Long-Term Study of Gabapentin Enacarbil (GEn, XP13512) vs. Placebo in Patients With Restless Legs Syndrome.

Study Overview
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Brief Summary
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The primary objective of this trial is to assess the maintenance of efficacy of gabapentin enacarbil (GEn, XP13512) taken once daily in the long-term treatment of patients suffering from Restless Legs Syndrome (RLS).

Detailed Description
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This study was a multicenter, blinded, randomized withdrawal study in subjects with primary Restless Legs Syndrome (RLS). Eligible subjects were initially enrolled in a 24-week single blind (SB) treatment period during which they received XP13512. Subjects who completed the initial treatment period and met the responder criteria were then randomized 1:1 to receive either XP13512 or placebo during the 12-week double-blind (DB) treatment period. The primary study objective was to assess the maintenance of efficacy of XP13512 1200 mg taken once daily in the long-term treatment of subjects with primary RLS. The secondary study objectives were to assess maintenance of improvements in sleep outcomes and quality of life, and to assess the safety and tolerability of XP13512 in the treatment of primary RLS subjects.

Official Title
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A Long-Term Study of XP13512 Versus Placebo Treatment Assessing Maintenance of Efficacy and Safety in Patients With Restless Legs Syndrome.

Conditions
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Restless Legs Syndrome

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with primary RLS, based on the International RLS Study Group Diagnostic Criteria. Exclusion Criteria: A sleep disorder (e.g., sleep apnea) that may significantly affect the assessment of RLS; Neurologic disease or movement disorder (e.g., diabetic neuropathy, Parkinson's disease, Multiple Sclerosis, dyskinesias, and dystonias); Abnormal laboratory results, electrocardiogram (ECG) or physical findings; Pregnant or lactating women; Women of childbearing potential who are not practicing an acceptable method of birth control.

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) 1200 mg<br>GEn (XP13512) 1200 mg | Drug: GEn (XP13512)<br>* 1200 mg GEn (XP13512) orally, once daily for 24 weeks followed by either 1200 mg GEn (XP13512) or placebo, orally, once daily for an additional 12 weeks<br>* Other names: XP13512;Drug: GEn (XP13512)<br>* 1200 mg GEn (XP13512), orally, once daily for 24 weeks followed by either 1200 mg GEn (XP13512) or placebo, orally, once daily for an additional 12 weeks<br>* Other names: XP13512;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo, orally, once daily for 12 weeks following single blind 24-week phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced a Relapse During the Double-Blind Treatment Period | Relapse was defined as worsening of Restless Legs Syndrome (RLS) symptoms or withdrawal due to lack of efficacy during the 12-week double-blind (DB) treatment period (the period from Randomization on Visit 14 [Week 24] through the end of treatment). Worsening of symptoms was defined as an increase in the total International RLS (IRLS) Scale score by at least 6 or more points relative to the participant's score at Randomization, achieving an IRLS score of at least 15, and an assessment of much worse or very much worse on the investigator-rated Clinical Global Impression of Change (CGI-C). | DB Treatment Period; Days 169 to 252 (Weeks 24 to 36) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Randomization to Week 36 (or End of Treatment) in the IRLS Rating Scale (IRLS) Total Score Using Last Observation Carried Forward (LOCF) | 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. LOCF: Missing data (MD) values were imputed using the last non-missing observation prior to the visit with MD; randomization visit data could be carried forward. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Percentage of Participants Who Responded to Treatment Based on Scores on the Investigator-Rated Clinical Global Impression of Change (CGI-C) Scale as a Dichotomous Variable at Week 36 (DB Treatment Phase) Using LOCF | The CGI-C scale is a widely used tool designed to allow clinicians to rate the severity of illness and the change 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. For this endpoint, response on the CGI-C was defined as participants with a rating of no change, (score of 4) minimally improved, (score of 3) much improved, (score of 2) or very much improved (score of 1) compared to Randomization (Week 24). | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants in Each Category of the Investigator-Rated CGI-C at Week 36 (DB Treatment Phase) Using LOCF | The CGI scale is a widely used tool designed to allow clinicians to rate the severity of illness and the change 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. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants in Each Category of the Participant-Rated CGI-I Scale at Week 36 (DB Treatment Phase) Using LOCF | 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 compared to baseline. | Week 36 (or end of DB treatment) | 
| Percentage of Participants Who Responded to Treatment Based on Scores on the Participant-Rated CGI-I at Week 36 (DB Treatment Phase) Using LOCF | 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. Response on the participant-rated CGI-I was defined as a rating of very much improved (score of 1) or much improved (score of 2) compared to Baseline of the SB phase. | Week 36 (or end of DB treatment) | 
| Mean Change From Randomization to Week 36 (DB Treatment Phase) in the Mean Daytime Somnolence Domain Score of the Medical Outcomes Study (MOS) Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. Responses are recoded so that a higher score reflects more of the attribute, and then converted to a 0 to 100 scale. The daytime somnolence score is based on questions pertaining to feeling drowsy or sleepy, trouble staying awake, and taking naps > 5 minutes. For daytime somnolence, a negative value indicates an improvement. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Mean Change From Randomization to Week 36 (DB Treatment Phase) in the Mean Sleep Disturbance Domain Score of the MOS Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (number of hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. The MOS Sleep Scale sleep disturbance domain is a participant-rated measure of sleep disturbance over the month prior to the measurement. Questions are scored, and responses are converted to a 0 to 100 scale, with lower scores representing less sleep disturbance. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Change From Randomization to Week 36 (DB Treatment Phase) in the Mean Sleep Adequacy Domain Score of the MOS Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (number of hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. The MOS Sleep Scale sleep adequacy domain is a participant-rated measure of the adequacy of sleep over the month prior to measurement. Questions are scored, and responses are converted to a 0 to 100 scale, with higher scores representing more adequate ratings of sleep. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Change From Randomization to Week 36 (DB Treatment Phase) in the Mean Sleep Quantity Domain Score of the MOS Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (number of hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. The Sleep Quantity Domain score is a participant-rated estimate of the average number of hours of sleep per night over the month. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Change From Randomization to Week 36 (DB Treatment Phase) in the RLS Quality of Life (QoL) Overall Life-Impact Score | The RLS QoL is an 18-item scale assessing the impact of RLS on daily life, emotional well-being, social and work life. Responses range from 1 (not at all/never) to 5 (a lot/all of the time). Ten items contribute to a single summary score, the Overall Life Impact, which is standardized to range from 0-100, with lower scores representing better QoL. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants With no Reported RLS Symptoms (Sx) During Each of the 4-hour Periods From the 24-hour RLS Record at Week 36 (DB Treatment Phase) | In the 24-hour RLS Record (diary), 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-hr intervals (8 AM to 12 PM, 12 to 4 PM, 4 to 8 PM, 6 to 10 PM, 8 to Midnight, Midnight to 4 AM, 4 to 8 AM) | Week 36 (or end of DB treatment) | 
| Median Time to Onset of First RLS Symptoms Using the 24-hour RLS Symptom Record at Week 36 (DB Treatment Phase) | 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. Note: The median is not estimable with Kaplan-Meier methodology when fewer than 50% of participants experience an event; thus, no data are presented for the DB GEn 1200 mg arm. | Week 36 (or end of DB treatment) | 
| Number of Participants With the Indicated Post-Sleep Questionnaire (PSQ) Responses to the Question Regarding Their Overall Quality of Sleep in the Week Prior to Measurement at Randomization and Week 36 (DB Treatment Phase) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants With the Indicated Post-Sleep Questionnaire (PSQ) Responses to the Question Regarding Their Ability to Function in the Week Prior to Measurement at Randomization and Week 36 (DB Treatment Phase) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Number of Nights With RLS Symptoms in the Week Prior to Measurement at Randomization and Week 36 (DB Treatment Phase) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Number of Awakenings During Night Due to RLS Symptoms in the Week Prior to Measurement at Randomization and Week 36 (DB Treatment Phase) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Number of Hours Awake Per Night Due to RLS Symptoms in the Week Prior to Measurement at Randomization and Week 36 (DB Treatment Phase) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Randomization (Week 24) and Week 36 (or end of DB treatment) | 
| Mean Change From Baseline in the IRLS Scale Total Score at Week 24 (SB Treatment Phase) Using LOCF | The IRLS Rating scale is a measure of disease severity. The scale reflects participant-reported assessment of sensory and motor features and associated sleep problems in RLS. In addition, items are included that assess the impact of symptoms on participants' mood, daily life, and activities. Total score ranges from 0-40 points, with 40 being the most severe. | Days 1 to 168 (Baseline to Week 24 of SB Phase) | 
| Number of Participants in Each Category of the Investigator-Rated CGI-I at Week 24/End of Treatment (SB Treatment Phase) Using LOCF | The CGI-I scale is a widely used tool designed to allow clinicians to rate the severity of illness and the change 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. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Number of Participants in Each Category of the Participant-Rated CGI-I at Week 24/End of Treatment (SB Treatment Phase) Using LOCF | 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 rating scale, with a score of 1 being very much improved and a score of 7 being very much worse compared to baseline. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Mean Change From Baseline to Week 24 (SB Treatment Period) in the Mean Daytime Somnolence Domain Score of the Medical Outcomes Study (MOS) Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. Responses are recoded so that a higher score reflects more of the attribute, and then converted to a 0 to 100 scale. The daytime somnolence score is based on questions pertaining to feeling drowsy or sleepy, trouble staying awake, and taking naps > 5 minutes. For daytime somnolence, a negative value indicates an improvement. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Mean Change From Baseline to Week 24 (SB Treatment Period) in the Mean Sleep Disturbance Domain Score of the MOS Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (number of hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. . The MOS Sleep Scale sleep disturbance domain is a participant-rated measure of sleep disturbance over the month prior to the measurement. Questions are scored, and responses are converted to a 0 to 100 scale, with lower scores representing less sleep disturbance. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Mean Change From Baseline to Week 24 (SB Treatment Period) in the Mean Sleep Adequacy Domain Score of the MOS Sleep Scale Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (number of hours slept), sleep disturbance, sleep adequacy, and daytime somnolence. The MOS Sleep Scale sleep adequacy domain is a participant-rated measure of the adequacy of sleep over the month prior to measurement. Questions are scored, and responses are converted to a 0 to 100 scale, with higher scores representing more adequate ratings of sleep. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Mean Change From Baseline in the MOS Sleep Scale Domain, Sleep Quantity, Score at Week 24 (SB Treatment Period) Using LOCF | The MOS Sleep Scale is a participant-rated non-disease-specific measure with questions relating to four areas related to sleep: quantity (number of hours slept), sleep disturbance, sleep adequacy, and somnolence. The Sleep Quantity Domain score is a participant-rated estimate of the average number of hours of sleep per night over the month. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Mean Change From Baseline in the Overall Quality of Life Impact Score of the RLS Quality of Life (QoL) Questionnaire at Week 24 (SB Treatment Phase) | The RLS QoL is an 18-item scale assessing the impact of RLS on daily life, emotional well-being, social and work life. Responses range from 1 (not at all/never) to 5 (a lot/all of the time). Ten items contribute to a single summary score, the Overall Life Impact, which is standardized to range from 0-100, with lower scores representing better QoL. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Overall Quality of Sleep in the Week Prior to Measurement at Baseline and Week 24 (SB Treatment Period) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Ability to Function in the Week Prior to Measurement at Baseline and Week 24 (SB Treatment Period) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Number of Nights With RLS Symptoms in the Week Prior to Measurement at Baseline and Week 24 (SB Treatment Period) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Number of Awakenings During the Night Due to RLS Symptoms in the Week Prior to Measurement at Baseline and Week 24 (SB Treatment Period) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Number of Participants With the Indicated Post-Sleep Questionnaire Responses to the Question Regarding the Number of Hours Awake Per Night Due to RLS Symptoms in the Week Prior to Measurement at Baseline and Week 24 (SB Treatment Period) Using LOCF | The PSQ is designed to evaluate sleep quality, ability to function, and the degree to which RLS symptoms interfere with sleep. Participants rated overall sleep quality and their ability to function on scales ranging from excellent to poor and were asked to provide the number of nights they experienced RLS symptoms and the number of times/hours they awoke at night during the week prior to the measurement. | Baseline and Day 168 or Week 24/End of Treatment of SB Treatment Phase | 
| Time From Randomization to Relapse in RLS Symptoms During the Double-Blind Treatment Period | Time to relapse was defined as the time until worsening of Restless Legs Syndrome (RLS) symptoms or withdrawal due to lack of efficacy during the 12-week Double-blind (DB) treatment period (same as primary outcome definition). Note: The median is not estimable with Kaplan-Meier methodology when fewer than 50% of participants experience an event. The median is not estimable for this outcome. | DB Treatment Period; Days 169 to 252 (Weeks 24 to 36) | 
| Time From Randomization to Relapse in RLS Symptoms During the Double-Blind Treatment Period (Excluding First Two Weeks of DB Phase) | Time to relapse was defined as the time until worsening of Restless Legs Syndrome (RLS) symptoms or withdrawal due to lack of efficacy during the 12-week Double-blind (DB) treatment period (same as primary outcome definition). Note: The median is not estimable with Kaplan-Meier methodology when fewer than 50% of participants experience an event. The median is not estimable for this outcome. | DB Treatment Period; Days 184 to 252 (Weeks 26 to 36) |