Acute Effects Of Donepezil On Brain Perfusion And Memory... | NCT01082965

Label	Type	Description	Intervention Names
Treatment	Experimental		Drug: Donepezil
Placebo	Placebo Comparator		Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Donepezil	Drug	5 mg tablets once daily for 7 days and then 10mg on 8th day	Treatment

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 4 on Day 1	Posterior cingulate cortex perfusion was measured by arterial spin labeling (ASL). ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for average relative perfusion rate. Average relative perfusion rate is defined as the average absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point. Average absolute perfusion rate is the average of left absolute perfusion rate and right absolute perfusion rate at the same time point.	Baseline, 4 hours post-dose on Day 1
Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 0 on Day 8	Posterior cingulate cortex perfusion was measured by ASL. ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for average relative perfusion rate. Average relative perfusion rate is defined as the average absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point. Average absolute perfusion rate is the average of left absolute perfusion rate and right absolute perfusion rate at the same time point.	Baseline, 1 minute post-dose (Hour 0) on Day 8
Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 4 on Day 8	Posterior cingulate cortex perfusion was measured by ASL. ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for average relative perfusion rate. Average relative perfusion rate is defined as the average absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point. Average absolute perfusion rate is the average of left absolute perfusion rate and right absolute perfusion rate at the same time point.	Baseline, 4 hours post-dose on Day 8

Secondary Outcomes

Measure	Description	Time Frame
Change From Baseline in Arterial Spin Label (ASL) Perfusion at Hour 4 on Day 1 and at Hour 0, 4 on Day 8	Perfusion in anterior cingulate cortex, medial prefrontal cortex, precuneus, inferior parietal cortex and other regions of interest (whole brain gray, superior, medial and inferior temporal cortex; inferior and superior prefrontal cortex; insula, amygdala, thalamus, basal ganglia, hippocampus, Landau) was measured by ASL technique. ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for relative perfusion rate. Relative perfusion rate is defined as the absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subjects and caregivers must provide written Informed Consent and be willing to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
AD: Diagnostic evidence of probable AD consistent with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria met by the site Physician at the time of the Screening visit. This evidence must be fully documented in the participant's file prior to the Baseline Visit.
For amnestic Mild Cognitive Impairment (MCI): A Clinical Dementia Rating (CDR) of 0.5 (with memory box score of at least 0.5) and a memory complaint that is objectively verified using a test of episodic memory: Delayed recall from one paragraph of the Wechsler Logical Memory scale (cutoff scores by education - maximum score of 25).
Less than or equal to 8 for 16 or more years of education; Less than or equal to 4 for 8-15 years of education; Less than or equal to 2 for 0-7 years of education.
Mini Mental State Exam (MMSE) score of 21-30
Male and female subjects of non child-bearing potential (or using appropriate birth control measures) who are at least 50 years of age.
In generally good health, in the opinion of the Principal Investigator (PI), based on medical history, Body Mass Index (BMI), physical examination, vital signs, 12-lead ECG, and laboratory values, including hematology and chemistry values.
No known genetic AD causes for early onset memory impairment (e.g., presenilin mutation), participants from a family with known autosomal dominant AD associated with mutations in APP, PS1, or PS2 genes or strongly suspected, but not yet identified mutations in APP, PS1 or PS2 genes or Down's syndrome are not eligible to enroll. Individuals from families with late onset AD with 2 or more affected family members may participate.

Type II diabetic subjects may be included provided that their disease and serum glucose values are controlled and being actively managed, as assessed by the PI using a fasting blood sugar and/or HgbA1C (per the PI's medical judgment in consultation with the Sponsor).

Rosen-Modified Hachinski Ischemia Score less than or equal to 4.

Exclusion Criteria:

Diagnosis or history of other possible cause for or significant contributor to dementia, including but not limited to other neurodegenerative disorders (eg, frontotemporal dementia, Lewy body disease, vascular dementia), vitamin B12 deficiency (reflex Methylmalonic Acid (MMA) and folate if B12 is low), untreated thyroid disease, syphilis, alcoholism, severe or recurrent head injury that is clinically relevant to the disease under study, or onset of dementia following heart surgery or cardiac arrest.
Diagnosis or history of cerebrovascular disease (eg, stroke, transient ischemic attack), severe carotid stenosis, cerebral hemorrhage, intracranial tumor, subarachnoid hemorrhage, or subdural hematoma that could contribute to the subject's current cognitive or functional status, impair ability to fully participate in the trial or that may impact status during the one week study.
Specific exclusionary brain MRI findings identified prior to study or at baseline as determined by the investigator that could either contribute to the subject's current cognitive or functional decline impair ability to fully participate in the trial or that may impact status during the trial:
History of cancer within the last year (except for cutaneous basal cell, squamous cell cancer resolved by excision, colon polyp resolved by excision, or non-progressive prostate cancer per investigator's judgment).
History of clinically significant cardiovascular or renal events.
Subjects with uncontrolled hypertension even with therapeutic intervention
History of clinically significant (as determined by the PI in consultation with the Sponsor) syncope, seizure, head trauma, or clinically significant unexplained loss of consciousness within the last 5 years.
A diagnosis of major depressive disorder or other psychiatric illness as the primary diagnosis per the DSM-IV text revision (TR) criteria per the investigator's judgment.
History of schizophrenia, bipolar disorder, or other severe mental illness.
Known history of alcohol or drug abuse (as defined by the DSM-IV-TR) within 5 years prior to dosing or a positive result regarding use of illicit drugs on the drug screening test.
History of clinically significant symptoms of pulmonary disease that requires treatment (eg. asthma, COPD, or other chronic respiratory conditions).
Known positive Human immunodeficiency virus (HIV) status.
Unwilling or unable to comply with the Life Style guidelines described in this protocol.

Exclusions Related to Medications or Procedures

Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) of Study Day 1.
Use of tobacco- or nicotine-containing products within three months of study Day 1.

Use of medication(s) for cognitive enhancement ≤ 90 days before the first dose of study medication.

Prescription: including but not limited to donepezil, galantamine, rivastigmine, tacrine, memantine, Axona™;
Reason for stoppage of donepezil may not be related to tolerability issues or to gain entry in this study.
Non-prescription treatments for cognitive enhancement.
- Subjects with either non-removable ferromagnetic implants (such as cardiac pacemaker), aneurysm clips or other foreign bodies that would contraindicate a brain MRI scan.
- A clinically significant (as determined by the PI) abnormality in the 12-lead ECG, including complete heart block, bradycardia (heart rate <40 beats/minute), sinus pauses >2 seconds, second or third degree heart block, QTc >450 or other abnormalities judged clinically significant by the PI.

Name	Affiliation	Role
Pfizer CT.gov Call Center	Pfizer	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Pfizer Investigational Site		San Francisco	California	94122	United States
Pfizer Investigational Site

Label	URL
To obtain contact information for a study center near you, click here.	View source

ID	Title	Description
FG000	Donepezil	Donepezil 5 milligram (mg) tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
FG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.

ID	Title	Description
BG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
BG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00010 BG0018 BG00218

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 4 on Day 1

Posterior cingulate cortex perfusion was measured by arterial spin labeling (ASL). ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for average relative perfusion rate. Average relative perfusion rate is defined as the average absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point. Average absolute perfusion rate is the average of left absolute perfusion rate and right absolute perfusion rate at the same time point.

Full analysis set (FAS) included all randomized participants who received at least 1 dose of the study drug (donepezil or placebo). Here, 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Posted

Mean

Standard Deviation

ratio

Baseline, 4 hours post-dose on Day 1

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.

Units	Counts
Participants	OG0009 OG0016

Title

Denominators

Categories

Baseline

Title	Measurements
	OG0001.243± 0.2586 OG0011.564± 0.2494

Change at Hour 4 on Day 1

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Mixed model for repeated measures (MMRM) was used with treatment, time, treatment-by-time interaction as fixed effects and baseline, age, gender, Apolipoprotein E (ApoE) genotype, site as covariates.	Mixed Models Analysis		0.9742	Statistical significance level alpha (2-sided) was 0.05.	Leasts Square (LS) Mean	-0.01	Standard Error of the Mean	0.265	2-Sided	95	-0.60	0.58				No	Superiority or Other

Primary

Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 0 on Day 8

Posterior cingulate cortex perfusion was measured by ASL. ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for average relative perfusion rate. Average relative perfusion rate is defined as the average absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point. Average absolute perfusion rate is the average of left absolute perfusion rate and right absolute perfusion rate at the same time point.

FAS included all randomized participants who received at least 1 dose of the study drug (donepezil or placebo). Here, 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Posted

Mean

Standard Deviation

ratio

Baseline, 1 minute post-dose (Hour 0) on Day 8

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.

Primary

Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 4 on Day 8

Posted

Mean

Standard Deviation

ratio

Baseline, 4 hours post-dose on Day 8

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.

Units

Secondary

Change From Baseline in Arterial Spin Label (ASL) Perfusion at Hour 4 on Day 1 and at Hour 0, 4 on Day 8

Perfusion in anterior cingulate cortex, medial prefrontal cortex, precuneus, inferior parietal cortex and other regions of interest (whole brain gray, superior, medial and inferior temporal cortex; inferior and superior prefrontal cortex; insula, amygdala, thalamus, basal ganglia, hippocampus, Landau) was measured by ASL technique. ASL is a completely noninvasive magnetic resonance method to measure regional cerebral perfusion. Results are reported for relative perfusion rate. Relative perfusion rate is defined as the absolute perfusion rate divided by the whole brain absolute perfusion rate at the same time point.

Posted

Mean

Standard Deviation

ratio

Baseline, 4 hours post-dose on Day 1, 1 minute post-dose (Hour 0), 4 hours post-dose on Day 8

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.

Secondary

Change From Baseline in CogState Continuous Paired Associate Learning (CPAL) at Hour 5 on Day 1 and at Hour 1, 5 on Day 8

CPAL: a cognitive test which assessed visual episodic learning. Participant was to learn and remember picture locations on the screen and was to tap the target on the central location to begin. As each picture was revealed, the participant was to remember where the picture was located and tap that location. After 4 pictures were placed correctly, second round started. In second round pictures remain in the same locations, but their order of presentation in the center of the screen was different to that of the first round (randomized). The same process was repeated for round 3 and round 4. The outcome was the number of errors made in correctly placing each of the 4 patterns in their location 4 times.

Posted

Mean

Standard Deviation

errors

Baseline, 5 hours post-dose on Day 1; 1, 5 hours post-dose on Day 8

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.

Secondary

Change From Baseline in Rey Auditory Verbal Learning Test (RAVLT): Immediate and Delayed Recall at Hour 5 on Day 8

RAVLT, in immediate recall (IR) list of 15 words (list A) was read aloud to participant 5 times followed by a test of spontaneous retrieval (A1 to A5). After fifth attempt a list of interference, comprising 15 words (list B) was read to participant followed by its retrieval (B1). After attempt B1 examiner asked individual to recall words from list A, without reading it again (A6). Score range: 0-105, higher scores=less impairment. Delayed recall (DR):after a 20-minute interval examiner asked individual to remember words from list A without reading this list; in recognition performance a list comprising 15 words from list A, 15 words from list B, 20 distracting words (similar to words in list A, B) was read to individual. Upon each word read aloud, individual asked to indicate if it belonged to list A, or not. Score range: 0-30, higher scores=less impairment.

Posted

Mean

Standard Deviation

units on a scale

Baseline, 5 hours post-dose on Day 8

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo

Secondary

Change From Baseline in CogState Test Battery at Hour 5 on Day 1 and at Hour 0, 5 on Day 8

Computerized test battery used to assess detection and identification task. CogState detection task: a measure of simple reaction time, provided valid assessment of psychomotor function. Participants were required to press a "YES" response key as soon as they detected an event (a card turning face up presented in center of the computer screen). The software measured the response time to detect each event. CogState identification task: measure of choice reaction time, provided a valid assessment of visual attention. Participants were required to decide "YES" or "NO" as to whether the event met a predefined and unchanging criterion (is the color of the card red?) while the event (a card turning face up) occurred in the center of the computer screen. The software measured the speed and accuracy of each response.

Posted

Mean

Standard Deviation

log10 milliseconds

Baseline, 5 hours post-dose on Day 1; 1, 5 hours post-dose on Day 8

ID	Title	Description
OG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.
OG001	Placebo

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal discomfort	Gastrointestinal disorders	MedDRA 15.1	Non-systematic Assessment	EG0001 affected10 at risk EG0010 affected8 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 15.1	Non-systematic Assessment	EG0001 affected10 at risk EG0011 affected8 at risk
Asthenia	General disorders	MedDRA 15.1	Non-systematic Assessment	EG0001 affected10 at risk EG0010 affected8 at risk
Fatigue	General disorders	MedDRA 15.1	Non-systematic Assessment	EG0000 affected10 at risk EG0011 affected8 at risk
Excoriation	Injury, poisoning and procedural complications	MedDRA 15.1	Non-systematic Assessment	EG0000 affected10 at risk EG0011 affected8 at risk
Sensory disturbance	Nervous system disorders	MedDRA 15.1	Non-systematic Assessment	EG0000 affected10 at risk EG0011 affected8 at risk

ID	Term
D003704	Dementia
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D024801	Tauopathies
D019636	Neurodegenerative Diseases
D019965	Neurocognitive Disorders
D001523	Mental Disorders

ID	Term
D007189	Indans
D007192	Indenes
D011084	Polycyclic Aromatic Hydrocarbons
D006841	Hydrocarbons, Aromatic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D010880	Piperidines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds
D011083	Polycyclic Compounds

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Donepezil	Donepezil 5 mg tablet orally once daily up to Day 7, followed by donepezil 10 mg tablet orally once on Day 8.			0	10	3	10
EG001	Placebo	Placebo matched to donepezil 5 mg tablet orally once daily up to Day 7, followed by placebo matched to donepezil 10 mg tablet orally once on Day 8.			0	8	2	8