A Ten Subject, Double-Blind, Placebo-Controlled Trial of Single Day Dosing of Sublingual Flumazenil in Individuals With Primary Hypersomnia or Excessively Long Total Sleep Time and Excess Endogenous Potentiation of GABA-A Receptors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in Psychomotor Vigilance Task (PVT) Median Reaction Time
研究概览
简要总结
The term 'hypersomnia' describes a group of symptoms that includes severe daytime sleepiness and sleeping long periods of time (more than 10 hours per night). Sometimes, hypersomnia is caused by a problem with the quality of sleep occurring at night, for instance when nighttime sleep is disrupted by frequent breathing pauses. In other cases, however, hypersomnia occurs even when nighttime sleep is of good quality. These cases of hypersomnia are presumed to be a symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain) origin, or primary hypersomnias.
The causes of most of these primary hypersomnias are not known. However, our group has recently identified a problem with the major brain chemical responsible for sedation, known as GABA. In a subset of our hypersomnia patients, there is a naturally-occurring substance that causes the GABA receptor to be hyperactive. In essence, it is as though these patients are chronically medicated with Valium (or Xanax or alcohol, all substances that act through the GABA system), even though they do not take these medications.
Current treatment of central hypersomnias is limited. For the fraction of cases with narcolepsy, there are FDA-approved, available treatments. However, for the remainder of patients, there are no treatments approved by the FDA. They are usually treated with medications approved for narcolepsy, but sleep experts agree that these medications are often not effective for this group of patients.
Based on our understanding of the GABA abnormality in these patients, we evaluated whether flumazenil (an medication approved by the FDA for the treatment of overdose of GABA medications or the reversal of GABA-based anesthesia) would reverse the GABA abnormality in our patients. In a test tube model of this disease, flumazenil does in fact return the function of the GABA system to normal. The investigators have treated a few patients with flumazenil and most have felt that their hypersomnia symptoms improved with this treatment.
To determine whether flumazenil is truly beneficial for primary hypersomnia, this study will compare flumazenil to an inactive pill (the placebo). All subjects will receive both flumazenil and the placebo at different times, and their reaction times and symptoms will be compared on these two treatments to determine if one is superior. Currently, flumazenil can only be given through an injection into a vein (i.e., intravenously). This study will evaluate this intravenous dosing as well as a new form of flumazenil, which is taken as a lozenge to be dissolved under the tongue. If this study shows that flumazenil is more effective than placebo in the treatment of hypersomnia, it will identify a potential new therapy for this difficult-to-treat disorder.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Hypersomnia (meeting clinical criteria for idiopathic hypersomnia with or without long sleep time, narcolepsy lacking cataplexy, or symptomatic hypersomnia not meeting International Classification of Sleep Disorders 2 (ICSD-2) criteria inclusive of habitually long sleep periods of > 10 hours/day)
- •evidence for GABA-related abnormality, as demonstrated by our in-house, in vitro assay
- •age > 18
- •high performance liquid chromatography/liquid chromatography tandem mass spectrometry verification of the absence of exogenous benzodiazepines (BZDs).
排除标准
- •Contraindications to use of flumazenil (pregnancy, hepatic impairment, seizure history, pre-menstrual dysphoric disorder, traumatic brain injury, cardiac disease (left ventricular diastolic dysfunction), or cardiac dysrrhythmia.
- •Current use of a BZD or BZD-receptor agonists
- •moderate or severe sleep apnea (RDI > 15/hr), severe periodic limb movement disorder (PLMI > 30/hr)
- •diagnosis of narcolepsy with cataplexy, as determined by ICSD-2 criteria and confirmed by absence of cerebrospinal fluid (CSF) hypocretin
- •metabolic disorders such as severe anemia, adrenal insufficiency, severe iron deficiency, vitamin B12 deficiency, or hypothyroidism that may explain symptoms of hypersomnia
研究组 & 干预措施
Placebo, then Flumazenil
Subjects in this arm will first receive a day of placebo, then a day of sublingual flumazenil
干预措施: Flumazenil (Drug)
Flumazenil, then Placebo
Subjects in this group will first receive a day of sublingual flumazenil, then a day of placebo.
干预措施: Flumazenil (Drug)
结局指标
主要结局
Change in Psychomotor Vigilance Task (PVT) Median Reaction Time
时间窗: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
The PVT measures the reaction time to button press following the presentation of a visual stimulus, reported here as the median reaction time for multiple presentations during the 10 minute task. The measure used was the change in median reaction time from baseline to drug administration, where the median reaction time at each of the time points (below) was averaged to provide a single on-treatment value for median reaction time. The measure was then calculated as baseline value - treatment value, such that higher numbers denote improvement from baseline.
次要结局
- PVT Additional Measure #2, Change in Duration of Lapse Domain(10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject))
- PVT Additional Measure #1, Change in Lapse Frequency(10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject))
- PVT Additional Measure #3, Change in Optimum Response Times(10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject))
- PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT(10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject))
- Electroencephalogram (EEG) Power(following drug administration)
- PVT Additional Measure #4, Change in False Response Frequency(10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject))
- Change in Stanford Sleepiness Scale(10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject))
研究者
Lynn Marie Trotti
Assistant Professor of Neurology
Emory University