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Completed

NCT Number: NCT01146600

Clarithromycin for the Treatment of Hypersomnia

The term 'hypersomnia' describes a group of symptoms that includes severe daytime sleepiness and sleeping long periods of time (more than 10 hours per night). Sometimes, hypersomnia is caused by a problem with the quality of sleep occurring at night, for instance when nighttime sleep is disrupted by frequent breathing pauses. In other cases, however, hypersomnia occurs even when nighttime sleep is of good quality. These cases of hypersomnia are presumed to be a symptom of brain dysfunction, and so are referred to as hypersomnias of central (i.e., brain) origin.

The causes of most of these central hypersomnias are not known. However, our group has recently identified a problem with the major brain chemical responsible for sedation, known as GABA. In a subset of our hypersomnia patients, there is a naturally-occurring substance that causes the GABA receptor to be hyperactive. In essence, it is as though these patients are chronically medicated with Valium (or Xanax or alcohol, all substances that act through the GABA system), even though they do not take these medications.

Current treatment of central hypersomnias is limited. For the fraction of cases with narcolepsy, there are FDA-approved, available treatments. However, for the remainder of patients, there are no treatments approved by the FDA. They are usually treated with medications approved for narcolepsy, but sleep experts agree that these medications are often not effective for this group of patients.

Based on our understanding of the GABA abnormality in these patients, we evaluated whether clarithromycin (an antibiotic approved by the FDA for the treatment of infections) would reverse the GABA abnormality. In a test tube model of this disease, clarithromycin does in fact return the function of the GABA system to normal. The investigators have treated a few patients with clarithromycin and most have felt that their hypersomnia symptoms improved with this treatment.

To determine whether clarithromycin is truly beneficial for central hypersomnia, this study will compare clarithromycin to an inactive pill (the placebo). All subjects will receive both clarithromycin and the placebo at different times, and their reaction times and symptoms will be compared on these two treatments to determine if one is superior. If this study shows that clarithromycin is more effective than placebo in the treatment of hypersomnia, it will identify a potential new therapy for this difficult-to-treat disorder.

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Key information

Conditions

Hypersomnia Disorders of Excessive Somnolence Dyssomnias Idiopathic Hypersomnia Mental Disorders Narcolepsy Nervous System Diseases Sleep Disorders, Intrinsic Sleep Wake Disorders

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Emory Sleep Center

Atlanta, Georgia, 30329, United States

About this study

Central hypersomnias are characterized by severe excessive daytime sleepiness despite long sleep periods (>10 hours/night) and the absence of nocturnal sleep pathology. They preferentially affect young adults, may result in loss of employment, and can lead to motor vehicle accidents (1). Despite these health, safety, and quality of life consequences, there are no FDA-approved therapies for several forms of central hypersomnia, including idiopathic hypersomnia (IH). Currently, IH is treated using therapies approved for narcolepsy, despite a lack of clinical trial data and a consensus that treatment response is poor (2). Treatments include traditional psychostimulants (e.g., amphetamine derivatives) as well as wake-promoting agents with unknown mechanisms of action such as modafinil and sodium oxybate. In addition to side effects including high abuse potential, tachycardia, and altered mental status, treatments are often ineffective and substantial residual sleepiness frequently persists despite poly-therapy.

The investigators hypothesize that pathology in the GABA neurotransmitter system, the brain's major inhibitory system, underlies these central hypersomnias. Currently, there are no hypersomnia therapies that are GABA-antagonists. However, the macrolide antibiotic clarithromycin has been shown to have GABA-modulating properties, resulting in the development of insomnia or mania in a subset of patients. Clarithromycin is therefore a potentially viable, promising therapeutic agent for hypersomnia related to positive modulation of the GABAA receptor. Open-label use of clarithromycin in six hypersomnia patients with known (n = 4) or suspected (n = 2) excess GABAA potentiation resulted in marked improvements in vigilance, as measured on the psychomotor vigilance task (PVT) (unpublished data). The investigators therefore propose a pilot, crossover trial comparing clarithromycin to placebo for the treatment of hypersomnia in patients with excess GABAA potentiation. The primary endpoint will be a decrease in PVT reaction time. Secondary endpoints will include a decrease in PVT lapses and changes in Epworth, Stanford, and FOSQ sleep scales. Successful results from this trial would provide early evidence for a more rational and efficacious treatment for hypersomnia that could avoid the potential abuse, toxicities, and treatment failures associated with traditional treatments.

This will be a pilot crossover trial of clarithromycin and placebo to treat central hypersomnia. Subjects who are untreated for hypersomnia or who experience persistent symptoms despite traditional therapies will be eligible. Subjects who are on medication for hypersomnia at the beginning of the study will be asked to maintain stable doses of these medications for one month before and throughout the study period. Twenty subjects will be assessed at baseline and one and two weeks after being on each study drug (clarithromycin 500 mg bid and matched placebo bid). After two weeks on study drug, they will undergo a one week washout period, then change to the other study drug for an additional two weeks. Patients will be randomized to order of presentation of study drugs such that ten subjects will be randomized to each group. Random sequence generation will be performed our pharmacy. All study investigators and subjects will remain blinded to group assignment.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Hypersomnia (meeting clinical criteria for Idiopathic hypersomnia with or without long sleep time, narcolepsy lacking cataplexy, or symptomatic hypersomnia not meeting ICSD criteria)
  • evidence for GABA-related abnormality, as demonstrated by in-house, in vitro assay
  • age > 18
  • high performance liquid chromatography/liquid chromatography tandem mass spectrometry verification of the absence of exogenous benzodiazepines

Exclusion criteria

  • Contraindications to use of clarithromycin (pregnancy, severe renal impairment, history of QT prolongation, hypomagnesemia, hypokalemia, bradycardia, history of myocardial infarction or cardiomyopathy, myasthenia gravis, age > 70)
  • Current use of cisapride, pimozide, astemizole, terfenadine, colchicines, and ergotamine or dihydroergotamine
  • Current use of benzodiazepines or benzodiazepine-receptor agonists
  • moderate or severe sleep apnea (RDI > 15/hr), severe periodic limb movement disorder (PLMI > 30/hr)
  • diagnosis of narcolepsy with cataplexy, as determined by cerebrospinal hypocretin levels
  • metabolic disorders such as anemia, severe iron deficiency, B12 deficiency, or hypothyroidism that may explain symptoms of hypersomnia

Treatment and study plan

Clarithromycin followed by placebo

Drug

Clarithromycin 500 mg po bid for two weeks, then one week with no medication, then matched placebo po bid for two weeks.

Other names: Biaxin

Placebo then Clarithromycin

Drug

Matched placebo po bid for two weeks, then one week with no intervention, then clarithromycin 500 mg po bid for two weeks

Other names: Biaxin

Primary outcomes

  1. Psychomotor Vigilance Task (PVT) Reaction Time

    Time frame: week 2 of each intervention

    Median reaction time on the PVT at the end of the second week of treatment. Lower values reflect faster reaction times (I.e., greater vigilance).

    Note that the PVT provides a median of reaction times to all stimuli (~100) presented during the 10 minute PVT test. Each subject had two PVT tests at each visit, resulting in two median values. These were averaged, and then, for the purposes of this outcome, we then obtained the MEAN across multiple subjects for each condition (baseline, clarithromycin week 2, placebo week 2)

Secondary outcomes

  1. PVT Median Reaction Time at Week 1

    Time frame: week 1

    median reaction time on the PVT at week 1 of each intervention. Lower values reflect faster reaction times (i.e., better vigilance)

    Note that the PVT provides a median of reaction times to all stimuli (~100) presented during the 10 minute PVT test. Each subject had two PVT tests at each visit, resulting in two median values. These were averaged, and then, for the purposes of this outcome, we then obtained the MEAN across multiple subjects for each condition (baseline, clarithromycin week 1, placebo week 1)

  2. PVT Number of Lapses

    Time frame: baseline, then after 1 week and 2 weeks on each study drug

    Number of lapses (no response for > 500 msec) on the PVT, averaged by subject across all administrations for a given drug condition (i.e. administered twice at baseline, four times on clarithromycin (twice during week 1 and twice during week 2), and four times on placebo (twice during week 1 and twice during week 2)). Higher numbers indicate worse vigilance.

  3. Epworth Sleepiness Scale

    Time frame: baseline, then after 1 week and 2 weeks on each study drug

    Scores on the Epworth Sleepiness Scale (ESS) were averaged by subject across all administrations for a given drug condition (i.e. administered twice on clarithromycin (once during week 1 and once during week 2) and twice on placebo (once during week 1 and once during week 2)).

    ESS scores can range from 0 to 24. Higher scores indicate higher levels of sleepiness.

  4. FOSQ

    Time frame: baseline, then after 1 week and 2 weeks on each study drug

    Scores on the Functional Outcomes of Sleep Questionnaire (FOSQ) were averaged by subject across all administrations for a given drug condition (i.e. administered twice on clarithromycin (once during week 1 and once during week 2) and twice on placebo (once during week 1 and once during week 2)).

    Scores on the FOSQ can range from 5 to 20. Higher FOSQ scores indicate less impairment due to sleepiness.

  5. SF-36, Vitality Subscale

    Time frame: baseline, then after 1 week and 2 weeks on each study drug

    The SF-36 is a health outcome scale with multiple subsections. Subjects were administered the entire SF-36; this analysis is of the vitality subscore provided by this scale. Scores were averaged by subject across all administrations for a given drug condition (i.e. administered once at baseline, twice on clarithromycin (once during week 1 and once during week 2) and twice on placebo (once during week 1 and once during week 2)).

    The vitality subscore is calculated using four questions from the SF-36, and can range from 0 to 100. Higher scores reflect more vitality.

  6. PSQI

    Time frame: baseline, then after 1 week and 2 weeks on each study drug

    Scores on the Pittsburgh Sleep Quality Index (PSQI), a questionnaire based assessment of sleep quality. Scores were averaged by subject across all administrations for a given drug condition (i.e. administered twice on clarithromycin (once during week 1 and once during week 2) and twice on placebo (once during week 1 and once during week 2)).

    Scores on the PSQI can range from 0 to 21. Higher scores indicate poorer sleep quality.

Sponsors and collaborators

Lead sponsor

Lynn Marie Trotti

Other

Registry information

Important dates

Study start
2010
Primary completion
2012
Study completion
2012
First posted
Jun 17, 2010
Registry last updated
Nov 6, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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