Trial Outcomes & Findings for Flumazenil for the Treatment of Primary Hypersomnia (NCT NCT01183312)

NCT ID: NCT01183312

Last Updated: 2017-12-12

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 10 participants
• Primary outcome timeframe: 10, 30, 60, 90, 120, and 150 minutes after drug administration (averaged for all time points for each subject)
• Results posted on: 2017-12-12

Participant Flow

Participants were recruited from the Sleep Center of the Emory Clinic, in Atlanta, Georgia, USA, between December 2010 and October 2011.

12 patients were enrolled; of these, 2 were excluded prior to randomization because screening laboratory test results were abnormal.

Participant milestones

Measure	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.
First Intervention Day STARTED	5	5
First Intervention Day COMPLETED	5	5
First Intervention Day NOT COMPLETED	0	0
Washout Period of at Least 1 Week STARTED	5	5
Washout Period of at Least 1 Week COMPLETED	5	5
Washout Period of at Least 1 Week NOT COMPLETED	0	0
Second Intervention Day STARTED	5	5
Second Intervention Day COMPLETED	5	5
Second Intervention Day NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Flumazenil for the Treatment of Primary Hypersomnia

Baseline characteristics by cohort

Measure	Placebo First, Then Flumazenil n=5 Participants Placebo during the first intervention day and sublingual flumazenil during the second intervention day (after washout period).	Flumazenil First, Then Placebo n=5 Participants Sublingual flumazenil during the first intervention day and placebo during the second intervention day (after washout period).	Total n=10 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	33.6 years STANDARD_DEVIATION 13.3 • n=5 Participants	41.8 years STANDARD_DEVIATION 18.1 • n=7 Participants	37.7 years STANDARD_DEVIATION 15.6 • n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	5 participants n=5 Participants	5 participants n=7 Participants	10 participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

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.

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
Change in Psychomotor Vigilance Task (PVT) Median Reaction Time	-9.86 msec Standard Deviation 28.2	-4.46 msec Standard Deviation 63.7

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
PVT Additional Measure #1, Change in Lapse Frequency	-3.3 number of lapses during PVT testing Standard Deviation 6.9	-2.6 number of lapses during PVT testing Standard Deviation 8.7

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
PVT Additional Measure #2, Change in Duration of Lapse Domain	0.18 1/msec Standard Deviation 0.30	0.25 1/msec Standard Deviation 0.45

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
PVT Additional Measure #3, Change in Optimum Response Times	-0.02 1/msec Standard Deviation 0.27	-0.04 1/msec Standard Deviation 0.63

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
PVT Additional Measure #4, Change in False Response Frequency	0.09 number of false starts Standard Deviation 0.56	-0.38 number of false starts Standard Deviation 0.45

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
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	1.01 units on a scale Standard Deviation 2.0

SECONDARY outcome

Timeframe: 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)

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).

Outcome measures

Measure	Placebo n=10 Participants Sublingual placebo administered three times over a single day, in either first or second intervention period	Sublingual Flumazenil n=10 Participants Sublingual flumazenil administered three times over a single day (12 mg, 6 mg, 6 mg dosing), in either the first or second intervention period
Change in Stanford Sleepiness Scale	0.84 units on a scale Standard Deviation 1.68	0.26 units on a scale Standard Deviation 1.36

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome data not reported

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Sublingual Flumazenil

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Placebo n=10 participants at risk	Sublingual Flumazenil n=10 participants at risk
Nervous system disorders feeling "dizzy", "lightheaded", or "spacey"	40.0% 4/10 • Symptoms experienced within 24 hours of drug administration	30.0% 3/10 • Symptoms experienced within 24 hours of drug administration
Nervous system disorders headache (during or following drug administration)	0.00% 0/10 • Symptoms experienced within 24 hours of drug administration	40.0% 4/10 • Symptoms experienced within 24 hours of drug administration
Nervous system disorders feeling "jittery"	0.00% 0/10 • Symptoms experienced within 24 hours of drug administration	10.0% 1/10 • Symptoms experienced within 24 hours of drug administration
Psychiatric disorders feeling of "panic", "anxiety", or "uneasy"	10.0% 1/10 • Symptoms experienced within 24 hours of drug administration	10.0% 1/10 • Symptoms experienced within 24 hours of drug administration
Musculoskeletal and connective tissue disorders back pain	0.00% 0/10 • Symptoms experienced within 24 hours of drug administration	10.0% 1/10 • Symptoms experienced within 24 hours of drug administration
Psychiatric disorders feeling "giggly" or "high"	0.00% 0/10 • Symptoms experienced within 24 hours of drug administration	10.0% 1/10 • Symptoms experienced within 24 hours of drug administration
Psychiatric disorders feeling dysphoria or "drugged"	0.00% 0/10 • Symptoms experienced within 24 hours of drug administration	10.0% 1/10 • Symptoms experienced within 24 hours of drug administration

Additional Information

Dr. Lynn Marie Trotti

Emory University School of Medicine

Phone: 404-728-4752

Email: lbecke2@emory.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place