose) in the Pittsburgh Sleep Diary (PghSD) Sleep Quality | The PghSD assessed a participant's previous night's sleep. Sleep quality was assessed using a Visual Analogue Scale (VAS). Participants indicated their sleep quality by marking a vertical line on a horizontal scale anchored by responses very bad and very good. VAS score was determined by measuring the distance in millimeters (mm) from the left hand end of the line to the point that the participant marked. Scores ranged from 0 to 100 mm with higher scores indicating better sleep quality and lower scores indicating worse sleep quality. | Baseline (Day -1and 1) and Days 14, 15, and 16 |