# Flumazenil for the Treatment of Primary Hypersomnia

This study has been completed.

Sponsor:

Lynn Marie Trotti

Collaborator:

Georgia Research Alliance

Information provided by (Responsible Party):

Lynn Marie Trotti, Emory University

ClinicalTrials.gov Identifier:

NCT01183312

First received: August 9, 2010

Last updated: November 13, 2013

Last verified: November 2013

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Results First Received: January 11, 2013

Study Type: | Interventional |
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Study Design: | Allocation: Randomized; Endpoint Classification: Efficacy Study; Intervention Model: Crossover Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment |

Conditions: |
Hypersomnia Primary Hypersomnia Idiopathic Hypersomnia Narcolepsy Without Cataplexy |

Intervention: |
Drug: Flumazenil |

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations |
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Participants were recruited from the Sleep Center of the Emory Clinic, in Atlanta, GA, USA, between December 2010 and October 2011. |

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment |
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12 patients were enrolled; of these, 2 were excluded prior to randomization because screening laboratory test results were abnormal. |

Reporting Groups

Description | |
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Placebo First, Then Flumazenil | Placebo administered sublingually three times during the first study day, followed by a washout of at least 7 days, then flumazenil administered sublingually three times during the second study day. |

Flumazenil First, Then Placebo | Flumazenil administered sublingually three times during the first study day (as 12 mg, then 6 mg, then 6 mg, at approximately 3 hour intervals), followed by a washout of at least 7 days, then placebo administered sublingually three times on the second study day. |

Participant Flow for 3 periods

Period 1: First Intervention Day

Placebo First, Then Flumazenil | Flumazenil First, Then Placebo | |
---|---|---|

STARTED | 5 | 5 |

COMPLETED | 5 | 5 |

NOT COMPLETED | 0 | 0 |

Period 2: Washout Period of at Least 1 Week

Placebo First, Then Flumazenil | Flumazenil First, Then Placebo | |
---|---|---|

STARTED | 5 | 5 |

COMPLETED | 5 | 5 |

NOT COMPLETED | 0 | 0 |

Period 3: Second Intervention Day

Placebo First, Then Flumazenil | Flumazenil First, Then Placebo | |
---|---|---|

STARTED | 5 | 5 |

COMPLETED | 5 | 5 |

NOT COMPLETED | 0 | 0 |

Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate. |
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No text entered. |

Reporting Groups

Description | |
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Placebo First, Then Flumazenil | Placebo during the first intervention day and sublingual flumazenil during the second intervention day (after washout period). |

Flumazenil First, Then Placebo | Sublingual flumazenil during the first intervention day and placebo during the second intervention day (after washout period). |

Total | Total of all reporting groups |

Baseline Measures

Placebo First, Then Flumazenil | Flumazenil First, Then Placebo | Total | |
---|---|---|---|

Number of Participants
[units: participants] |
5 | 5 | 10 |

Age
[units: participants] |
|||

<=18 years | 0 | 0 | 0 |

Between 18 and 65 years | 5 | 5 | 10 |

>=65 years | 0 | 0 | 0 |

Age
[units: years] Mean (Standard Deviation) |
33.6 (13.3) | 41.8 (18.1) | 37.7 (15.6) |

Gender
[units: participants] |
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Female | 5 | 5 | 10 |

Male | 0 | 0 | 0 |

Region of Enrollment
[units: participants] |
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United States | 5 | 5 | 10 |

Outcome Measures

1. Primary: | 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) ] |

Measure Type | Primary |
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Measure Title | Change in Psychomotor Vigilance Task (PVT) Median Reaction Time |

Measure Description | 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) |

Safety Issue | No |

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate. |
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Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
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Placebo | Sublingual placebo administered three times over a single day, in either first or second intervention period |

Sublingual Flumazenil | Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

Change in Psychomotor Vigilance Task (PVT) Median Reaction Time
[units: msec] Mean (Standard Deviation) |
-9.86 (28.2) | -4.46 (63.7) |

Statistical Analysis 1 for Change in Psychomotor Vigilance Task (PVT) Median Reaction Time

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
wilcoxon signed rank (paired) |

P Value ^{[3]} |
0.77 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance: |

No text entered. |

2. Secondary: | 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) ] |

Measure Type | Secondary |
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Measure Title | PVT Additional Measure #1, Change in Lapse Frequency |

Measure Description | 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) |

Safety Issue | No |

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate. |
---|

Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
---|---|

Placebo | Sublingual placebo administered three times over a single day, in either first or second intervention period |

Sublingual Flumazenil | Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

PVT Additional Measure #1, Change in Lapse Frequency
[units: number of lapses during PVT testing] Mean (Standard Deviation) |
-3.3 (6.9) | -2.6 (8.7) |

Statistical Analysis 1 for PVT Additional Measure #1, Change in Lapse Frequency

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
Wilcoxon Signed Rank (paired) |

P Value ^{[3]} |
0.51 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance: |

No text entered. |

3. Secondary: | 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) ] |

Measure Type | Secondary |
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Measure Title | PVT Additional Measure #2, Change in Duration of Lapse Domain |

Measure Description | 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) |

Safety Issue | No |

Population Description

Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
---|---|

Placebo | Sublingual placebo administered three times over a single day, in either first or second intervention period |

Sublingual Flumazenil | Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

PVT Additional Measure #2, Change in Duration of Lapse Domain
[units: 1/msec] Mean (Standard Deviation) |
0.18 (0.30) | 0.25 (0.45) |

Statistical Analysis 1 for PVT Additional Measure #2, Change in Duration of Lapse Domain

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
Wilcoxon Signed Rank (paired) |

P Value ^{[3]} |
0.32 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance: |

No text entered. |

4. Secondary: | 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) ] |

Measure Type | Secondary |
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Measure Title | PVT Additional Measure #3, Change in Optimum Response Times |

Measure Description | 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 | |

Safety Issue | No |

Population Description

Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
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Placebo | |

Sublingual Flumazenil |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

PVT Additional Measure #3, Change in Optimum Response Times
[units: 1/msec] Mean (Standard Deviation) |
-0.02 (0.27) | -0.04 (0.63) |

Statistical Analysis 1 for PVT Additional Measure #3, Change in Optimum Response Times

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
Wilcoxon Signed Rank (paired) |

P Value ^{[3]} |
0.56 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | |

No text entered. |

5. Secondary: | 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) ] |

Measure Type | Secondary |
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Measure Title | PVT Additional Measure #4, Change in False Response Frequency |

Measure Description | 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 | |

Safety Issue | No |

Population Description

Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
---|---|

Placebo | |

Sublingual Flumazenil |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

PVT Additional Measure #4, Change in False Response Frequency
[units: number of false starts] Mean (Standard Deviation) |
0.09 (0.56) | -0.38 (0.45) |

Statistical Analysis 1 for PVT Additional Measure #4, Change in False Response Frequency

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
Wilcoxon Signed Rank (paired) |

P Value ^{[3]} |
0.14 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | |

No text entered. |

6. Secondary: | 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) ] |

Measure Type | Secondary |
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Measure Title | PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT |

Measure Description | 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 | |

Safety Issue | No |

Population Description

Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
---|---|

Placebo | |

Sublingual Flumazenil |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT
[units: units on a scale] Mean (Standard Deviation) |
1.23 (1.49) | 1.01 (2.0) |

Statistical Analysis 1 for PVT Additional Measure #5, Change in Visual Analog Scale Rating of Sleepiness at the Completion of PVT

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
Wilcoxon Signed Rank (paired) |

P Value ^{[3]} |
0.89 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | |

No text entered. |

7. Secondary: | 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) ] |

Measure Type | Secondary |
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Measure Title | Change in Stanford Sleepiness Scale |

Measure Description | 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 | |

Safety Issue | No |

Population Description

Intention to treat (all randomized subjects were included) |

Reporting Groups

Description | |
---|---|

Placebo | |

Sublingual Flumazenil |

Measured Values

Placebo | Sublingual Flumazenil | |
---|---|---|

Number of Participants Analyzed
[units: participants] |
10 | 10 |

Change in Stanford Sleepiness Scale
[units: units on a scale] Mean (Standard Deviation) |
0.84 (1.68) | 0.26 (1.36) |

Statistical Analysis 1 for Change in Stanford Sleepiness Scale

Groups ^{[1]} |
All groups |
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Method ^{[2]} |
Wilcoxon Signed Rank (paired) |

P Value ^{[3]} |
0.13 |

[1] | Additional details about the analysis, such as null hypothesis and power calculation: |
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No text entered. | |

[2] | Other relevant method information, such as adjustments or degrees of freedom: |

No text entered. | |

[3] | |

No text entered. |

8. Secondary: | EEG Power [ Time Frame: following drug administration ] |

Results not yet reported. Anticipated Reporting Date:
No text entered.
Safety Issue:
No

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data |
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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. |