Detecting an Early Response to Donepezil With Measures of Visual Attention

NCT03073876 | Completed Phase 4 Results FDA Drug

• 1 other identifier: WUH 05030
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

Acetylcholinesterase inhibitors (AChE-I) comprise a class of drugs used to treat Alzheimer's disease (AD), but controversy about their usefulness remains. Modest response rates of treated versus placebo groups, small effect sizes with respect to efficacy, drug costs, and clinical relevance of the effects are problematic. Standard efficacy measures of efficacy are not sufficiently sensitive, and trying to assess cognitive change after 4-6 months of therapy confounds the drug effect and the natural progression of the disease. Surprisingly, attention has never been included in the assessment of AChE-I drugs. The rationale for using attentional measures are that (1) Attentional deficits are recognized as a critical cognitive change in the earliest phases of AD; (2) Attentional function is directly mediated by the cholinergic system, and responds rapidly to cholinergic augmentation, particularly on tasks that tax available attentional capacity are dose dependent; and (3) Acetylcholine is depleted in AD. However, the link between attention and cholinergic depletion in AD has not been fully explored, especially with regard to response to cholinergic treatment. The study tests if attentional performance can be a more sensitive marker of response. In a longitudinal study we measure attentional, as well as cognitive and behavioral performance in de novo AD patients undergoing donepezil treatment. The investigators develop visual attentional measures and contrast them to global and domain-specific cognitive scores on three occasions (T1) baseline pre-treatment, (T2) after approximately 6 weeks, and (T3) after 6 months treatment. The T1-to-T2 arm is a double-blind placebo control period, after which members of the placebo group start open-label treatment. The assessment at 6 months allows us to determine whether the changes seen earlier at T2 can predict patients who respond, or determine which measures best predict response. We hypothesize that attention measures are more sensitive than standard global measures or other cognitive domains and that the change of attentional function can be detected after only after approximately 6 weeks treatment. Knowledge from this project will facilitate and inform our decisions about individual patients undergoing pharmacological treatment.

Conditions

Alzheimer Disease

Keywords

Alzheimer Disease; Attention; Donepezil hydrochloride

Outcome Measures

Primary Outcomes (10)

• Change in Foreperiod Effect Task - Processing Speed

  Computerized attention task measures response time to detect a target presented at varied interstimulus intervals (350ms and 500ms). Participants respond to centrally presented asterisk on computer screen. Time elapsed from prior stimulus (= interstimulus interval) indicates when prior stimulus was presented. xx

  Baseline to 6 weeks

• Change in Covert Orienting Task

  Computerized attention task measuring response time to detect a target after a spatial orienting cues of either valid (cue on same side in space as target) or Invalid Cue (cue on opposite side of space as target). Longer response time (msec) indicates worse performance.

  Baseline to 6 weeks

• Change in Attentional Blink Task Baseline to 6 Weeks - Stimulus Onset Asynchrony (SOA) 266ms

  Computerized attention task measures the accuracy of reporting stimuli presented at time intervals, varying load. Faster reaction time and accuracy represents better performance.

  Baseline to 6 weeks

• Change in Attentional Blink Task Baseline to 6 Weeks - SOA 399ms

  Computerized attention task measures the accuracy of reporting stimuli presented within 399 ms interval. Higher accuracy represents better performance.

  Baseline to 6 weeks

• Change of ADAS-COG From Baseline to 6 Months

  Change of Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog); primary outcome measure of drug efficacy. Minimum value = 0, maximum value = 70. Higher scores represent worse cognitive functioning.

  Baseline to 6 months

• Foreperiod Effect Task at 6 Weeks - Fatigue (Blocks 1 & 2)

  Computerized attention task measures reaction time (RT) to detect a target presented at varied interstimulus interval comparing Block 1 (presented at beginning of session) and Block 2 (presented at end of session)

  6 weeks

• Change in Foreperiod Effect Task - Variability (350ms & 500ms)

  Computerized attention task measures the variability (SD) in response time to detect a target presented at varied interstimulus intervals (350ms and 500ms)

  Baseline to 6 weeks

• Covert Orienting at 6 Weeks - Fatigue Across Blocks

  Computerized attention task measures response time to detect a target across blocks of stimuli. Data shown for performance at Block1 and Block5

  6 weeks

• Neuropsychiatric Inventory Score

  Neuropsychiatric Inventory (NPI) is a scale that measures neuropsychiatric symptoms. We reported a score that captures the frequency of each symptom multiplied by the severity rating score. Scores range from 0 - 144; Higher scores represent worse outcomes.

  6 months

• Instrumental Activities of Daily Living

  Scale of instrumental activities of daily living (IADLs), adapted from Lawton Brody scale. Caregiver rates 8 functional items from 0-2 severity. Total score is the sum of ratings for each item. Total score ranges from 0 (minimum) to 16 (maximum) with higher scores representing worse functional outcomes.

  6 months

Secondary Outcomes (10)

• Change in Dementia Rating Scale

  Baseline to 6 weeks

• Mini Mental Status Examination

  Baseline to 6 weeks

• Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)

  Baseline to 6 weeks

• Change in Digit Span Forward

  Baseline to 6 weeks

• Change in Hopkins Verbal Learning Test- Revised - Recall

  Baseline to 6 weeks

Study Arms (2)

Drug

EXPERIMENTAL

Participants in the Drug group received oral 5mg of Donepezil Hydrochloride daily for 6 months. The Drug group was assessed at baseline, after approximately 6 weeks and after 6 months of treatment. The baseline to 6 weeks phase was part of the double-blind, placebo controlled portion of the trial.

Drug: Donepezil Hydrochloride

Placebo

PLACEBO COMPARATOR

Participants in the placebo group first received oral administration of a placebo pill for approximately 6 weeks. After that initial interval, the study was unblinded and participants in the placebo group then received 5mg of donepezil hydrochloride treatment for 6 months. The Placebo group was evaluated at baseline, after 6 weeks of placebo, after 6 weeks of donepezil hydrochloride drug treatment, and 6 months of donepezil hydrochloride treatment.

Drug: Donepezil Hydrochloride; Drug: Placebo

Interventions

Donepezil Hydrochloride DRUG

5mg of Donepezil Hydrochloride by mouth

Also known as: Aricept

Drug; Placebo

Placebo DRUG

prepared placebo looking exactly the same as drug. Participants took placebo by mouth for approximately 6 weeks, and after unblinding, they took donepezil hydrochloride for 6 months.

Also known as: Placebo pill

Placebo

Eligibility Criteria

• Age: 50 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Clinical diagnosis of Alzheimer's Disease
• Mini Mental State Examination score \>15 / 30
• Can swallow pills

You may not qualify if:

• No other dementia due to Parkinson's disease, Lewy Body dementia, Normal Pressure Hydrocephalus, Fronto-temporal dementia, or prominent cerebral vascular accident
• No prior or concurrent use of cholinesterase inhibitors
• No prior or concurrent use of memantine hydrochloride
• No other concurrent anticholinergic treatments

Sponsors & Collaborators

• NYU Langone Health: lead
• Queens College, The City University of New York: collaborator

Study Sites (1)

Winthrop-University Hospital

Mineola, New York, 11501, United States

Location

Related Publications (1)

• Vila-Castelar C, Ly JJ, Kaplan L, Van Dyk K, Berger JT, Macina LO, Stewart JL, Foldi NS. Attention Measures of Accuracy, Variability, and Fatigue Detect Early Response to Donepezil in Alzheimer's Disease: A Randomized, Double-blind, Placebo-Controlled Pilot Trial. Arch Clin Neuropsychol. 2019 May 1;34(3):277-289. doi: 10.1093/arclin/acy032.

  PMID: 29635383 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Donepezil

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Nancy S. Foldi, PhD; Professor
• Organization: City University of New York - Queens College and The Graduate Center

nfoldi@qc.cuny.edu

718.997.3253

Study Officials

• Nancy Foldi, PhD

  NYU Winthrop Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Study drug was prepared by research pharmacist who was the only person privy to group assignment. Drug and Placebo pills looked identical.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Double Blind Placebo Control

Study Record Dates

• First Submitted: February 15, 2017
• First Posted: March 8, 2017
• Study Start: December 1, 2005
• Primary Completion: July 31, 2009
• Study Completion: January 13, 2021
• Last Updated: February 4, 2021
• Results First Posted: November 5, 2019

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)