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

Alzheimer's Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01028911
• Other study ID #: A8801016
• Status: Terminated
• Phase: Phase 1
• First received: December 7, 2009
• Last updated: May 16, 2014
• Start date: December 2009
• Est. completion date: May 2010

Study information

• Verified date: May 2014
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 9
• Est. completion date: May 2010
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years to 85 Years

Eligibility

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

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	Pfizer Investigational Site	Wichita	Kansas
United States	Pfizer Investigational Site	Wichita	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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)	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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)	Yes
Primary	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	Yes
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.	Baseline, Day 10	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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)	Yes
Secondary	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	No
Secondary	Maximum Serum Concentration (Cmax) for PF-03654746		0 hour (pre-dose), 0.5, 1, 3, 8 and 12 hours post-dose on Day 30	No
Secondary	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	No
Secondary	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	No
Secondary	Maximum Plasma Concentration (Cmax) for Donepezil		0 hour (pre-dose), 0.5, 1, 3, 8, 12 hours post-dose on Day 0, Day 30	No
Secondary	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	No

External Links

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