Clinical trial NCT01183312: Flumazenil for the Treatment of Primary Hypersomnia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hypersomnia
Primary Hypersomnia
Idiopathic Hypersomnia
Narcolepsy Without Cataplexy
Keywords: Hypersomnia
Primary Hypersomnia
Idiopathic Hypersomnia
Narcolepsy without Cataplexy
Flumazenil
Lead sponsor: Emory University
Sponsor class: OTHER
Collaborators: name: Georgia Research Alliance
First posted: 2010-08-17
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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, 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.


Eligibility 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

Primary outcomes:
measure: Change in Psychomotor Vigilance Task (PVT) Median Reaction Time
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Secondary outcomes:
measure: PVT Additional Measure #1, Change in Lapse Frequency
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
measure: PVT Additional Measure #2, Change in Duration of Lapse Domain
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
measure: PVT Additional Measure #3, Change in Optimum Response Times
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
measure: PVT Additional Measure #4, Change in False Response Frequency
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
measure: PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
measure: Change in Stanford Sleepiness Scale
timeFrame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
measure: Electroencephalogram (EEG) Power
timeFrame: following drug administration
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Sleep Center
state: Georgia
Study officials:
affiliation: Emory University
name: Lynn Marie Trotti, MD
role: PRINCIPAL_INVESTIGATOR
References: