Clinical Trial: Clarithromycin for the Treatment of Hypersomnia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Clarithromycin for the Treatment of Hypersomnia

Brief Summary:

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 norm

Detailed Summary:

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 clarithro
Sponsor: Lynn Marie Trotti

Current Primary Outcome: 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)



Original Primary Outcome: Psychomotor Vigilance Task (PVT) Reaction Time [ Time Frame: change from baseline to week 2 of each intervention ]

Median reaction time on the PVT will be collected at baseline and 1 and 2 weeks on each intervention. The difference at each timepoint from baseline will be calculated, with the difference at week 2 the primary outcome


Current Secondary Outcome:

  • 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)

  • 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.
  • 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.

  • 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.

  • 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.

  • 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.

  • Reported Adverse Events [ Time Frame: baseline, week 1, week 2 ]


Original Secondary Outcome:

  • PVT reaction time at week 1 [ Time Frame: week 1 compared to baseline ]
    Difference in reaction time at week 1 of each intervention compared to baseline
  • PVT Number of Lapses [ Time Frame: baseline, week 1, week 2 ]
    Number of lapses (no response for > 500 msec) will be computed for each PVT trial and difference from baseline calculated for each timepoint
  • ESS [ Time Frame: baseline, week 1, week 2 ]
    Changes in scores on the Epworth Sleepiness Scale (ESS) will be calculated at each time point relative to baseline
  • FOSQ [ Time Frame: baseline, 1 week, 2 weeks ]
    Changes in scores on the Functional Outcomes of Sleep Questionnaire (FOSQ) will be calculated at each time point relative to baseline
  • SF-36 [ Time Frame: baseline, week 1, week 2 ]
    changes relative to baseline
  • PSQI [ Time Frame: baseline, 1 week, 2 weeks ]
    changes in the Pittsburgh Sleep Quality Index (PSQI) at all time points compared to baseline
  • Reported Adverse Events [ Time Frame: baseline, week 1, week 2 ]


Information By: Emory University

Dates:
Date Received: June 15, 2010
Date Started: July 2010
Date Completion:
Last Updated: August 25, 2014
Last Verified: August 2014