Clarithromycin Mechanisms in Hypersomnia Syndromes

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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. Hypothesis 1a: Changes in cerebrospinal fluid (CSF) enhancement of gamma-aminobutyric acid-A (GABA-A) receptor function in vitro will be associated with improvements in self-reported and objectively measured sleepiness. Hypothesis 1b: Changes in functional connectivity will be associated with improvements in self-reported and objectively measured sleepiness. Aim 2: To probe extra-neuronal mechanisms by which clarithromycin may reduce sleepiness, including changes in systemic inflammation and changes in gastrointestinal microbiota composition, in patients with central hypersomnia syndromes. Hypothesis 2a: Improvement in sleepiness with clarithromycin use will be positively associated with reductions in systemic inflammation, especially reductions in levels of tumor necrosis factor-alpha (TNFα). Hypothesis 2b: Improvement in sleepiness with clarithromycin use will be positively correlated with modulation of gastrointestinal dysbiosis.

Official Title
-----------------
Antibiotic-mediated Improvements in Vigilance: Mechanisms of Action of Clarithromycin in Hypersomnia Syndromes

Conditions
-----------------
Narcolepsy Without Cataplexy, Idiopathic Hypersomnia, Narcolepsy With Cataplexy

Intervention / Treatment
-----------------
* Drug: Clarithromycin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clarithromycin<br>Participants in this study arm will receive clarithromycin for 14 days. | Drug: Clarithromycin<br>* Clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days.<br>* Other names: Biaxin;|
| Placebo Comparator: Placebo<br>Participants in this study arm will receive a placebo to match clarithromycin for 14 days. | Drug: Placebo<br>* A placebo to match clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Epworth Sleepiness Scale Score | 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. | Day -1, Day 14 | 
| Change in Maintenance of Wakefulness Test (MWT) | The MWT polysomnographic procedure examining 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. Sleep latency will be compared between study arms. | Day -1, Day 14 | 
| Change in gamma-aminobutyric acid receptor A (GABA-A) potentiation | Cerebrospinal fluid (CSF) will be 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 will yield a measure of potentiation for each CSF sample in each condition. | Day -1, Day 14 | 
| Change in Default Mode Network (DMN) Connectivity | The default mode network (DMN) consists of a group of highly correlated brain regions most active during quiet rest. DMN connectivity changes with sleep states and it is increasingly implicated in the symptomatology of sleepiness. During resting state, sleep deprived participants demonstrate reduced connectivity with the DMN. Changes in DMN between the Baseline 1 and Day 13 visits will be compared between treatment groups. | Day -2, Day 13 | 
| Change in tumor necrosis factor - alpha (TNF-α) | Blood will be drawn 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. | Day -1, Day 14 | 
| Change in gastrointestinal microbiome composition | Changes in microbiome composition via 16S ribosomal ribonucleic acid (rRNA) sequencing results will be compared between study arms. | Day -1, Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sleep Duration | Participants will log when they go to bed and when they wake up in order to calculate the number of minutes spent sleeping. Duration of sleep will be compared between study arms. | Day -1, Day 14 | 
| Change in Fatigue Severity Scale (FSS) Score | Fatigue severity will be measured with the Fatigue Severity Scale (FSS). The FSS is a 9-item instrument where responses are on a scale of 1 to 7 where 1 = disagree and 7 = agree. Total scores range from 9 to 63 where higher scores indicate greater fatigue. | Day -1, Day 14 | 
| Change in Multidimensional Fatigue Inventory (MFI-20) Score | The MFI-20 is a 20-item instrument assessing fatigue severity. Responses are on a 5-point scale where 1 = yes, that is true and 5 = no, that is not true. Positively phrased items are reverse scored so that the total score ranges from 20 to100 where higher scores indicate greater severity of fatigue. | Day -1, Day 14 | 
| Change in Sleep Inertia Questionnaire (SIQ) Score | The SIQ is an instrument with 21 items with responses on a 5-point scale where 1 = not at all and 5 = all the time. Two additional questions relate to how much time it takes for the respondent to wake up in the morning. Total scores range from 21 to 105 and higher scores indicate increased difficulty from tiredness. | Day -1, Day 14 | 
| Change in Sleep Inertia Scale | Sleep inertia will be measured with a single item on a 10-point Likert scale asking participants how difficult it was for them to wake up in the morning, were 1 = not difficult at all and 10 = very difficult. | Day -1, Day 14 | 
| Change in Interleukin 1 alpha (IL-1α) | Blood will be drawn to determine the change in levels of IL-1α between the study arms. IL-1α is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Interleukin 1 beta (IL-1β) | Blood will be drawn to determine the change in levels of IL-1β between the study arms. IL-1β is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Interleukin 2 (IL-2) | Blood will be drawn to determine the change in levels of IL-2 between the study arms. IL-2 is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Interleukin 6 (IL-6) | Blood will be drawn to determine the change in levels of IL-6 between the study arms. IL-6 is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Interleukin (IL-8) | Blood will be drawn to determine the change in levels of IL-8 between the study arms. IL-8 is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Interleukin (IL-15) | Blood will be drawn to determine the change in levels of IL-15 between the study arms. IL-15 is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Interleukin (IL-18) | Blood will be drawn to determine the change in levels of IL-18 between the study arms. IL-18 is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in tumor necrosis factor beta (TNF-β) | Blood will be drawn to determine the change in levels of TNF-β between the study arms. TNF-β is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in interferon alpha (INF-α) | Blood will be drawn to determine the change in levels of INF-α between the study arms. INF-α is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. | Day -1, Day 14 | 
| Change in Functional Outcomes of Sleep Questionnaire (FOSQ) Score | The FOSQ is a 30-item instrument assessing how sleepiness impacts daily activities. There are five subscales assessing General Productivity, Activity Level, Vigilance, Social Outcomes, and Intimate and Sexual Relationships. Items are scored on a 4-point scale where 1 = extreme difficulty and 4 = no difficulty. Subscale scores are obtained by calculating the mean score for the items in that subscale and each can range from 1 to 4, where higher scores indicate less difficulty due to sleepiness. A total score is obtained by calculating the means of the subscale scores and multiplying that by the number of subscales with a score. The total score ranges from 5 to 20 and higher scores indicate fewer difficulty from sleepiness. | Day -1, Day 14 | 
| Change in Hypersomnia Severity Index (HSI) | The HSI is a 9-item instrument assessing the severity of excessive sleepiness (hypersomnolence). Items are scored on a Likert scale where 0 = not at all and 4 = very much. Total scores range from 0 to 36 and higher scores indicate greater severity of symptoms of hypersomnia. | Day -1, Day 14 | 
| Change in MRI Functional Connectivity | For functional connectivity analyses, each functional scan will be parceled into the 273 regions of interest (ROIs) contained in the Brainnetome Atlas and mean timecourse will be calculated for each ROI within the default mode network (DMN). Pearson correlations between each pair of ROIs will be calculated, to determine the strength of functional connectivity between each pair of regions. This will yield a functional connectivity matrix for each functional scan. These correlation matrices will be Fischer z-transformed and averaged across each condition to create a mean functional connectivity matrix for each condition. | Day -2, Day 13 | 
| Change in MRI Activation Patterns | Participants will complete a working memory task during functional magnetic resonance imaging (fMRI). Activity during the task (vs non-task) will be calculated for each participant within regions of interest defined by prior meta-analysis identifying areas involved in this working memory task. Activation in these areas at baseline will be compared to activation on study treatment, and differences between clarithromycin and placebo groups compared. | Day -2, Day 13 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Neurology