Antibiotic-mediated Improvements in Vigilance: Mechanisms of Action of Clarithromycin in Hypersomnia Syndromes
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 83
- 试验地点
- 1
- 主要终点
- Change in Default Mode Network (DMN) Connectivity
研究概览
简要总结
The purpose of this study is to evaluate a medication called clarithromycin for treating sleepiness in narcolepsy and idiopathic hypersomnia. Studies have shown that clarithromycin can reduce sleepiness, but researchers do not know how clarithromycin does this. This study will look at brain activity (on magnetic resonance imaging [MRI]), inflammation, bacteria living in the gut, and cerebrospinal fluid, to better understand how clarithromycin can reduce sleepiness. This study will recruit 92 participants who will be randomized to receive clarithromycin or a placebo for 14 days.
详细描述
Excessive daytime sleepiness and long sleep durations are common features of many neurologic disorders, including myotonic dystrophy, Parkinson's disease, and the central nervous system hypersomnia syndromes.
Pathologic daytime sleepiness in the central nervous system hypersomnia disorders impairs occupational performance, limits quality of life, and more than doubles motor vehicle and other accident risk. Because the underlying cause of the majority of these hypersomnia syndromes is not known, treatments are aimed at increasing monoaminergic signaling involved in wake promotion. Yet, at least one-fourth of patients with hypersomnia syndromes cannot achieve satisfactory control of symptoms with these treatments and disability or medical leaves of absence are often necessary. There is a clear need for novel treatments for excessive daytime sleepiness to resolve this failure of the current standard of care.
In prior studies, clarithromycin resulted in significant, clinically meaningful improvements in sleepiness severity, sleepiness-related limitations in extended activities of daily living, and sleepiness-related quality of life. Long sleep durations and sleep inertia, both ancillary symptoms of hypersomnia disorders that contribute to functional impairments, were also improved with clarithromycin.
Hypothesis: Clarithromycin will reduce excessive sleepiness and other symptoms of hypersomnia disorders, as measured by self-report and objective testing.
Aim 1: To identify central nervous system mediators of clarithromycin's ability to promote wakefulness and reduce sleepiness, among patients with central hypersomnia syndromes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •diagnosis of idiopathic hypersomnia or narcolepsy
- •age 18-60
- •free of wake-promoting medication, sleepy despite current wake-promoting medications, or willing to discontinue current wake-promoting medication for at least 5 half-lives prior to baseline measures
排除标准
- •other potential causes of hypersomnolence, including untreated moderate or severe sleep apnea, severe periodic limb movement disorder with arousals, uncontrolled metabolic disorders
- •contraindication to clarithromycin
- •contraindication to any of the study procedures
研究组 & 干预措施
Placebo
Participants in this study arm will receive a placebo to match clarithromycin for 14 days.
干预措施: Placebo (Drug)
Clarithromycin
Participants in this study arm will receive clarithromycin for 14 days.
干预措施: Clarithromycin (Drug)
结局指标
主要结局
Change in Default Mode Network (DMN) Connectivity
时间窗: Day -2, Day 13
The default mode network (DMN) consists of a group of highly correlated brain regions most active during quiet rest, while the task positive network (TPN) is the brain network activated for goal-directed tasks. DMN connectivity changes with sleep states and it is increasingly implicated in the symptomatology of sleepiness. During resting state, sleep deprived participants demonstrate reduced static connectivity with the DMN. Changes in DMN between the Baseline 1 (Day - 2) and Day 13 visits are compared between treatment groups, particularly using quasi-periodic patterns (QPPs), which interrogate network-level connectivity on a dynamic scale. Preservation of the temporal dimension provides more insight into how this spatiotemporal network propagates across condition and pathology. The DMN/TPN QPP correlation is reported.
Change in Epworth Sleepiness Scale (ESS) Score
时间窗: Day -1, Day 14
The Epworth Sleepiness Scale asks participants to respond to 8 scenarios with how likely they are to fall asleep on a 4-point scale where 0 = "would never doze" and 3 = "high chance of dozing". Total scores range from 0 to 24 where higher scores indicate a higher chance of falling asleep during daytime activities. The change in ESS score is obtained by subtracting the total score at Day 14 from the baseline score. Scores above 0 mean that the mean score at Day 14 was lower than the mean score at Baseline, indicating less sleepiness.
Change in Maintenance of Wakefulness Test (MWT) for Sleep Latency
时间窗: Day -1, Day 14
The MWT polysomnographic procedure for sleep latency examines how well participants stay awake during several trials where participants relax in a quiet room for 40 minutes. One study found the mean sleep latency among persons without a sleep disorder to be 35.2 minutes. The change from baseline is calculated as baseline sleep latency minus sleep latency at Day 14, in minutes. Positive values result when the duration of sleep latency at Day 14 is lower than at Baseline.
Change in Gamma-aminobutyric Acid Receptor A (GABA-A) Potentiation
时间窗: Day -1, Day 14
Cerebrospinal fluid (CSF) is drawn to determine the change in levels of GABA-A potentiation between the study arms. The difference between measured current with GABA alone and the current measured with GABA + CSF yields a measure of potentiation for each CSF sample in each condition. The change from baseline is calculated as the baseline value minus the value at Day 14.
Change in Tumor Necrosis Factor - Alpha (TNF-α)
时间窗: Day -1, Day 14
Blood samples are used to determine the change in levels of TNF-α between the study arms. TNF-α is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness.
Change in Gastrointestinal Microbiome Composition
时间窗: Day -1, Day 14
Changes in microbiome composition, as measured by alpha diversity using the Shannon Index, via 16S ribosomal ribonucleic acid (rRNA) sequencing results are compared between study arms. The Shannon Index measures both abundance and evenness of microbial species, values of 0 indicate that a community has only one species. The higher the value the higher the diversity of species in a particular community. Change from baseline is calculated by subtracting the Day 14 value from the value at Baseline. Numbers greater than 0 indicate that the Day 14 Shannon index value is lower than at Baseline.
Change in Epworth Sleepiness Scale Score
时间窗: Day -1, Day 14
The Epworth Sleepiness Scale asks participants to respond to 8 scenarios with how likely they are to fall asleep on a 4-point scale where 0 = "would never doze" and 3 = "high chance of dozing". Total scores range from 0 to 24 where higher scores indicate a higher chance of falling asleep during daytime activities.
Change in gamma-aminobutyric acid receptor A (GABA-A) potentiation
时间窗: Day -1, Day 14
Cerebrospinal fluid (CSF) is drawn to determine the change in levels of GABA-A potentiation between the study arms. The difference between measured current with GABA alone and the current measured with GABA + CSF yields a measure of potentiation for each CSF sample in each condition.
Change in gastrointestinal microbiome composition
时间窗: Day -1, Day 14
Changes in microbiome composition via 16S ribosomal ribonucleic acid (rRNA) sequencing results are compared between study arms.
次要结局
- Change in Interleukin 6 (IL-6)(Day -1, Day 14)
- Change in Interleukin 2 (IL-2)(Day -1, Day 14)
- Change in Fatigue Severity Scale (FSS) Score(Day -1, Day 14)
- Change in Multidimensional Fatigue Inventory (MFI-20) Score(Day -1, Day 14)
- Change in Sleep Inertia Questionnaire (SIQ) Score(Day -1, Day 14)
- Change in Interleukin (IL-8)(Day -1, Day 14)
- Change in Interleukin (IL-15)(Day -1, Day 14)
- Change in Interleukin (IL-18)(Day -1, Day 14)
- Change in Functional Outcomes of Sleep Questionnaire (FOSQ) Score(Day -1, Day 14)
- Change in Hypersomnia Severity Index (HSI)(Day -1, Day 14)
- Change in MRI Functional Connectivity(Day -2, Day 13)
- On-Treatment Sleep Duration(Day 1 through Day 14)
- On-Treatment Sleep Inertia Likert Scale(Day 1 through Day 14)
- Change in Interleukin 1 Alpha (IL-1α)(Day -1, Day 14)
- Change in Interleukin 1 Beta (IL-1β)(Day -1, Day 14)
- Change in Tumor Necrosis Factor Beta (TNF-β)(Day -1, Day 14)
- Change in Interferon Alpha (INF-α2a)(Day -1, Day 14)
- Change in MRI Task Performance - N-Back Accuracy(Day -2, Day 13)
- Change in MRI Task Performance - N-Back Reaction Time(Day -2, Day 13)
- Change in Fatigue Severity Scale (FSS) Score(Day -1, Day 14)
- Change in Multidimensional Fatigue Inventory (MFI-20) Score(Day -1, Day 14)
- Change in Sleep Inertia Questionnaire (SIQ) Score(Day -1, Day 14)
- Change in Interleukin 1 alpha (IL-1α)(Day -1, Day 14)
- Change in Interleukin 1 beta (IL-1β)(Day -1, Day 14)
- Change in Interleukin 2 (IL-2)(Day -1, Day 14)
- Change in Interleukin 6 (IL-6)(Day -1, Day 14)
研究者
Lynn Marie Trotti
Associate Professor
Emory University