A Study to Evaluate the Safety, Tolerability, and Blood Levels of PF-03654746 in Subjects With Mild to Moderate Alzheimer's Disease

Phase 1

Terminated

Conditions: Alzheimer's Disease

Interventions: Drug: Placebo
Drug: PF-03654746

Registration Number: NCT01028911

Lead Sponsor: Pfizer

Brief Summary: This is a study to evaluate the safety, tolerability and blood levels of PF-03654746 in subjects will mild to moderate Alzheimer's disease.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Probable Alzheimer's disease
Mini Mental State Examination score 18-26 inclusive
Aged 55-85

Exclusion Criteria

Dementia other than Alzheimer's disease
Clinically significant cardiovascular disease in the past 6 months prior to screening
Creatinine clearance <30 mL/min

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	-
PF-03654746	PF-03654746	-

Primary Outcome Measures

Name	Time	Method
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 10	Day 10	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 15	Day 15	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Number of Participants With Clinically Significant Change From Baseline in Physical Examination	Baseline up to 7 to 10 days after last dose	Physical examination included examination of the skin, eyes, ears, throat, neck, and cardiac, respiratory, gastrointestinal and musculoskeletal systems. The examination assessed the participants for any potential changes in physical status, as determined by the investigator. Any untoward findings identified on physical exams conducted after the administration of the first dose of study medication was captured as an adverse event.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 25	Day 25	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 30	Day 30	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Number of Participants With Clinically Significant Vital Sign Abnormalities	Baseline up to 7 to 10 days after last dose	Criteria for potential clinical concern in vital signs: supine and standing systolic blood pressure (SBP) less than (\<) 90 millimeter of mercury (mmHg), supine and standing diastolic BP (DBP) \<50 mmHg, supine pulse rate \<40 beats per minute (bpm) or \>120 bpm, standing pulse rate \<40 bpm or \>140 bpm. Maximum increase or decrease from baseline in supine (Su) and standing (St) SBP \>=30 mmHg and maximum increase or decrease from baseline in supine and standing DBP \>=20 mmHg.
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	Baseline up to 7 to 10 days after last dose	Criteria for potential clinical concern in ECG parameters: maximum PR interval of \>=300 milliseconds (msec), maximum QRS interval \>=200 msec, maximum fridericia's corrected QT (QTcF) interval \>=500 msec, PR interval or QRS interval increase from baseline \>=25 percent (%) or 50 percent (%), QTCF interval increase from baseline 30 to 60 msec or \>=60 msec.
Number of Participants With Clinically Significant Laboratory Test Abnormalities	Baseline up to 7 to 10 days after last dose	Criteria for laboratory tests abnormalities included: hemoglobin, hematocrit and red blood cells (\< 0.8\lower limit of normal\[LLN\]); leucocytes (\<0.6/\>1.5\upper limit of normal \[ULN\]); platelets (\<0.5\LLN/\>1.75\ULN); neutrophils, lymphocytes (\<0.8\LLN/\>1.2\ULN); eosinophils, basophils, monocytes (\>1.2\ULN); total bilirubin (\>1.5\ULN); aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (\>3\ULN), total protein, albumin (\<0.8\LLN/\>1.2\ULN); creatinine, urea (\>1.3\ULN); glucose (\<0.6\LLN/\>1.5\ULN); uric acid (\>1.2\ULN); sodium, potassium, chloride, calcium, bicarbonate (\<0.9\LLN/\>1.1\*ULN); urine red blood cells (RBCs), urine white blood cells (WBCs), urine epithelial cells (\>=6 high-powered field), urine bacteria \>20 high-powered field; qualitative urine glucose, ketones, protein values \>=1 in urine dipstick test. Total number of participants with any laboratory abnormalities was reported.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 5	Day 5	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 20	Day 20	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Baseline	Baseline	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 5	Baseline, Day 5	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 25	Baseline, Day 25	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Follow-up	Baseline, Follow-up (7 to 10 days after last dose)	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 10	Baseline, Day 10	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 25	Baseline, Day 25	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 30	Baseline, Day 30	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Follow-up	Baseline, Follow-up (7 to 10 days after last dose)	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 15	Baseline, Day 15	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 30	Baseline, Day 30	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 5	Baseline, Day 5	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 20	Baseline, Day 20	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Follow-up	Follow-up (7 to 10 days after last dose)	Participant-rated 12-item questionnaire to assess sleep quality and quantity. The items contribute to each scale and are averaged to create the 7 subscale scores: sleep disturbance, snoring, awaken short of breath (ASoB) or with a headache, somnolence, sleep adequacy, sleep quantity (range 0 to 24) and optimal sleep (yes: 1, no: 0), and overall sleep problem index (SPI) I and II. Except for sleep quantity and optimal sleep, scores are transformed (actual raw score minus lowest possible score divided by possible raw score range\* 100); total score range: 0 to 100; higher score = greater intensity of attribute. Except for sleep quantity, sleep adequacy and optimal sleep, higher scores=greater impairment. Scales with at least one item answered was used to generate a scale score.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 10	Baseline, Day 10	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 20	Baseline, Day 20	NPI: 12-domain caregiver assessment of behavioral disturbances occurring in dementia: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, appetite/eating, night-time behavior. Severity (1=Mild to 3=Severe), frequency (1=occasionally to 4=very frequently) scales recorded for each domain; frequency\*severity=each domain score (range 0-12). Total score=sum of each domain score (range 0-144); higher score=greater behavioral disturbances; negative change score from baseline=improvement.
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 15	Baseline, Day 15	MMSE measured general cognitive functioning: orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy two intersecting polygons. Total score derived from sub-scores; total ranged from 0 to 30, higher score indicates better cognitive state.

Secondary Outcome Measures

Name	Time	Method
Time to Reach Maximum Observed Serum Concentration (Tmax) for PF-03654746	0 hour (pre-dose), 0.5, 1, 3, 8 and 12 hours post-dose on Day 30
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for PF-03654746	0 hour (pre-dose), 0.5, 1, 3, 8 and 12 hours post-dose on Day 30
Maximum Plasma Concentration (Cmax) for Donepezil	0 hour (pre-dose), 0.5, 1, 3, 8, 12 hours post-dose on Day 0, Day 30
Time to Reach Maximum Observed Plasma Concentration (Tmax) for Donepezil	0 hour (pre-dose), 0.5, 1, 3, 8, 12 hours post-dose on Day 0, Day 30
Maximum Serum Concentration (Cmax) for PF-03654746	0 hour (pre-dose), 0.5, 1, 3, 8 and 12 hours post-dose on Day 30
Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) for Donepezil	0 hour (pre-dose), 0.5, 1, 3, 8, 12 hours post-dose on Day 0, Day 30