Flumazenil for the Treatment of Primary Hypersomnia

NCT01183312 | Completed Phase 1 Results

• 1 other identifier: IRB00044836
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Hypersomnia; Primary Hypersomnia; Idiopathic Hypersomnia; Narcolepsy Without Cataplexy

Keywords

Hypersomnia; Primary Hypersomnia; Idiopathic Hypersomnia; Narcolepsy without Cataplexy; Flumazenil

Outcome Measures

Primary Outcomes (1)

• 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.

  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

  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

  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

  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

  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

  10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)

Study Arms (2)

Placebo, then Flumazenil

EXPERIMENTAL

Subjects in this arm will first receive a day of placebo, then a day of sublingual flumazenil

Drug: Flumazenil

Flumazenil, then Placebo

EXPERIMENTAL

Subjects in this group will first receive a day of sublingual flumazenil, then a day of placebo.

Drug: Flumazenil

Interventions

Flumazenil DRUG

Sublingual flumazenil

Flumazenil, then Placebo; Placebo, then Flumazenil

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Lynn Marie Trotti: lead
• Georgia Research Alliance: collaborator

Study Sites (1)

Emory Sleep Center

Atlanta, Georgia, 30329, United States

Location

MeSH Terms

Conditions

Disorders of Excessive Somnolence; Idiopathic Hypersomnia

Interventions

Flumazenil

Condition Hierarchy (Ancestors)

Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzodiazepinones; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

EEG power was specified as a secondary outcome measure. Second-by-second manual artifact removal has been necessary to ensure interpretable data. This artifact removal is in progress and results will be reported separately.

Results Point of Contact

• Title: Dr. Lynn Marie Trotti
• Organization: Emory University School of Medicine

lbecke2@emory.edu

404-728-4752

Study Officials

• Lynn Marie Trotti, MD

  Emory University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Neurology

Study Record Dates

• First Submitted: August 9, 2010
• First Posted: August 17, 2010
• Study Start: September 1, 2010
• Primary Completion: January 1, 2012
• Study Completion: January 1, 2012
• Last Updated: December 12, 2017
• Results First Posted: March 27, 2013

Record last verified: 2017-11

Locations

US (1)