Hypersomnia, Idiopathic Hypersomnia, Narcolepsy Without Cataplexy, Primary Hypersomnia
Conditions
Keywords
Hypersomnia, Primary Hypersomnia, Idiopathic Hypersomnia, Narcolepsy without Cataplexy, Flumazenil
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.
Interventions
DRUGFlumazenil
Sublingual flumazenil
Sponsors
Georgia Research Alliance
Lynn Marie Trotti
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Psychomotor Vigilance Task (PVT) Median Reaction Time | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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
| Measure | Time frame | Description |
|---|---|---|
| PVT Additional Measure #2, Change in Duration of Lapse Domain | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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 | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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 | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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 #1, Change in Lapse Frequency | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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). |
| Change in Stanford Sleepiness Scale | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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). |
| Electroencephalogram (EEG) Power | following drug administration | EEG signals reflect the state of excitability of the cerebral cortex and correlate highly with levels of behavioral arousal. This is quantifiable as 'power' of the signal (microvolts squared/signal frequency). The EEG signals will be acquired and stored for off-line power analysis and comparison between treatment conditions. |
| PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT | 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject) | 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). |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Sleep Center of the Emory Clinic, in Atlanta, Georgia, USA, between December 2010 and October 2011.
Pre-assignment details
12 patients were enrolled; of these, 2 were excluded prior to randomization because screening laboratory test results were abnormal.
Participants by arm
| Arm | Count |
|---|---|
| Placebo First, Then Flumazenil Placebo during the first intervention day and sublingual flumazenil during the second intervention day (after washout period). | 5 |
| Flumazenil First, Then Placebo Sublingual flumazenil during the first intervention day and placebo during the second intervention day (after washout period). | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Flumazenil First, Then Placebo | Placebo First, Then Flumazenil | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Continuous | 41.8 years STANDARD_DEVIATION 18.1 | 33.6 years STANDARD_DEVIATION 13.3 | 37.7 years STANDARD_DEVIATION 15.6 |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 9 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Change in Psychomotor Vigilance Task (PVT) Median Reaction Time
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.
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Psychomotor Vigilance Task (PVT) Median Reaction Time | -9.86 msec | Standard Deviation 28.2 |
| Sublingual Flumazenil | Change in Psychomotor Vigilance Task (PVT) Median Reaction Time | -4.46 msec | Standard Deviation 63.7 |
p-value: 0.77wilcoxon signed rank (paired)
Secondary
Change in Stanford Sleepiness Scale
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).
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Stanford Sleepiness Scale | 0.84 units on a scale | Standard Deviation 1.68 |
| Sublingual Flumazenil | Change in Stanford Sleepiness Scale | 0.26 units on a scale | Standard Deviation 1.36 |
p-value: 0.13Wilcoxon Signed Rank (paired)
Secondary
Electroencephalogram (EEG) Power
EEG signals reflect the state of excitability of the cerebral cortex and correlate highly with levels of behavioral arousal. This is quantifiable as 'power' of the signal (microvolts squared/signal frequency). The EEG signals will be acquired and stored for off-line power analysis and comparison between treatment conditions.
Time frame: following drug administration
Population: EEG signal processing analyses have not been performed. This would require an additional set of extensive analyses, very distinct from the statistics performed for the other study outcomes. EEG data were collected for possible future analyses, pending resources and expertise, and as such we have no data to report here.
Secondary
PVT Additional Measure #1, Change in Lapse Frequency
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).
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PVT Additional Measure #1, Change in Lapse Frequency | -3.3 number of lapses during PVT testing | Standard Deviation 6.9 |
| Sublingual Flumazenil | PVT Additional Measure #1, Change in Lapse Frequency | -2.6 number of lapses during PVT testing | Standard Deviation 8.7 |
p-value: 0.51Wilcoxon Signed Rank (paired)
Secondary
PVT Additional Measure #2, Change in Duration of Lapse Domain
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).
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PVT Additional Measure #2, Change in Duration of Lapse Domain | 0.18 1/msec | Standard Deviation 0.3 |
| Sublingual Flumazenil | PVT Additional Measure #2, Change in Duration of Lapse Domain | 0.25 1/msec | Standard Deviation 0.45 |
p-value: 0.32Wilcoxon Signed Rank (paired)
Secondary
PVT Additional Measure #3, Change in Optimum Response Times
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).
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PVT Additional Measure #3, Change in Optimum Response Times | -0.02 1/msec | Standard Deviation 0.27 |
| Sublingual Flumazenil | PVT Additional Measure #3, Change in Optimum Response Times | -0.04 1/msec | Standard Deviation 0.63 |
p-value: 0.56Wilcoxon Signed Rank (paired)
Secondary
PVT Additional Measure #4, Change in False Response Frequency
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).
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PVT Additional Measure #4, Change in False Response Frequency | 0.09 number of false starts | Standard Deviation 0.56 |
| Sublingual Flumazenil | PVT Additional Measure #4, Change in False Response Frequency | -0.38 number of false starts | Standard Deviation 0.45 |
p-value: 0.14Wilcoxon Signed Rank (paired)
Secondary
PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT
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).
Time frame: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Population: Intention to treat (all randomized subjects were included)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT | 1.23 units on a scale | Standard Deviation 1.49 |
| Sublingual Flumazenil | PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT | 1.01 units on a scale | Standard Deviation 2 |
p-value: 0.89Wilcoxon Signed Rank (paired)