HypersomniaPhase 1/2NCT01183312
Flumazenil for the Treatment of Primary Hypersomnia
A Phase 1/2 study testing Flumazenil in people with Hypersomnia and Primary Hypersomnia, run by Lynn Marie Trotti at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hypersomnia, Primary Hypersomnia, Idiopathic Hypersomnia
- What is being tested?
- Flumazenil
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2010to Jan 2012
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read more
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.
- Being tested
- Flumazenil
- Keywords
- Hypersomnia, Primary Hypersomnia, Idiopathic Hypersomnia, Narcolepsy without Cataplexy, Flumazenil
- Medical subject headings
- Disorders of Excessive Somnolence, Idiopathic Hypersomnia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
FlumazenilDrug
Sublingual flumazenil
| Study group | Role | What they receive |
|---|---|---|
| Placebo, then Flumazenil | Experimental | Subjects in this arm will first receive a day of placebo, then a day of sublingual flumazenil Receives: Drug: Flumazenil |
| Flumazenil, then Placebo | Experimental | Subjects in this group will first receive a day of sublingual flumazenil, then a day of placebo. Receives: Drug: Flumazenil |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
Secondary outcomes (7)
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).
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
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).
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
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).
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
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).
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
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).
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
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).
Measured: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
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.
Measured: following drug administration
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Aug 2010 (estimated)
- Study startSep 2010
- Primary completionJan 2012
- Study completionJan 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for HypersomniaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Lynn Marie Trotti
- Sponsor type
- University, hospital or other
- Collaborators
- Georgia Research Alliance
- Responsible party
- Sponsor-investigator, Lynn Marie Trotti, Emory University
- Investigators
- Lynn Marie Trotti, MD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01183312
- Sponsor's protocol ID
- IRB00044836
- Status last verified
- Nov 2017
- First submitted
- 9 Aug 2010
- Last updated
- 12 Dec 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01183312
- Acronym / sponsor ID
- IRB00044836
- Keywords
- Hypersomnia, Primary Hypersomnia, Idiopathic Hypersomnia, Narcolepsy without Cataplexy, Flumazenil
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Lynn Marie TrottiUniversity, hospital or other
- Collaborators
- Georgia Research Alliance
- Study start
- Sep 2010
- Primary completion
- Jan 2012 (actual)
- Study completion
- Jan 2012 (actual)
- First posted
- 17 Aug 2010 (estimated)
- Results
- Posted 27 Mar 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo, then Flumazenil | Experimental | Drug: FlumazenilSubjects in this arm will first receive a day of placebo, then a day of sublingual flumazenil |
| Flumazenil, then Placebo | Experimental | Drug: FlumazenilSubjects in this group will first receive a day of sublingual flumazenil, then a day of placebo. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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).
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| FlumazenilSublingual flumazenil | Drug | Flumazenil, then Placebo, Placebo, then Flumazenil |
Primary outcome
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)
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.
7 secondary outcomes
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)
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)
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)
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)
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)
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)
Electroencephalogram (EEG) Power
Time frame: following drug administration
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Dec 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lynn Marie Trotti, MD principal investigator
Emory University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Flumazenil in people with Hypersomnia and Primary Hypersomnia, run by Lynn Marie Trotti at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Dec 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Mar 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2017.