Idiopathic Hypersomnia, Narcolepsy With Cataplexy, Narcolepsy Without Cataplexy
Conditions
Keywords
Neurology
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.
Interventions
DRUGClarithromycin
Clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days.
DRUGPlacebo
A placebo to match clarithromycin will be dosed as 500 mg twice daily, once upon awakening and once with lunch, for 14 days.
Sponsors
Emory University
National Institute of Neurological Disorders and Stroke (NINDS)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Epworth Sleepiness Scale (ESS) Score | Day -1, 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. The change in ESS score is obtained by subtracting the total score at Day 14 from the baseline score. Scores above 0 mean that the mean score at Day 14 was lower than the mean score at Baseline, indicating less sleepiness. |
| Change in Maintenance of Wakefulness Test (MWT) for Sleep Latency | Day -1, Day 14 | The MWT polysomnographic procedure for sleep latency examines 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. The change from baseline is calculated as baseline sleep latency minus sleep latency at Day 14, in minutes. Positive values result when the duration of sleep latency at Day 14 is lower than at Baseline. |
| Change in Gamma-aminobutyric Acid Receptor A (GABA-A) Potentiation | Day -1, Day 14 | Cerebrospinal fluid (CSF) is 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 yields a measure of potentiation for each CSF sample in each condition. The change from baseline is calculated as the baseline value minus the value at Day 14. |
| Change in Default Mode Network (DMN) Connectivity | Day -2, Day 13 | The default mode network (DMN) consists of a group of highly correlated brain regions most active during quiet rest, while the task positive network (TPN) is the brain network activated for goal-directed tasks. DMN connectivity changes with sleep states and it is increasingly implicated in the symptomatology of sleepiness. During resting state, sleep deprived participants demonstrate reduced static connectivity with the DMN. Changes in DMN between the Baseline 1 (Day - 2) and Day 13 visits are compared between treatment groups, particularly using quasi-periodic patterns (QPPs), which interrogate network-level connectivity on a dynamic scale. Preservation of the temporal dimension provides more insight into how this spatiotemporal network propagates across condition and pathology. The DMN/TPN QPP correlation is reported. |
| Change in Tumor Necrosis Factor - Alpha (TNF-α) | Day -1, Day 14 | Blood samples are used 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 | Day -1, Day 14 | Changes in microbiome composition, as measured by alpha diversity using the Shannon Index, via 16S ribosomal ribonucleic acid (rRNA) sequencing results are compared between study arms. The Shannon Index measures both abundance and evenness of microbial species, values of 0 indicate that a community has only one species. The higher the value the higher the diversity of species in a particular community. Change from baseline is calculated by subtracting the Day 14 value from the value at Baseline. Numbers greater than 0 indicate that the Day 14 Shannon index value is lower than at Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| On-Treatment Sleep Duration | Day 1 through Day 14 | Participants log when they go to bed and when they wake up in order to calculate the number of minutes spent sleeping. The average duration of sleep across 14 days is compared between study arms. |
| Change in Fatigue Severity Scale (FSS) Score | Day -1, Day 14 | Fatigue severity is 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. The change in FSS score is obtained by subtracting the total score at Day 14 from the Baseline score. Scores above 0 signify that the mean score at Day 14 was lower than the mean score at Baseline, indicating decreased fatigue. |
| Change in Multidimensional Fatigue Inventory (MFI-20) Score | Day -1, 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 to 100 where higher scores indicate greater severity of fatigue. The change in MFI-20 score is obtained by subtracting the total score at Day 14 from the Baseline score. Scores above 0 signify that the mean score at Day 14 was lower than the mean score at Baseline, indicating decreased fatigue. |
| Change in Sleep Inertia Questionnaire (SIQ) Score | Day -1, 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. The change in SIQ score is obtained by subtracting the total score at Day 14 from the baseline score. Scores above 0 signify that the mean score at Day 14 was lower than the mean score at Baseline, indicating reduced difficulty awakening. |
| On-Treatment Sleep Inertia Likert Scale | Day 1 through Day 14 | Sleep inertia is 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, where 1 = "not difficult at all" and 10 = "very difficult". The average scores across 14 days are compared between study arms. |
| Change in Interleukin 1 Alpha (IL-1α) | Day -1, Day 14 | Blood samples are used 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. The change in IL-1α is obtained by subtracting the IL-1α level at Day 14 from the Baseline level. |
| Change in Interleukin 1 Beta (IL-1β) | Day -1, Day 14 | Blood samples are used 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. The change in IL-1β is obtained by subtracting the IL-1β level at Day 14 from the Baseline level. |
| Change in Interleukin 2 (IL-2) | Day -1, Day 14 | Blood samples are used 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. The change in IL-2 is obtained by subtracting the IL-2 level at Day 14 from the Baseline level. |
| Change in Interleukin 6 (IL-6) | Day -1, Day 14 | Blood samples are used 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. The change in IL-6 is obtained by subtracting the IL-6 level at Day 14 from the Baseline level. |
| Change in Interleukin (IL-8) | Day -1, Day 14 | Blood samples are used 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. The change in IL-8 is obtained by subtracting the IL-8 level at Day 14 from the Baseline level. |
| Change in Interleukin (IL-15) | Day -1, Day 14 | Blood samples are used 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. The change in IL-15 is obtained by subtracting the IL-15 level at Day 14 from the Baseline level. |
| Change in Interleukin (IL-18) | Day -1, Day 14 | Blood samples are used 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. The change in IL-18 is obtained by subtracting the IL-18 level at Day 14 from the Baseline level. |
| Change in Tumor Necrosis Factor Beta (TNF-β) | Day -1, Day 14 | Blood samples are used 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. The change in TNF-β is obtained by subtracting the TNF-β level at Day 14 from the Baseline level. |
| Change in Interferon Alpha (INF-α2a) | Day -1, Day 14 | Blood samples are used to determine the change in levels of INF-α2a between the study arms. INF-α2a is a soporific cytokine and a reduction in soporific cytokines is hypothesized to reduce daytime sleepiness. The change in INF-α2a is obtained by subtracting the INF-α2a level at Day 14 from the Baseline level. |
| Change in Functional Outcomes of Sleep Questionnaire (FOSQ) Score | Day -1, Day 14 | 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 less difficulty from sleepiness. The change in FOSQ score is obtained by subtracting the total score at Day 14 from the Baseline score. Scores below 0 signify that the mean score at Day 14 was higher than the mean score at Baseline, indicating reduced difficulty from sleepiness. |
| Change in Hypersomnia Severity Index (HSI) | Day -1, Day 14 | 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. The change from baseline is calculated as the baseline score minus the score at Day 14. The change in HSI score is obtained by subtracting the total score at Day 14 from the baseline score. Scores above 0 signify that the mean score at Day 14 was lower than the mean score at Baseline, indicating reduced severity of hypersomnia symptoms. |
| Change in MRI Functional Connectivity | Day -2, Day 13 | For functional connectivity analyses, each functional scan is parceled into the 246 regions of interest (ROIs), spanning Yeo's 7 networks contained in the Brainnetome Atlas and mean timecourse is calculated for each group. Pearson correlations between each pair of ROIs are calculated, to determine the strength of functional connectivity between each pair of regions and inter/intra-network. This yields a functional connectivity matrix for each functional scan (at both a subject- and group-level). These correlation matrices are Fischer z-transformed and averaged across each condition to create a mean functional connectivity matrix for each condition. Here, the average default mode network (DMN) connectivity is reported. Z-scores have a mean of 0 and scores higher than 0 indicate increased functional connectivity. The change from Baseline is calculated by subtracting the Day 13 score from the score at Day -2. Values lower than 0 mean that the Day 13 score was higher than at baseline. |
| Change in MRI Task Performance - N-Back Accuracy | Day -2, Day 13 | Participants complete a working memory task during functional magnetic resonance imaging (fMRI). The change in task performance is measured as accuracy during 3 different levels of back tasks (0-back, 1-back, and 2-back), from baseline to on-treatment (Day 13). The 0-back test has participants respond to a prespecified stimulus and is a control condition. The 1-back involves remembering and responding to a prior stimulus, while a stimulus two trials earlier is responded to with the 2-back. The change in the percentage of correct responses is obtained by subtracting the percentage at Day 14 from the Baseline percentage. Values below 0 signify that the mean percent accuracy at Day 14 was higher than the mean percent accuracy at Baseline, indicating increased accuracy. |
| Change in MRI Task Performance - N-Back Reaction Time | Day -2, Day 13 | Participants complete a working memory task during functional magnetic resonance imaging (fMRI). he change in task performance is measured as reaction time during 3 different levels of back tasks (0-back, 1-back, and 2-back), from baseline to on-treatment (Day 13). The 0-back test has participants respond to a prespecified stimulus and is a control condition. The 1-back involves remembering and responding to a prior stimulus, while a stimulus two trials earlier is responded to with the 2-back. The change in the reaction time of responses is obtained by subtracting the time at Day 14 from the Baseline time. Scores above 0 signify that the mean time at Day 14 was lower than the mean time at Baseline, indicating faster reaction time. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORLynn Marie Trotti, MD, MSc
Emory University
Participant flow
Recruitment details
Participants were recruited from the Emory Sleep Center in Atlanta, Georgia in the United States. Participant enrollment began September 4, 2019 and all follow-up assessments were completed by June 18, 2025.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 32.6 years STANDARD_DEVIATION 9.7 |
| Epworth Sleepiness Scale Score | 14.9 score on a scale STANDARD_DEVIATION 4.1 |
| Maintenance of Wakefulness Test (MWT) Mean Latency | 18.6 minutes STANDARD_DEVIATION 12.8 |
| Race and Ethnicity Not Collected | 0 Participants |
| Region of Enrollment United States | 83 Participants |
| Sex/Gender, Customized Female | 67 Participants |
| Sex/Gender, Customized Male | 8 Participants |
| Sex/Gender, Customized Non-binary | 1 Participants |
| Type of Hypersomnia Idiopathic Hypersomnia | 38 Participants |
| Type of Hypersomnia Narcolepsy Type 1 | 3 Participants |
| Type of Hypersomnia Narcolepsy Type 2 | 10 Participants |
| Type of Hypersomnia Subjective Sleepiness | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 40 | 0 / 43 |
| other Total, other adverse events | 24 / 40 | 25 / 43 |
| serious Total, serious adverse events | 0 / 40 | 0 / 43 |
Outcome results
None listed