Clinical trial NCT01082965: Acute Effects Of Donepezil On Brain Perfusion And Memory In Subjects With Cognitive Impairment And Mild Alzheimer's Disease
Official title: A Methodology Study To Evaluate The Acute Effects Of Donepezil On Regional Cerebral Perfusion And Cognition In Subjects With Amnestic MCI And Mild Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Alzheimer's Disease
Keywords: ASL MRI
perfusion
cognition
donepezil
alzheimer's disease
translational medicine
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2010-03-09
Enrollment: 18
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The study hypothesizes that donepezil will have a positive impact on brain blood flow deficits in subjects with memory deficits and/or mild dementia and that improvements in brain blood flow will be accompanied by improvements in memory.


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.

Primary outcomes:
measure: Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 4 on Day 1
timeFrame: Baseline, 4 hours post-dose on Day 1
measure: Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 0 on Day 8
timeFrame: Baseline, 1 minute post-dose (Hour 0) on Day 8
measure: Change From Baseline in Posterior Cingulate Cortex Perfusion at Hour 4 on Day 8
timeFrame: Baseline, 4 hours post-dose on Day 8
Secondary outcomes:
measure: Change From Baseline in Arterial Spin Label (ASL) Perfusion at Hour 4 on Day 1 and at Hour 0, 4 on Day 8
timeFrame: Baseline, 4 hours post-dose on Day 1, 1 minute post-dose (Hour 0), 4 hours post-dose on Day 8
measure: Change From Baseline in CogState Continuous Paired Associate Learning (CPAL) at Hour 5 on Day 1 and at Hour 1, 5 on Day 8
timeFrame: Baseline, 5 hours post-dose on Day 1; 1, 5 hours post-dose on Day 8
measure: Change From Baseline in Rey Auditory Verbal Learning Test (RAVLT): Immediate and Delayed Recall at Hour 5 on Day 8
timeFrame: Baseline, 5 hours post-dose on Day 8
measure: Change From Baseline in CogState Test Battery at Hour 5 on Day 1 and at Hour 0, 5 on Day 8
timeFrame: Baseline, 5 hours post-dose on Day 1; 1, 5 hours post-dose on Day 8
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: Pfizer Investigational Site
state: California
city: San Francisco
country: United States
facility: Pfizer Investigational Site
state: California
city: Baltimore
country: United States
facility: Pfizer Investigational Site
state: Maryland
city: Baltimore
country: United States
facility: Pfizer Investigational Site
state: Maryland
city: St. Louis
country: United States
facility: Pfizer Investigational Site
state: Missouri
city: St. Louis
country: United States
facility: Pfizer Investigational Site
state: Missouri
city: Philadelphia
country: United States
facility: Pfizer Investigational Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Pfizer Investigational Site
state: Pennsylvania
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: