A Study Of A Novel Compound For Excessive Daytime Sleepiness Associated With Narcolepsy

Study Overview
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Brief Summary
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Histaminergic agents are known to be involved with the sleep/wake cycle. This compound is a histaminergic agent which therefore may improve alertness and awakeness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy. Significant improvement in EDS when treated with this compound compared to placebo in patients with narcolepsy is hypothesized.

Official Title
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A Randomized Phase 2, Double Blind, Placebo-Controlled, Multi-Center Crossover Study Of PF-03654746 As A Daily Treatment For Excessive Daytime Sleepiness (EDS) Associated With Narcolepsy

Conditions
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Excessive Daytime Sleepiness, Narcolepsy

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-03654746


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ISDC diagnosis of narcolepsy Excessive Daytime Sleepiness in association with a diagnosis of narcolepsy An MWT (Maintenance of Wakefulness Test) average sleep latency of under 15 minutes at Baseline Exclusion Criteria: No other diagnosed sleep disorders (e.g., sleep apnea) Major medical disorders Major psychiatric disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Patients receiving placebo will undergo the same procedures as those receiving active treatment. Each patient will receive matching placebo tablets in a fixed dose escalation schedule beginning at 0.25 mg QD for 5 days; then up to 0.50 mg QD for another 5 days; and up to 1.0 mg QD for an additional 5 days. At the end of this fixed titration schedule, the patient will either stay at 1.0 mg; decrease to 0.5 mg or increase to 2.0 mg based upon the clinicians judgment regarding efficacy and side effects at the 1.0 dose level. The patient will then remain at the determined dose for a 3 week stable dosing period, with a 7 (-2/+ 9) day wash out and then crossover to repeat the same sequence for the second arm of the study.<br>|
| Active Comparator: PF-03654746<br>At the end of the second arm of the study, the patient will have completed the study and have a 7-10 day follow-up visit. | Drug: PF-03654746<br>* Each patient will receive PF-03654746 tablets in a fixed dose titration schedule beginning at 0.25 mg QD for 5 days; then up to 0.50 mg QD for another 5 days; and up to 1.0 mg QD for an additional 5 days. At the end of this fixed titration schedule, the patient will either stay at the 1.0 mg dose; decrease to 0.50 mg or increase to 2.0 mg based upon the clinician's judgement regarding efficacy and side effects at the 1.0 mg dose. The patient will remain at the determined dose for a 3 week stable dosing period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Maintenance of Wakefulness Test (MWT) Score at Day 21 of Stable Dosing Phase | MWT measured ability of participant to remain awake. Participants were instructed to try and remain awake during series of six 20-minute periods in a semi-recumbent position in dark room. Each period was terminated immediately after sleep onset or at end of 20 minutes if no sleep occurred. Poorest outcome was 0 minute the best was 20 minutes. | Baseline, Day 21 of stable dosing phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Epworth Sleepiness Scale (ESS) Total Score at Day 5, 10, 15, 20 of Titration Phase and Day 7, 14, 21 of Stable Dosing Phase | ESS is a simple, self-administered questionnaire which provides a measurement of the participant's general level of daytime sleepiness. The participant rates the chance that he/she would fall asleep when in 8 different situations (e.g. sitting and reading, talking to someone, etc.) commonly encountered in daily life on a scale of 0 (no daytime sleep) to 3 (maximum daytime sleep). Total score was the sum of 8 situations ranges from 0 to 24 with a higher score indicating greater daytime sleepiness. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 7, 14, 21 of stable dosing phase | 
| Change From Baseline in Brief Fatigue Inventory (BFI) Global Score at Day 5, 10, 15, 20 of Titration Phase and Day 7, 14, 21 of Stable Dosing Phase | BFI is a subjective-completed tool for the assessment of the impact of fatigue on daily functioning. There are 3 questions that pertain specifically to level of fatigue and 6 questions regarding general activity level, mood and quality of life, all are answered on an 11-point scale, with 0 being No fatigue at all to 10 being As bad as you can imagine. The global score is calculated by taking the sum of all 9 rating scales for a minimum score of 0 and a maximum score of 90. Higher global scores are associated with more severe fatigue. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 7, 14, 21 of stable dosing phase | 
| Change From Baseline in Cataplexy Episodes at Day 7, 14, 21 of Stable Dosing Phase | Cataplexy is a medical condition in which a person suffers sudden physical collapse though remaining conscious. Cataplexy episodes is number of counts the participant had cataplexy. | Baseline, Day 7, 14, 21 of stable dosing phase | 
| Change From Baseline in 36-Item Short Form Health Survey (SF-36) at Day 21 of Stable Dosing Phase | SF-36 is a standardized survey evaluating 8 aspects of functional health and well-being: physical functioning (PF), role physical (RP), bodily pain (BP), general health (GH), vitality, social functioning (SF), role emotional (RE) and mental health (MH). The score for a section is an average of the individual question scores, which are scaled 0-100 (100=highest level of functioning). | Baseline, Day 21 of stable dosing phase | 
| Clinical Global Impression of Improvement (CGI-I) Scale Score | CGI-I: 7-point clinician rated scale ranging from 1 (very much improved) to 7 (very much worse). Clinician responded to a question: Compared to your subject's condition at the beginning of treatment, how much has your subject changed?. Improvement was compared to baseline and was defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved) on the scale. Higher score = more affected. | Day 5, 10, 15, 20 of titration phase; Day 7, 14, 21 of stable dosing phase | 
| Computer Based Objective Cognition Testing (CogState) Groton Maze Learning Task (GMLT) | GMLT: a cognitive test which assessed executive function. Participant was shown a 10 multiplied by 10 grid of tiles on a computer touch screen. A 28-step pathway was hidden among 100 possible locations. The participant was instructed to move 1 step from the start location and then continue 1 tile at a time, toward the end to find the pathway. The outcome measure was total number of errors made in attempting to learn the same hidden pathway on 5 consecutive trials at a single session. Score ranges from 0 to infinity. Lower scores meant a better performance. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase | 
| Computer Based Objective Cognition Testing (CogState) Detection Speed | Detection speed: a cognitive test which assessed psychomotor function. A playing card was presented face up in the center of the screen. As soon as this happened, the participant was to press the 'Yes' key. The outcome measure was speed of performance; mean of the log10 transformed reaction time for correct responses [measured in log10 milliseconds (msec)]. Scores ranges from 2 (best) to 3.3 (worst). Lower scores meant a better performance. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase | 
| Computer Based Objective Cognition Testing (CogState) Identification Speed | Identification speed: a cognitive test which assessed visual attention. A playing card was presented face up in the center of the screen. As soon as this happened, the participant had to decide whether the card was red or not. The outcome measure was speed of performance; mean of the log10 transformed reaction time for correct responses (measured in log10 msec). Score ranges from 2 (best) to 3.3 (worst). Lower scores meant a better performance. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase | 
| Computer Based Objective Cognition Testing (CogState) One Card Learning | One card learning: a cognitive test which assessed visual learning. Participants were to remember which cards were previously shown in a task. The outcome measure was accuracy of performance; arcsine transformation of the square root of the proportion of correct responses. Score ranges from 0 (worse) to 1.57 (best). Higher scores meant a better performance. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase | 
| Computer Based Objective Cognition Testing (CogState) Continuous Paired Associate Learning (CPAL) | CPAL: a cognitive test which assessed visual episodic learning. Participant was to learn and remember picture locations on the screen and was to tap the target on the central location to begin. As each picture was revealed, the participant was to remember where the picture was located and tap that location. The outcome measure was the number of errors made in correctly placing each of the 4 patterns in their location 4 times. Score ranges from 0 to infinity. Lower scores meant a better performance. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase | 
| Computer Based Objective Cognition Testing (CogState ) Composite Score | CogState had 5 outcome measures that measured the cognitive constructs. GMLT, detection, identification, one card learning and CPAL. GMLT score range: 0 (best) to infinity (worst), detection and identification score range: 2 (best) to 3.3 (worst); One card learning score range: 0 (worse) to 1.57 (best) and CPAL score range: 0 (best) to infinity (worst). The individual score was standardized at each assessment and was then averaged to yield a composite score; total possible score: minus infinity to plus infinity. Positive composite score=improved performance. | Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, double-blind, placebo-controlled, crossover study of PF-03654746 in Excessive Daytime Sleepiness associated with Narcolepsy