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

• ClinicalTrials.gov Identifier: NCT01028911
• Recruitment Status: Terminated
• First Posted: December 9, 2009
• Results First Posted: June 4, 2014
• Last Update Posted: June 4, 2014
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: PF-03654746; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: December 2009
• Actual Primary Completion Date: May 2010
• Actual Study Completion Date: May 2010

Arms and Interventions

Arm	Intervention/treatment
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.
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.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: 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.
2. Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities [ Time Frame: 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.
3. Number of Participants With Clinically Significant Laboratory Test Abnormalities [ Time Frame: 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.
4. Number of Participants With Clinically Significant Change From Baseline in Physical Examination [ Time Frame: 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.
5. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Baseline [ Time Frame: 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.
6. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 5 [ Time Frame: 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.
7. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 10 [ Time Frame: 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.
8. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 15 [ Time Frame: 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.
9. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 20 [ Time Frame: 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.
10. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 25 [ Time Frame: 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.
11. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Day 30 [ Time Frame: 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.
12. Medical Outcomes Study - Sleep Scale (MOS-SS) Score at Follow-up [ Time Frame: 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.
13. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 5 [ Time Frame: 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.
14. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 10 [ Time Frame: 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.
15. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 15 [ Time Frame: 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.
16. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 20 [ Time Frame: 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.
17. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 25 [ Time Frame: 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.
18. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Day 30 [ Time Frame: 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.
19. Change From Baseline in Neuropsychiatric Inventory (NPI) Total Score at Follow-up [ Time Frame: 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.
20. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 5 [ Time Frame: 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.
21. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 10 [ Time Frame: 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.
22. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 15 [ Time Frame: 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.
23. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 20 [ Time Frame: 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.
24. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 25 [ Time Frame: 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.
25. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Day 30 [ Time Frame: 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.
26. Change From Baseline in Mini Mental State Examination (MMSE) Total Score at Follow-up [ Time Frame: 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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Kansas

Pfizer Investigational Site

Wichita, Kansas, United States, 67207

Pfizer Investigational Site

Wichita, Kansas, United States, 67211

Sponsors and Collaborators

Pfizer

Investigators

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

More Information

Additional Information:

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

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01028911
• Other Study ID Numbers: A8801016
• First Posted: December 9, 2009
• Results First Posted: June 4, 2014
• Last Update Posted: June 4, 2014
• Last Verified: May 2014

Keywords provided by Pfizer:

Phase 1 Alzheimer's disease Safety Tolerability Pharmacokinetics

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders