Trial record 1 of 65 for:    Hypersomnia
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Flumazenil for the Treatment of Primary Hypersomnia

This study has been completed.
Sponsor:
Collaborator:
Georgia Research Alliance
Information provided by (Responsible Party):
Lynn Marie Trotti, Emory University
ClinicalTrials.gov Identifier:
NCT01183312
First received: August 9, 2010
Last updated: November 13, 2013
Last verified: November 2013
  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, or primary hypersomnias.

The causes of most of these primary 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 flumazenil (an medication approved by the FDA for the treatment of overdose of GABA medications or the reversal of GABA-based anesthesia) would reverse the GABA abnormality in our patients. In a test tube model of this disease, flumazenil does in fact return the function of the GABA system to normal. The investigators have treated a few patients with flumazenil and most have felt that their hypersomnia symptoms improved with this treatment.

To determine whether flumazenil is truly beneficial for primary hypersomnia, this study will compare flumazenil to an inactive pill (the placebo). All subjects will receive both flumazenil 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. Currently, flumazenil can only be given through an injection into a vein (i.e., intravenously). This study will evaluate this intravenous dosing as well as a new form of flumazenil, which is taken as a lozenge to be dissolved under the tongue. If this study shows that flumazenil 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
Primary Hypersomnia
Idiopathic Hypersomnia
Narcolepsy Without Cataplexy
Drug: Flumazenil
Phase 1
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: A Ten Subject, Double-Blind, Placebo-Controlled Trial of Single Day Dosing of Sublingual Flumazenil in Individuals With Primary Hypersomnia or Excessively Long Total Sleep Time and Excess Endogenous Potentiation of GABA-A Receptors

Resource links provided by NLM:


Further study details as provided by Emory University:

Primary Outcome Measures:
  • Change in Psychomotor Vigilance Task (PVT) Median Reaction Time [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    The PVT measures the reaction time to button press following the presentation of a visual stimulus, reported here as the median reaction time for multiple presentations during the 10 minute task. The measure used was the change in median reaction time from baseline to drug administration, where the median reaction time at each of the time points (below) was averaged to provide a single on-treatment value for median reaction time. The measure was then calculated as baseline value - treatment value, such that higher numbers denote improvement from baseline.


Secondary Outcome Measures:
  • PVT Additional Measure #1, Change in Lapse Frequency [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    A PVT lapse is defined as a reaction time exceeding 500 msec following the presentation of a single stimulus, which are then summed for the entire 10 minute PVT testing period. The measure used was the change in the frequency of lapses from baseline to drug administration (calculated as baseline value - average value with study drug, where higher numbers denote improvement from baseline).

  • PVT Additional Measure #2, Change in Duration of Lapse Domain [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    The PVT duration of lapse domain is defined as the reciprocal of the reaction time averaged across the slowest 10% of responses. The measure used was the change in duration of lapse domain from baseline to drug administration (calculated as baseline value - average value with study drug, where lower numbers denote improvement from baseline).

  • PVT Additional Measure #3, Change in Optimum Response Times [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    The optimum response times is defined as the reciprocal of the reaction time averaged across the fastest 10% of responses. The measure used was the change in optimum response time from baseline to following drug administration (calculated as baseline value - average value with study drug, where lower numbers denote improvement from baseline).

  • PVT Additional Measure #4, Change in False Response Frequency [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    The false response frequency is defined as the number of button presses when no stimulus is presented. The measure used was the change in false response frequency from baseline to drug administration (calculated as baseline value - average value with study drug, where higher numbers denote improvement from baseline).

  • PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    At the end of the 10 minute PVT testing period, subjects were asked to rate their current level of sleepiness along a line, which was transformed into a numeric value from 1-10, such that high levels indicated more severe subjective sleepiness. The measure used was the change in this rating from baseline to drug administration (calculated as baseline value - average value with study drug, where higher numbers denote improvement from baseline).

  • Change in Stanford Sleepiness Scale [ Time Frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) ] [ Designated as safety issue: No ]
    The Stanford Sleepiness Scale (SSS) is a subjective rating of sleepiness, with score ranging from 1 to 7, where higher values reflect more severe sleepiness. The measure used was change in SSS from baseline to drug administration (calculated as baseline value - average value with study drug, where higher numbers denote improvement from baseline).

  • EEG Power [ Time Frame: following drug administration ] [ Designated as safety issue: No ]

Enrollment: 10
Study Start Date: September 2010
Study Completion Date: January 2012
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Placebo, then Flumazenil
Subjects in this arm will first receive a day of placebo, then a day of sublingual flumazenil
Drug: Flumazenil
Sublingual flumazenil
Experimental: Flumazenil, then Placebo
Subjects in this group will first receive a day of sublingual flumazenil, then a day of placebo.
Drug: Flumazenil
Sublingual flumazenil

  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 International Classification of Sleep Disorders 2 (ICSD-2) criteria inclusive of habitually long sleep periods of > 10 hours/day)
  • evidence for GABA-related abnormality, as demonstrated by our in-house, in vitro assay
  • age > 18
  • high performance liquid chromatography/liquid chromatography tandem mass spectrometry verification of the absence of exogenous benzodiazepines (BZDs).

Exclusion Criteria:

  • Contraindications to use of flumazenil (pregnancy, hepatic impairment, seizure history, pre-menstrual dysphoric disorder, traumatic brain injury, cardiac disease (left ventricular diastolic dysfunction), or cardiac dysrrhythmia.
  • Current use of a BZD or BZD-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 ICSD-2 criteria and confirmed by absence of cerebrospinal fluid (CSF) hypocretin
  • metabolic disorders such as severe anemia, adrenal insufficiency, severe iron deficiency, vitamin B12 deficiency, or hypothyroidism that may explain symptoms of hypersomnia
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01183312

Locations
United States, Georgia
Emory Sleep Center
Atlanta, Georgia, United States, 30329
Sponsors and Collaborators
Lynn Marie Trotti
Georgia Research Alliance
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: NCT01183312     History of Changes
Other Study ID Numbers: IRB00044836
Study First Received: August 9, 2010
Results First Received: January 11, 2013
Last Updated: November 13, 2013
Health Authority: United States: Institutional Review Board
United States: Food and Drug Administration

Keywords provided by Emory University:
Hypersomnia
Primary Hypersomnia
Idiopathic Hypersomnia
Narcolepsy without Cataplexy
Flumazenil

Additional relevant MeSH terms:
Cataplexy
Narcolepsy
Disorders of Excessive Somnolence
Hypersomnolence, Idiopathic
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Disorders
Nervous System Diseases
Mental Disorders
Flumazenil
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Antidotes
Protective Agents

ClinicalTrials.gov processed this record on April 17, 2014