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

A Phase 1, Double-Blind, Placebo-Controlled, Sponsor-Open, Randomized, Multiple Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of PF-03654746 in Mild to Moderate Alzheimer's Disease Patients on Stable Donepezil Therapy

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

Study Overview

• Status: Terminated
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: PF-03654746; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Wichita, Kansas, United States, 67211
      • Pfizer Investigational Site
    • Wichita, Kansas, United States, 67207
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Matching placebo capsules to PF-03654746 with strengths of 0.25 mg, 0.5 mg, and 1.0 mg. Drug is dosed orally once a day. Forced titration dosing for the first 15 days of the study being at 0.25 mg for 5 days, then 0.5 mg for days 6-10, then 1.0 mg for days 11-15. Flexible dosing for the next 15 days depending on tolerability and safety assessments done by the investigator.
EXPERIMENTAL: PF-03654746	Drug: PF-03654746; PF-03654746 capsule of 0.25 mg, 0.5 mg, and 1.0 mg strength. Drug is dosed orally once a day. Forced titration dosing for the first 15 days of the study being at 0.25 mg for 5 days, then 0.5 mg for days 6-10, then 1.0 mg for days 11-15. Flexible dosing for the next 15 days depending on tolerability and safety assessments done by the investigator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinically Significant Vital Sign Abnormalities	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.	Baseline up to 7 to 10 days after last dose
Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	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.	Baseline up to 7 to 10 days after last dose
Number of Participants With Clinically Significant Laboratory Test Abnormalities	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.	Baseline up to 7 to 10 days after last dose
Number of Participants With Clinically Significant Change From Baseline in Physical Examination	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.	Baseline up to 7 to 10 days after last dose
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Baseline
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Day 5
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Day 10
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Day 15
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Day 20
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Day 25
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at 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.	Day 30
Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Follow-up	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.	Follow-up (7 to 10 days after last dose)
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at 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.	Baseline, Day 5
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at 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.	Baseline, Day 10
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at 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.	Baseline, Day 15
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at 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.	Baseline, Day 20
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at 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.	Baseline, Day 25
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at 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.	Baseline, Day 30
Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Follow-up	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.	Baseline, Follow-up (7 to 10 days after last dose)
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at 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.	Baseline, Day 5
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at 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.	Baseline, Day 10
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at 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.	Baseline, Day 15
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at 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.	Baseline, Day 20
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at 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.	Baseline, Day 25
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at 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.	Baseline, Day 30
Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Follow-up	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.	Baseline, Follow-up (7 to 10 days after last dose)

Secondary Outcome Measures

Outcome Measure	Time Frame
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 Serum Concentration (Cmax) for PF-03654746	0 hour (pre-dose), 0.5, 1, 3, 8 and 12 hours post-dose on Day 30
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 Donepezil	0 hour (pre-dose), 0.5, 1, 3, 8, 12 hours post-dose on Day 0, 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

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (ACTUAL): May 1, 2010
• Study Completion (ACTUAL): May 1, 2010

Study Registration Dates

• First Submitted: December 7, 2009
• First Submitted That Met QC Criteria: December 8, 2009
• First Posted (ESTIMATE): December 9, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): June 4, 2014
• Last Update Submitted That Met QC Criteria: May 16, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Phase 1 Alzheimer's disease Safety Tolerability Pharmacokinetics
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease
• Other Study ID Numbers: A8801016