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

• ClinicalTrials.gov Identifier: NCT01006122
• Recruitment Status: Completed
• First Posted: November 1, 2009
• Results First Posted: May 9, 2014
• Last Update Posted: May 9, 2014
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Excessive Daytime Sleepiness; Narcolepsy	Drug: Placebo; Drug: PF-03654746	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 95 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: November 2009
• Actual Primary Completion Date: November 2010
• Actual Study Completion Date: November 2010

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo	Drug: Placebo; 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.
Active Comparator: PF-03654746; 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; 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.

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline in Maintenance of Wakefulness Test (MWT) Score at Day 21 of Stable Dosing Phase [ Time Frame: Baseline, 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.

Secondary Outcome Measures :

1. 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 [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; 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.
2. 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 [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; 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.
3. Change From Baseline in Cataplexy Episodes at Day 7, 14, 21 of Stable Dosing Phase [ Time Frame: Baseline, 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.
4. Change From Baseline in 36-Item Short Form Health Survey (SF-36) at Day 21 of Stable Dosing Phase [ Time Frame: Baseline, 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).
5. Clinical Global Impression of Improvement (CGI-I) Scale Score [ Time Frame: Day 5, 10, 15, 20 of titration phase; Day 7, 14, 21 of stable dosing phase ]
   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.
6. Computer Based Objective Cognition Testing (CogState) Groton Maze Learning Task (GMLT) [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase ]
   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.
7. Computer Based Objective Cognition Testing (CogState) Detection Speed [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase ]
   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.
8. Computer Based Objective Cognition Testing (CogState) Identification Speed [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase ]
   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.
9. Computer Based Objective Cognition Testing (CogState) One Card Learning [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase ]
   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.
10. Computer Based Objective Cognition Testing (CogState) Continuous Paired Associate Learning (CPAL) [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase ]
    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.
11. Computer Based Objective Cognition Testing (CogState ) Composite Score [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 21 of stable dosing phase ]
    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.

Other Outcome Measures:

1. Number of Participants With Vital Signs Data [ Time Frame: Baseline up to 7-10 days after Day 21 (stable dosing phase) ]
   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.
2. Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to Day 21 of stable dosing phase ]
   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.
3. Number of Participants With Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to Day 21 of stable dosing phase ]
   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.
4. Medical Outcomes Study (MOS) Sleep Scale Score [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 7, 14, 21 of stable dosing phase ]
   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.
5. Number of Participants With Response to Sheehan Suicidality Tracking Scale (STS) [ Time Frame: Baseline, Day 5, 10, 15, 20 of titration phase; Day 7, 14, 21 of stable dosing phase ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Pfizer Investigational Site

Phoenix, Arizona, United States, 85006

Pfizer Investigational Site

Phoenix, Arizona, United States, 85051

Pfizer Investigational Site

Tucson, Arizona, United States, 85712

United States, California

Pfizer Investigational Site

Los Angeles, California, United States, 90048

Pfizer Investigational Site

Orange, California, United States, 92868

United States, Florida

Pfizer Investigational Site

Brandon, Florida, United States, 33511

Pfizer Investigational Site

St. Petersburg, Florida, United States, 33707

United States, Georgia

Pfizer Investigational Site

Atlanta, Georgia, United States, 30342

Pfizer Investigational Site

Macon, Georgia, United States, 31201

United States, Illinois

Pfizer Investigational Site

Vernon Hills, Illinois, United States, 60061

United States, Kentucky

Pfizer Investigational Site

Crestview Hills, Kentucky, United States, 41017

Pfizer Investigational Site

Louisville, Kentucky, United States, 40217

United States, Mississippi

Pfizer Investigational Site

Hattiesburg, Mississippi, United States, 39401

Pfizer Investigational Site

Hattiesburg, Mississippi, United States, 39402

United States, North Carolina

Pfizer Investigational Site

Durham, North Carolina, United States, 27710

United States, Ohio

Pfizer Investigational Site

Dublin, Ohio, United States, 43017

United States, Pennsylvania

Pfizer Investigational Site

Philadelphia, Pennsylvania, United States, 19114

Pfizer Investigational Site

Philadelphia, Pennsylvania, United States, 19139

United States, South Carolina

Pfizer Investigational Site

Columbia, South Carolina, United States, 29201

United States, Texas

Pfizer Investigational Site

Austin, Texas, United States, 78731

Pfizer Investigational Site

Houston, Texas, United States, 77063

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01006122
• Other Study ID Numbers: A8801015
• First Posted: November 1, 2009
• Results First Posted: May 9, 2014
• Last Update Posted: May 9, 2014
• Last Verified: April 2014

Keywords provided by Pfizer:

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

Additional relevant MeSH terms:

Narcolepsy; Disorders of Excessive Somnolence; Sleepiness; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Mental Disorders