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

Status

Terminated

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01028911

Enrollment

Registered

2009-12-09

Start date

2009-12-31

Completion date

2010-05-31

Last updated

2014-06-04

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer's Disease

Keywords

Phase 1 Alzheimer's disease Safety Tolerability Pharmacokinetics

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.

Interventions

DRUGPF-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.

DRUGPlacebo

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.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

55 Years to 85 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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 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 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 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.
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.
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.
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.
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 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.
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 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.
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 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.
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 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 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 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 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 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 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 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.

Secondary

Measure	Time frame
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
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

Countries

United States

Participant flow

Recruitment details

Participants who were on a stable dose of donepezil (Aricept) 10 milligram (mg) once daily for at least 30 days before screening and on stable morning dosing at least 14 days before Day 0 were enrolled in this study.

Participants by arm

Arm	Count
PF-03654746 and Donepezil PF-03654746 0.25 milligram (mg) powder in capsule orally once daily on Day 1 to 5, followed by PF-03654746 0.5 mg powder in capsule orally once daily on Day 6 to 10 and PF-03654746 1 mg powder in capsule orally once daily on Day 11 to 15 during the forced titration phase. PF-03654746 0.5 mg to 2 mg powder in capsule orally once daily, based on investigator's discretion and tolerability, on Day 16 to 30 during the flexible titration phase. Background donepezil (Aricept) 10 mg tablet orally once daily throughout the study.	7
Placebo and Donepezil Placebo matched to PF-03654746 powder in capsule once daily on Day 1 to 30 along with background donepezil (Aricept) 10 mg tablet orally once daily throughout the study.	2
Total	9

Baseline characteristics

Characteristic	PF-03654746 and Donepezil	Placebo and Donepezil	Total
Age, Customized 45 to 64 years	1 participants	0 participants	1 participants
Age, Customized Greater than or equal to (>=) 65 years	6 participants	2 participants	8 participants
Sex: Female, Male Female	1 Participants	0 Participants	1 Participants
Sex: Female, Male Male	6 Participants	2 Participants	8 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	5 / 7	0 / 2
serious Total, serious adverse events	0 / 7	0 / 2

Outcome results

Primary

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.

Time frame: Baseline, Day 10