• Change in Epworth Sleepiness Scale Score [ Time Frame: Day 2, 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 Maintenance of Wakefulness Test (MWT) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in gamma-aminobutyric acid receptor A (GABA-A) potentiation [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Default Mode Network (DMN) Connectivity [ Time Frame: Day 1, Day 13 ]
  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.
• Change in tumor necrosis factor - alpha (TNF-α) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in gastrointestinal microbiome composition [ Time Frame: Day 2, Day 14 ]
  Changes in microbiome composition via 16S ribosomal ribonucleic acid (rRNA) sequencing results will be compared between study arms.

• Change in Sleep Duration [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Fatigue Severity Scale (FSS) Score [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Multidimensional Fatigue Inventory (MFI-20) Score [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Sleep Inertia Questionnaire (SIQ) Score [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Sleep Inertia Scale [ Time Frame: Day 2, Day 14 ]
  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".
• Change in Idiopathic Hypersomnia Severity Scale (IHSS) Score [ Time Frame: Day 2, Day 14 ]
  The IHSS is a 14-item instrument assessing symptoms, consequences, and treatment of hypersomnia. Items are scored on a 4 or 5-point scale (depending on severity) and total scores range from 0 to 50, with higher scores indicating more symptoms of hypersomnia.
• Change in Interleukin 1 alpha (IL-1α) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Interleukin 1 beta (IL-1β) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Interleukin 2 (IL-2) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Interleukin 6 (IL-6) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Interleukin (IL-8) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Interleukin (IL-15) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in Interleukin (IL-18) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in tumor necrosis factor beta (TNF-β) [ Time Frame: Day 2, Day 14 ]
  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.
• Change in interferon alpha (INF-α) [ Time Frame: Day 2, Day 14 ]
  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.

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. These latter syndromes are a group of disorders with overlapping clinical phenotypes and, except in the case of narcolepsy due to hypocretin deficiency (narcolepsy type 1), potentially shared pathophysiology.

Pathologic daytime sleepiness in these 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.

• Narcolepsy Without Cataplexy
• Idiopathic Hypersomnia

• Drug: Clarithromycin
  Clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days.
  Other Name: Biaxin
• Drug: Placebo
  A placebo to match clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days.

• Experimental: Clarithromycin
  Participants in this study arm will receive clarithromycin for 14 days.
  Intervention: Drug: Clarithromycin
• Placebo Comparator: Placebo
  Participants in this study arm will receive a placebo to match clarithromycin for 14 days.
  Intervention: Drug: Placebo

Inclusion Criteria:

• diagnosis of idiopathic hypersomnia, established via International Classification of Sleep Disorders, third edition (ICSD-3) criteria, including objective confirmation via multiple sleep latency test mean sleep latency < 8 minutes, actigraphic daily sleep times > 660 minutes, averaged over at least 7 days, and/or polysomnographic sleep time > 660 minutes in < 24 hour monitoring; or diagnosis of narcolepsy type 2, established via ICSD-3 criteria including multiple sleep latency test mean sleep latency < 8 minutes in the presence of at least 2 sleep onset rapid eye movement (REM) periods
• age 18-45 (with the upper limit established because of age-dependent changes in DMN resting state functional magnetic resonance imaging connectivity and to minimize risk of side effects)
• free of wake-promoting medication or willing to discontinue current wake-promoting medication for at least 5 half-lives prior to baseline measures
• free of pre- or probiotic supplements for at least six months prior to baseline measures

Exclusion Criteria:

• other potential causes of hypersomnolence, including moderate or severe sleep apnea, severe periodic limb movement disorder with arousals, uncontrolled metabolic disorders, hypocretin deficiency, or cataplexy
• contraindication to clarithromycin
• contraindication to any of the study procedures