Clarithromycin Mechanisms in Hypersomnia Syndromes
Ključne besede
Povzetek
Opis
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.
Datumi
| Nazadnje preverjeno: | 04/30/2020 |
| Prvič predloženo: | 07/16/2019 |
| Predviden vpis oddan: | 07/17/2019 |
| Prvič objavljeno: | 07/18/2019 |
| Zadnja posodobitev oddana: | 05/11/2020 |
| Zadnja posodobitev objavljena: | 05/13/2020 |
| Dejanski datum začetka študija: | 09/03/2019 |
| Predvideni datum primarnega zaključka: | 06/30/2024 |
| Predvideni datum zaključka študije: | 06/30/2024 |
Stanje ali bolezen
Intervencija / zdravljenje
Drug: Clarithromycin
Drug: Placebo
Faza
Skupine rok
| Roka | Intervencija / zdravljenje |
|---|---|
| Experimental: Clarithromycin Participants in this study arm will receive clarithromycin for 14 days. | Drug: Clarithromycin Clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days. |
| Placebo Comparator: Placebo Participants in this study arm will receive a placebo to match clarithromycin for 14 days. | 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. |
Merila upravičenosti
| Starost, primerna za študij | 18 Years Za 18 Years |
| Spol, upravičen do študija | All |
| Sprejema zdrave prostovoljce | Da |
| Merila | 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 |
Izid
Primarni izidni ukrepi
1. Change in Epworth Sleepiness Scale Score [Day 2, Day 14]
2. Change in Maintenance of Wakefulness Test (MWT) [Day 2, Day 14]
3. Change in gamma-aminobutyric acid receptor A (GABA-A) potentiation [Day 2, Day 14]
4. Change in Default Mode Network (DMN) Connectivity [Day 1, Day 13]
5. Change in tumor necrosis factor - alpha (TNF-α) [Day 2, Day 14]
6. Change in gastrointestinal microbiome composition [Day 2, Day 14]
Ukrepi sekundarnega rezultata
1. Change in Sleep Duration [Day 2, Day 14]
2. Change in Fatigue Severity Scale (FSS) Score [Day 2, Day 14]
3. Change in Multidimensional Fatigue Inventory (MFI-20) Score [Day 2, Day 14]
4. Change in Sleep Inertia Questionnaire (SIQ) Score [Day 2, Day 14]
5. Change in Sleep Inertia Scale [Day 2, Day 14]
6. Change in Idiopathic Hypersomnia Severity Scale (IHSS) Score [Day 2, Day 14]
7. Change in Interleukin 1 alpha (IL-1α) [Day 2, Day 14]
8. Change in Interleukin 1 beta (IL-1β) [Day 2, Day 14]
9. Change in Interleukin 2 (IL-2) [Day 2, Day 14]
10. Change in Interleukin 6 (IL-6) [Day 2, Day 14]
11. Change in Interleukin (IL-8) [Day 2, Day 14]
12. Change in Interleukin (IL-15) [Day 2, Day 14]
13. Change in Interleukin (IL-18) [Day 2, Day 14]
14. Change in tumor necrosis factor beta (TNF-β) [Day 2, Day 14]
15. Change in interferon alpha (INF-α) [Day 2, Day 14]
