Clinical trial NCT04026958: Clarithromycin Mechanisms in Hypersomnia Syndromes
Official title: Antibiotic-mediated Improvements in Vigilance: Mechanisms of Action of Clarithromycin in Hypersomnia Syndromes
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Narcolepsy Without Cataplexy
Idiopathic Hypersomnia
Narcolepsy With Cataplexy
Keywords: Neurology
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2019-07-19
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Change in Epworth Sleepiness Scale Score
timeFrame: Day -1, Day 14
measure: Change in Maintenance of Wakefulness Test (MWT)
timeFrame: Day -1, Day 14
measure: Change in gamma-aminobutyric acid receptor A (GABA-A) potentiation
timeFrame: Day -1, Day 14
measure: Change in Default Mode Network (DMN) Connectivity
timeFrame: Day -2, Day 13
measure: Change in tumor necrosis factor - alpha (TNF-α)
timeFrame: Day -1, Day 14
measure: Change in gastrointestinal microbiome composition
timeFrame: Day -1, Day 14
Secondary outcomes:
measure: Change in Sleep Duration
timeFrame: Day -1, Day 14
measure: Change in Fatigue Severity Scale (FSS) Score
timeFrame: Day -1, Day 14
measure: Change in Multidimensional Fatigue Inventory (MFI-20) Score
timeFrame: Day -1, Day 14
measure: Change in Sleep Inertia Questionnaire (SIQ) Score
timeFrame: Day -1, Day 14
measure: Change in Sleep Inertia Scale
timeFrame: Day -1, Day 14
measure: Change in Interleukin 1 alpha (IL-1α)
timeFrame: Day -1, Day 14
measure: Change in Interleukin 1 beta (IL-1β)
timeFrame: Day -1, Day 14
measure: Change in Interleukin 2 (IL-2)
timeFrame: Day -1, Day 14
measure: Change in Interleukin 6 (IL-6)
timeFrame: Day -1, Day 14
measure: Change in Interleukin (IL-8)
timeFrame: Day -1, Day 14
measure: Change in Interleukin (IL-15)
timeFrame: Day -1, Day 14
measure: Change in Interleukin (IL-18)
timeFrame: Day -1, Day 14
measure: Change in tumor necrosis factor beta (TNF-β)
timeFrame: Day -1, Day 14
measure: Change in interferon alpha (INF-α)
timeFrame: Day -1, Day 14
measure: Change in Functional Outcomes of Sleep Questionnaire (FOSQ) Score
timeFrame: Day -1, Day 14
measure: Change in Hypersomnia Severity Index (HSI)
timeFrame: Day -1, Day 14
measure: Change in MRI Functional Connectivity
timeFrame: Day -2, Day 13
measure: Change in MRI Activation Patterns
timeFrame: Day -2, Day 13
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Sleep Center
state: Georgia
Study officials:
affiliation: Emory University
name: Lynn Marie Trotti, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References: