Clarithromycin for the Treatment of Hypersomnia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Lynn Marie Trotti, Emory University
ClinicalTrials.gov Identifier:
NCT01146600
First received: June 15, 2010
Last updated: August 25, 2014
Last verified: August 2014
  Purpose

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.


Condition Intervention Phase
Hypersomnia
Idiopathic Hypersomnia
Narcolepsy
Drug: Clarithromycin followed by placebo
Drug: Placebo then Clarithromycin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Clarithromycin for the Treatment of Hypersomnia

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Psychomotor Vigilance Task (PVT) Reaction Time [ Time Frame: week 2 of each intervention ] [ Designated as safety issue: No ]

    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 Outcome Measures:
  • PVT Median Reaction Time at Week 1 [ Time Frame: week 1 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: Yes ]

Enrollment: 26
Study Start Date: July 2010
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
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.
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01146600

Locations
United States, Georgia
Emory Sleep Center
Atlanta, Georgia, United States, 30329
Sponsors and Collaborators
Lynn Marie Trotti
Investigators
Principal Investigator: Lynn Marie Trotti, MD Emory University
  More Information

No publications provided

Responsible Party: Lynn Marie Trotti, Assistant Professor of Neurology, Emory University
ClinicalTrials.gov Identifier: NCT01146600     History of Changes
Other Study ID Numbers: IRB00044170
Study First Received: June 15, 2010
Results First Received: September 28, 2013
Last Updated: August 25, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Emory University:
Primary hypersomnia
CNS hypersomnia
hypersomnia
idiopathic hypersomnia
narcolepsy without cataplexy
clarithromycin
Narcolepsy without Cataplexy

Additional relevant MeSH terms:
Sleep Disorders, Intrinsic
Hypersomnolence, Idiopathic
Narcolepsy
Disorders of Excessive Somnolence
Dyssomnias
Mental Disorders
Nervous System Diseases
Sleep Disorders
Clarithromycin
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Synthesis Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 29, 2014