Effects of Gabapentin Enacarbil on Intensity of Cortical Arousal, Heart Rate, Blood Pressure and Anterior Tibialis EMG Responses Associated With PLMs During Sleep in Patients With RLS Using a Novel Computer Assisted Scoring System
试验速览
- 阶段
- 4 期
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- The mean change from baseline to week 4 in intensity of cortical arousals associated with periodic limb movements (PLMs)
研究概览
简要总结
This is a phase IV single-blind, placebo run-in fixed dose single-group study to assess objective and subjective effects of GEn on sleep EEG, BP, and anterior tibialis EMG responsivity in patients with RLS. The study will include 8 visits over a period of up to 8 weeks for eligible subjects including a 1 to 3-week Screening/Washout Period, a 1-week placebo run-in period, and a 4-week Treatment Period.The first placebo dose will be administered within 1 to 3 weeks after Screening/Washout. The total duration of the study from the first subject enrolled to the last subject completed will be approximately 1 year.
详细描述
Evidence from the Sleep Heart Health Study suggests that nocturnal arousals from sleep impact heart rate variability and sleep disorders associated with frequent nocturnal arousals, including restless legs syndrome (RLS), increase the risks of developing cardiovascular disease. The majority of RLS patients, once asleep, exhibit frequent periodic limb movements (PLMs), which cause electroencephalographic (EEG) arousals and sleep fragmentation resulting in poor quality of sleep and daytime consequences. PLMs are also reported to increase heart rate.The precise nature of the relationship between PLMs and their impact on heart rate and blood pressure is not clear. This may relate to the fact that PLMs are scored as either present or absent and without accounting for the differences in intensity of muscle activity during individual PLMs and intensity of associated arousals. In fact PLMs have been reported to vary from barely visible to very intense changes in the anterior tibialis electromyogram (EMG). This study will evaluate the effects of gabapentin encarbil (GEn) on intensity of cortical arousals associated with PLMs using a newly developed computer assisted scoring system which allows for scaling microarousals in the EEG. The anterior tibialis EMG intensity, continuous blood pressure and heart rate will be measured.
The study design is a phase IV single center, single blind, placebo run-in fixed dose single group study in twenty subjects with moderate to severe restless leg syndrome. It includes a one- three week screening washout period, one week of placebo run-in and four- week treatment period with GEn 600 mg once daily. Subjects will be instructed to take their study medication once daily with food in the evening at approximately 5 PM. If the dose is not taken at the recommended time, the next dose should be taken the following day at the regularly scheduled time (about 5 PM the next evening). Subjects will be blinded to treatment (placebo versus active drug).
Polysomnography (PSG) will be obtained for two nights of baseline at the end of placebo run-in and at the end of four weeks of treatment with gabapentin encarbil 600 mg. Medical history and cardiovascular risk factors will be assessed at Screening. RLS disease history, previous/current RLS therapy, augmentation history and evidence of sleep disturbance will be obtained.Severity of RLS will be determined using the International Restless Legs Syndrome (IRLS) scale. The Berlin questionnaire will be used to identify the risk (low to high) of sleep disordered breathing. The Beck Depression Inventory (BDI-II) will be administered to identify depression and its severity at Screening. Electrocardiogram (ECG), clinical laboratory test and urine pregnancy test will be conducted at Screening to determine eligibility. Also to determine eligibility, subjective evidence of sleep disturbance will be assessed per daily sleep diary at Visit 2. A physical exam will be performed at the beginning of the Placebo Run-in Period.
The visit schedule includes: Screening; Scheduled Tests/Exams; Placebo administration visit; Baseline PSG visits; Baseline Visit; End of treatment PSG visits; Adverse Event Evaluation (for all subjects);Unscheduled clinical evaluation visit; and End of Study Visit.
Primary outcome will involve change from baseline (end of run-in period) in cortical arousal intensity associated with PLMs for subjects treated with Gen 600 mg QD for 4 weeks. PSG studies will be recorded for 8 hours using standard techniques described by R&K. Cortical EEG arousals will be scored using wavelet analysis of C3/A2 and C4/A1 EEG signals. Arousals scored in NREM sleep will be assigned a score from 0-9. This arousal scaling is entirely subjective. Wavelet analysis will be performed on each of the scaled arousals using wavelet features that correlate with arousal intensity. The arousal intensity will be measured using Wavelet Transform which is superior for analyzing signals such as EEG.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female subjects ages 18 to 65 years with a diagnosis of primary moderate to severe RLS
- •A minimum of 6-month history of RLS symptoms
- •IRLS score >15 points (at visits 1 and 2) and a score of > 2 on item 4
- •RLS symptoms on at least 15 days during the month prior to screening (or if on treatment, similar symptom frequency before the start of treatment)
- •RLS symptoms for >4 out of 7 evenings /day during the week prior to screening
- •History of sleep disturbance due to RLS over the last 3 months
- •Subjective history of WASO ≥ 60 min; TST < 6.5 hours; subjective sleep latency ≥ 30 min on at least 3 nights per week within the last 3 months
- •Subjective complaint of WASO ≥ 60 min; TST< 6.5 hours; subjective sleep latency ≥ 30 min on at least 3 nights out of 7on the SSQ during the 1 week prior to Visit 2
- •Objective WASO of ≥30 minutes, TST < 6.5 hours and PLMI ≥ 10 during adaptation in baseline PSG 1
- •Females of child bearing potential willing to use birth control
- •Subject can read understand and sign consent form
- •Subject able to complete the study and to comply with study instructions and procedures
排除标准
- •Subject has an apnea-hypopnea index of ≥10/ hour during adaptation/baseline night PSGs. Subjects with OSA controlled by CPAP will be accepted
- •Evidence of secondary RLS
- •Subject has any of the following medical conditions, laboratory abnormalities or disorders:
- •Hepatic impairment Impaired renal function or renal dysfunction requiring hemodialysis; Serum ferritin level <20 mcg/L (ng/mL)
- •Clinically significant ECG abnormalities
- •Any unstable medical condition that could impact subject's safety and study outcomes
- •Uncontrolled hypertension at Screening or at time of treatment initiation
- •Subjects diagnosed with additional sleep disorders other than RLS-associated sleep disturbance
- •Neurologic disease or movement disorder, rheumatoid arthritis, fibromyalgia, uncontrolled psychiatric illness, current diagnosis or history of epilepsy or seizure disorder
- •Chronic hepatitis B or hepatitis C
- •Subject currently suffering from moderate or severe depression
- •Subject unable to discontinue prohibited medications during the Screening period and throughout the duration of the study.
- •Subject has consumed food or beverages containing more than 400 mg of caffeine or other xanthines (e.g., coffee, cola, tea, chocolate) per day over the preceding month prior to Screening or unwilling to refrain from consuming any caffeinated food or beverage within 8 hours prior to any PSG assessment.
- •Subject has typical consumption of >14 alcoholic units in any week, or more than 5 alcoholic units in any single day, over the month preceding the Screening visit or unwilling to refrain from consuming alcohol within 24 hours of any PSG assessment
- •Night workers, shift workers or any others whose sleeping habits are incompatible with the study design, or who would be required to make significant changes to their bedtime during the course of the study
- •Subject who might be non-compliant with the visit schedule, procedures, or medication administration
- •Subject is a pregnant or nursing female
- •A history of allergy or medically significant adverse reaction or intolerance to gabapentin or GEn
- •A history of alcohol, narcotic, benzodiazepine, or other substance abuse or dependence within the past year
- •A history of augmentation or early morning rebound of RLS symptoms without a history of prior response to treatment.
- •Subject has received previous treatment with levodopa/carbidopa, dopamine agonists, pregabalin, gabapentin or GEn in the 3 weeks prior to Visit
- •Subject has received' other treatments for RLS (e.g., opioids, benzodiazepines) at least 2 weeks prior to Visit 2
- •Participation in any clinical drug or device trial within 30 days prior to Baseline
研究组 & 干预措施
Single Gabapentin Enacarbil Arm
Gabapentin Enacarbil (Gen) 600 mg will be administered once daily for 4 weeks
Matching placebo will be administered once daily for one week prior initiation of treatment with GEn
干预措施: Gabapentin Enacarbil (GEn) (Drug)
Single Gabapentin Enacarbil Arm
Gabapentin Enacarbil (Gen) 600 mg will be administered once daily for 4 weeks
Matching placebo will be administered once daily for one week prior initiation of treatment with GEn
干预措施: Placebo (Drug)
结局指标
主要结局
The mean change from baseline to week 4 in intensity of cortical arousals associated with periodic limb movements (PLMs)
时间窗: 4 weeks
Cortical EEG arousals will be scored using wavelet analysis of C3/A2 and C4/A1 EEG signals. Arousals scored in NREM sleep will be assigned a score from 0-9. This arousal scaling is entirely subjective. Wavelet analysis will be performed on each of the scaled arousals using wavelet features that correlate with arousal intensity. The arousal intensity will be measured using Wavelet Transform which is superior for analyzing signals such as EEG.
次要结局
- The mean change from baseline to week 4 in International Restless Legs Syndrome (IRLS) Rating Scale total score(4 weeks)
- The mean change from Baseline to week 4 in Post Sleep Questionnaire (PSQ)scores(4 weeks)
- The mean change from Baseline to week 4 in Restless Legs Syndrome Quality of Life Questionnaire (RLSQoL) scores(4 weeks)
- The mean change from baseline to week 4 in heart rate variability associated with arousals secondary to periodic limb movements (PLMs)(4 weeks)
- The mean change from baseline to week 4 in blood pressure associated with arousals secondary to periodic limb movements (PLMs)(4 weeks)
- The mean change from baseline to week 4 in periodic limb movement (PLM) intensity(4 weeks)
- The mean change from Baseline to week 4 in proportion of responders ("much"/ "very much" improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale(4 weeks)
- The mean change from Baseline to week 4 in Subjective Sleep Questionnaire (SSQ) scores(4 weeks)
- The mean change from Baseline to week 4 in the Epworth Sleepiness Scale (ESS) scores(4 weeks)
- Number of subjects with mild, moderate and severe adverse events(4 weeks)
- The mean change from Baseline to week 4 in Rechtschaffen and Kales polysomnography parameters(4 weeks)
- The mean change from Baseline to week 4 in proportion of responders ("moderately better" to "a great deal better") on the patient Global Impression of Change (PGIC) scale(4 weeks)
- The mean change from Baseline to week 4 in Restless Legs Syndrome- Next Day Impact Questionnaire (RLS-NDI) scores(4 weeks)
- Number of subjects with treatment emergent adverse events(4 weeks)
研究者
Mansoor Ahmed M.D.
Medical Director
Cleveland Sleep Research Center