Flumazenil for the Treatment of Primary Hypersomnia

This study has been completed.
Sponsor:
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
Results First Received: January 11, 2013  
Study Type: Interventional
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
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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
12 patients were enrolled; of these, 2 were excluded prior to randomization because screening laboratory test results were abnormal.

Reporting Groups
  Description
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
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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.
No text entered.

Reporting Groups
  Description
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]
     
Female     5     5     10  
Male     0     0     0  
Region of Enrollment  
[units: participants]
     
United States     5     5     10  



  Outcome Measures
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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
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.
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  
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
Method [2] wilcoxon signed rank (paired)
P Value [3] 0.77
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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
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
Method [2] Wilcoxon Signed Rank (paired)
P Value [3] 0.51
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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
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
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 #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
Method [2] Wilcoxon Signed Rank (paired)
P Value [3] 0.32
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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
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 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 #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
Method [2] Wilcoxon Signed Rank (paired)
P Value [3] 0.56
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.



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
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 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 #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
Method [2] Wilcoxon Signed Rank (paired)
P Value [3] 0.14
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.



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
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 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 #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
Method [2] Wilcoxon Signed Rank (paired)
P Value [3] 0.89
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.



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
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 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  
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
Method [2] Wilcoxon Signed Rank (paired)
P Value [3] 0.13
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  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.



8.  Secondary:   EEG Power   [ Time Frame: following drug administration ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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
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.


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