Flumazenil for the Treatment of Primary Hypersomnia
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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 |
- Psychomotor Vigilance Task (PVT) Reaction Time [ Time Frame: after drug administration ] [ Designated as safety issue: No ]Median reaction time on the PVT will be collected at baseline and after drug administration.
- Psychomotor Vigilance Task other measures [ Time Frame: after drug administration ] [ Designated as safety issue: No ]Other measures from the PVT, including: frequency of lapses; 2) duration of lapse domain; 3) optimum response times; 4) false response frequency; 5) the visual analog rating made by the subject at the end of the PVT trial
- EEG Power [ Time Frame: after drug administration ] [ Designated as safety issue: No ]
- Stanford Sleepiness Scale [ Time Frame: after each 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
|
Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Hypersomnia (meeting clinical criteria for idiopathic hypersomnia with or without long sleep time, narcolepsy lacking cataplexy, or symptomatic hypersomnia not meeting 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 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 CSF hypocretin
- metabolic disorders such as severe anemia, adrenal insufficiency, severe iron deficiency, vitamin B12 deficiency, or hypothyroidism that may explain symptoms of hypersomnia
United States, Georgia | |
Emory Sleep Center | |
Atlanta, Georgia, United States, 30329 |
Principal Investigator: | Lynn Marie Trotti, MD | Emory University |
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: | Emory44836 |
Study First Received: | August 9, 2010 |
Last Updated: | March 16, 2012 |
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 October 17, 2012