Clarithromycin Mechanisms in Hypersomnia Syndromes

Emory University

Status and phase: Enrolling; Phase 2

Conditions: Idiopathic Hypersomnia; Narcolepsy Without Cataplexy; Narcolepsy With Cataplexy

Treatments: Drug: Clarithromycin; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT04026958

IRB00108681

1R01NS111280 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 92 estimated patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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92 participants in 2 patient groups, including a placebo group

Clarithromycin

Experimental group

Description:

Participants in this study arm will receive clarithromycin for 14 days.

Treatment:

Drug: Clarithromycin

Placebo

Placebo Comparator group

Description:

Participants in this study arm will receive a placebo to match clarithromycin for 14 days.

Treatment:

Drug: Placebo