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

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

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.

Randomized, double-blind, placebo-controlled, crossover study of PF-03654746 in Excessive Daytime Sleepiness associated with Narcolepsy

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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.

Criteria for potential clinical concern in vital signs: supine and standing systolic blood pressure (BP) less than (<) 90 millimeter of mercury (mmHg), supine and standing diastolic BP <50 mmHg, supine and standing heart rate <40 beats per minute (bpm) or >140 bpm. Number of participants who met the criteria for potential clinical concern was reported.

Laboratory parameters included hematology (hemoglobin, hematocrit, red blood cell count, platelets, leukocytes, total neutrophils, eosinophils, basophils, lymphocytes, monocytes); liver function (total bilirubin, direct bilirubin, indirect bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, albumin, total protein); renal function (creatinine, blood urea nitrogen, uric acid, sodium, potassium, chloride, bicarbonate, calcium); urinalysis (protein, blood), and clinical chemistry (glucose). Total number of participants with laboratory abnormalities was reported.

Criteria for potential clinical concern in ECG parameters: maximum PR interval of greater than or equal to (>=) 300 milliseconds (msec), maximum QRS interval >=200 msec, maximum Fridericia's correction of QT (QTcF) interval of 450 to <480 msec, 480 to <500 msec and >=500 msec. Number of participants who met the criteria for potential clinical concern in ECG findings were reported.

Participant-rated questionnaire to assess sleep quality and quantity. Consists of 12-item questionnaires answered on a range of 1 to 6 for questions (Q) 3 to 12, 1 to 5 for Q1(some questions are reversed so that high score reflects more of the attributes); and Q2 answered on 0 to 24. Scores are transformed (actual raw score minus lowest possible score divided by possible raw score range multiplied by 100); total score range:0 to 100; higher score = greater intensity of attribute. The items contribute to each scale and are averaged to create 7 scale scores and 2 sleep scale index. Scales with at least one item answered was used to generate a scale score. Scales include; sleep disturbance (SD), sleep quantity, snoring, awaken short of breath (ASoB), somnolence, sleep adequacy and optimal sleep; and a 9-item overall sleep problems index(SPI) I and II Subscales range from 0-100 except for sleep quantity (SQ) ranging from0 to 24. Except for sleep quantity, higher scores=greater impairment.

Sheehan-STS is an 8-item clinician/participant administered prospective rating scale and an indicator of trigger assessment that tracks both treatment-emergent suicidal ideation and behaviors). Items 1a, 2-6, 8 scored on 5-point Likert scale (0=not at all, 1=a little, 2=moderately, 3=very, and 4=extremely). Items 1, 1b, 7, an indicator of trigger assessment (TA) require yes/no response. Items included 1= Ever suffer any accident, 1a= Extent plan/intend to hurt yourself, 1b= Intend to die, 2= Wish dead, 3= Want to harm yourself, 4= Think about suicide, 5= Plan for a suicide, 6= Prepare for suicide (PS) with intent to die (ITD), 7= Injure yourself on purpose, 8= Attempt suicide. Result for item 1 indicates if any of the participant ever suffered any accident, 1b indicates if any of the participant intended to die, 7 indicates if any of the participant injured themselves purposely and trigger assessment indicates if any of the participant evoked trigger assessment.

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