Clarithromycin for the Treatment of Hypersomnia

• PVT reaction time at week 1 [ Time Frame: week 1 compared to baseline ] [ Designated as safety issue: No ]
  Difference in reaction time at week 1 of each intervention compared to baseline
• PVT number of lapses [ Time Frame: baseline, week 1, week 2 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  changes relative to baseline
• PSQI [ Time Frame: baseline, 1 week, 2 weeks ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: Yes ]

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.

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 modafanil 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 vigiliance 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.

• Hypersomnia
• Idiopathic Hypersomnia
• Narcolepsy

• Drug: Clarithromycin followed by placebo
  Clarithromycin 500 mg po bid for two weeks, then one week with no medication, then matched placebo po bid for two weeks.
  Other Name: Biaxin
• Drug: Placebo then Clarithromycin
  Matched placebo po bid for two weeks, then one week with no intervention, then clarithromycin 500 mg po bid for two weeks
  Other Name: Biaxin

• Experimental: Random Group A
  Subjects will be randomized to group A or group B. The order of presentation of placebo and clarithromycin will be opposite in these two groups, but investigators and subjects will remain blinded to group allocation and order of treatment presentation within the groups.
  Intervention: Drug: Clarithromycin followed by placebo
• Experimental: Random Group B
  Subjects will be randomized to group A or group B. The order of presentation of placebo and clarithromycin will be opposite in these two groups, but investigators and subjects will remain blinded to group allocation and order of treatment presentation within the groups.
  Intervention: Drug: Placebo then Clarithromycin

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