A Phase 4 interventional study of Donepezil Hydrochloride and Placebo in Alzheimer Disease, sponsored by NYU Langone Health. Completed at 1 site in United States. Open to participants aged 50 Years to 95 Years. Per ClinicalTrials.gov, last updated 2021-02-04.
Sponsored by NYU Langone Health · Phase 4, Interventional, and Other
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.
Acetylcholinesterase inhibitors (AChE-I) comprise the major class of drugs used to treat Alzheimer's disease (AD). Despite widespread use, there is controversy about the usefulness of these medications. Concerns have been modest response rates of treated versus placebo groups, relatively small effect sizes with respect to efficacy, drug costs, and clinical relevance of the effects. One problem is that measures of efficacy used may not be sufficiently sensitive to detect a true drug effect. Another problem is that changes noted after 4-6 months of therapy confound the drug effect and the natural progression of the disease. Lastly, patient heterogeneity may contribute to the wide range of degree of response, further decreasing overall effect sizes. The investigators address three important issues to improve the clinical usefulness of cholinergic therapy. First, outcome measures are needed that are sensitive to the effects of cholinergic treatment. Second, outcome measures should be sensitive to the drug effect early in the course of treatment before a measurable decline of the disease progression occurs. Third, improved treatment would be attained if specific patient characteristics or performance measures were identified, which contributed to, or even predicted who will likely benefit. The premise of the current proposal is that measures of higher-order attention - currently omitted from standard assessments of treatment outcome - can provide insight into early efficacy of cholinergic treatment. The investigators are conducting a preliminary study that supports our hypotheses by testing the value of such attentional measures. The rationale for using attentional measures is as follows: (1) Attentional deficits are recognized as a critical cognitive change in the earliest phases of AD; (2) Attentional function, particularly tasks that tax available attentional capacity, is mediated by the cholinergic system; and (3) Acetylcholine is depleted in AD. However, the link between attention and cholinergic depletion in AD has not been fully explored, particularly with regard to response to cholinergic treatment. Surprisingly, attentional measures have not been included in the evaluation of AChE-I in the treatment of AD. The investigators propose that attentional performance could serve as a highly sensitive outcome measure and a marker of response.
Study aims and hypotheses
2b. To examine whether cholinergic treatment changes the relationships among measures of attention and measures of other cognitive function. The prediction is that that the relationships among attention and cognitive domain measures will change with treatment.
3b. To determine whether an attentional change seen in patients early in the treatment course predicts drug response. It is hypothesized that change in attention measured between baseline and 7±1 weeks will predict overall improvement in those patients who show positive treatment response at six months.
Knowledge gained from this project will facilitate and inform our decisions about individual patients undergoing pharmacological treatment. The application of these goals can apply to current AChE-I treatment as well as other treatments, such as those now involving combined cholinergic and glutaminergic agents.
BACKGROUND AND SIGNIFICANCE Attention and Alzheimer's disease (AD): The vulnerability of higher-order attention tasks in AD occurs in tasks such as selective attention, and covert orienting. Attentional deficits are documented in patients with prodromal AD who later develop the disease, suggesting potential sensitivity of attention to disease onset. Mechanisms of attention are mediated via anterior executive control (required in conjunctive search and inhibitory control) and via posterior disengagement. The deficits in AD may be explained by regional frontal or posterior dysfunction, or by a disconnection between the frontal and posterior attentional networks that disrupt the feedback system. Acetylcholine and attention: A primary modulator of attention is acetylcholine (ACh). Decreased ACh impairs attentional function in animals and humans including vigilance in rat, covert orienting in primate and AD, and complex attention in human airplane pilots. ACh functions in a dose related manner, with increased task load of higher background noise correlating with increased ACh release. Cholinergic antagonists (e.g., scopolamine) slow reaction time (RT) and increase omission errors on visual search, and increase omission and commission errors on signal detection. Higher scopolamine doses slow RT in covert orienting in primates involving inferior parietal regions.
AD, attention and cholinesterase inhibitors: The relationship between attention and acetylcholine has not been well demonstrated in the assessment of AChE-I. Efficacy studies of donepezil, galantamine or rivastigmine show modest effect sizes ranging from 1.8-4.1 points on the 70 point Alzheimer Disease Assessment Scale - Cognitive section (ADAS-Cog) scale. These small effect sizes may partially be a function of using this outcome measure, which obscures the sensitivity to attention and memory with a global score. Targeted cognitive domains may be better response indicators. In a post-mortem analysis of AD patients, regions of low cholinergic activity correlated to memory and attention.
Moreover, after 12 weeks of galantamine treatment, AD patients who reached therapeutic dose showed faster RT, better choice reaction time and in memory, recognition of faces. Also, on functional imaging, early response to AChE-I appears to affect regions that mediate directed attention.
In summary, if attentional function is intrinsically linked to the level of cholinergic activity, it should used be an outcome measure of AChE-I treatment in AD to improve treatment sensitivity.
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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
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
5mg of Donepezil Hydrochloride by mouth
Also known as: Aricept
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
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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 6 months
Change in Dementia Rating Scale
Dementia Rating Scale (DRS) change score (performance at 6 weeks minus performance at baseline). This is a global measure of cognitive function. Scores range from 0 - 144; higher scores represent better cognitive functioning.
Time frame: Baseline to 6 weeks
Mini Mental Status Examination
Mini Mental Status Examination (MMSE) is a commonly used cognitive screener. Scores range from 0-30; higher scores mean better cognitive functioning.
Time frame: Baseline to 6 weeks
Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)
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.
Time frame: Baseline to 6 weeks
Change in Digit Span Forward
This measure represents the change in the variable longest Digit Span Forward (LDSF) from baseline to 6 weeks. Score represents the maximum length of number repeated in the forward condition. Score ranges from 0 to 9. Higher scores represent better outcome.
Time frame: Baseline to 6 weeks
Change in Hopkins Verbal Learning Test- Revised - Recall
Hopkins Verbal Learning Test- Revised (HVLT-R) (Brandt, 1991) is a list-learning task. Recall variable is computed by adding the number of words repeated in each of the three learning trials. Raw scores of each measure were used in the analyses. Total Recall ranges from 0-30. Higher scores represent better outcome.
Time frame: Baseline to 6 weeks
Change in Language Function Assessed With the Letter Fluency Test
Letter fluency (FAS) (Benton, 1967) was selected to assess speed of verbal generativity. Participants are required to generate words that start with a particular letter (excluding n; three trials (words starting with 'F', 'A', 'S' each for 1 minute minutes) are administered. Higher performance is better with range from 0 to unlimited.
Time frame: Baseline to 6 weeks
Change on Trail Making Test - Condition
The Delis-Kaplan Executive Function (D-KEFS Trail) Subtest 4: Number-Letter Switching Scaled Score was used to assess executive functioning. Scaled scores range from 1-19. Higher scores represent less impairment (below 8 = low; 8-12 = average; \> 12 = above average). Scores represent seconds to complete the task. Faster performance is better.
Time frame: Baseline to 6 weeks
Change in Visual Form Discrimination
Measure of visuospatial function requiring matching designs from the Benton Visual Form Discrimination test. Total scores is calculated by adding the number of items correct. Total score ranges from 0-32, higher score is better.
Time frame: Baseline to 6 weeks
Change in Category Fluency Test
Measure of language / semantic function. This task requires participants to generate words belonging to specific categories within 1 minute. There are three trials. Total scores is computed by obtaining the mean number of words generated across the three trials (fruits/vegetables/animals). Higher score represents better outcome.
Time frame: Baseline to 6 weeks
Change in Digit Span Backwards
This measure represents the change in the variable longest Digit Span Backwards (LDSB) from baseline to 6 weeks. Score represents the maximum length of number repeated in the backward condition. Score ranges from 0 to 8. Higher scores represent better outcome.
Time frame: Baseline to 6 weeks
Of 25 individuals enrolled, 2 participants allocated to the placebo group discontinued: one complained of side-effects (n = 1); one moved from NY area (n = 1). Total N= 23.
| Milestone | Drug | Placebo |
|---|---|---|
| Started | 12 | 11 |
| Completed | 12 | 11 |
| Not completed | 0 | 0 |
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
| response time in msec | Drug | Placebo |
|---|---|---|
| 350 | 42 ± 176.3 | 13 ± 9 |
| 500 | 33 ± 176.7 | 13 ± 9 |
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.
| milliseconds | Drug | Placebo |
|---|---|---|
| Change in Covert Orienting Task | 496.5 (414.6 to 578.4) | 452.5 (401.7 to 503.3) |
Computerized attention task measures the accuracy of reporting stimuli presented at time intervals, varying load. Faster reaction time and accuracy represents better performance.
| milliseconds | Drug Treatment |
|---|---|
| Change in Attentional Blink Task Baseline to 6 Weeks - Stimulus Onset Asynchrony (SOA) 266ms | -.06 ± .32 |
Computerized attention task measures the accuracy of reporting stimuli presented within 399 ms interval. Higher accuracy represents better performance.
| milliseconds | Drug Treatment |
|---|---|
| Change in Attentional Blink Task Baseline to 6 Weeks - SOA 399ms | -.022 ± .33 |
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.
| units on a scale | Drug Treatment |
|---|---|
| Change of ADAS-COG From Baseline to 6 Months | -.29 ± 4.70 |
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)
| msec | Drug | Placebo |
|---|---|---|
| Block 1 | 400 ± 87.4 | 331 ± 200.7 |
| Block 2 | 395 ± 85.3 | 385 ± 254.2 |
Computerized attention task measures the variability (SD) in response time to detect a target presented at varied interstimulus intervals (350ms and 500ms)
| msec | Drug | Placebo |
|---|---|---|
| 350ms | -26.7 ± 42.97 | -4.5 ± 34.44 |
| 500ms | 28.46 ± 110.63 | 8.37 ± 39.73 |
Computerized attention task measures response time to detect a target across blocks of stimuli. Data shown for performance at Block1 and Block5
| msec | Drug | Placebo |
|---|---|---|
| Block 1 | 415 ± 145.1 | 402 ± 95.1 |
| Block 5 | 451 ± 134.2 | 487 ± 144.3 |
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.
| score on a scale | Drug Treatment |
|---|---|
| Neuropsychiatric Inventory Score | 14.09 ± 14.26 |
Dementia Rating Scale (DRS) change score (performance at 6 weeks minus performance at baseline). This is a global measure of cognitive function. Scores range from 0 - 144; higher scores represent better cognitive functioning.
| units on a scale | Drug | Placebo |
|---|---|---|
| Change in Dementia Rating Scale | 1.67 ± 6.91 | -.54 ± 6.27 |
Mini Mental Status Examination (MMSE) is a commonly used cognitive screener. Scores range from 0-30; higher scores mean better cognitive functioning.
| units on a scale | Drug | Placebo |
|---|---|---|
| Mini Mental Status Examination | -.17 ± 2.44 | -1.09 ± 2.02 |
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.
| score on a scale | Drug | Placebo |
|---|---|---|
| Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) | -1.90 ± 4.92 | .99 ± 2.25 |
This measure represents the change in the variable longest Digit Span Forward (LDSF) from baseline to 6 weeks. Score represents the maximum length of number repeated in the forward condition. Score ranges from 0 to 9. Higher scores represent better outcome.
| units on a scale | Drug | Placebo |
|---|---|---|
| Change in Digit Span Forward | -0.6 ± 1 | -0.4 ± 0.75 |
Hopkins Verbal Learning Test- Revised (HVLT-R) (Brandt, 1991) is a list-learning task. Recall variable is computed by adding the number of words repeated in each of the three learning trials. Raw scores of each measure were used in the analyses. Total Recall ranges from 0-30. Higher scores represent better outcome.
| score on a scale | Drug | Placebo |
|---|---|---|
| Change in Hopkins Verbal Learning Test- Revised - Recall | .17 ± 1.8 | .40 ± 4.79 |
Letter fluency (FAS) (Benton, 1967) was selected to assess speed of verbal generativity. Participants are required to generate words that start with a particular letter (excluding n; three trials (words starting with 'F', 'A', 'S' each for 1 minute minutes) are administered. Higher performance is better with range from 0 to unlimited.
| score on a scale | Drug | Placebo |
|---|---|---|
| Change in Language Function Assessed With the Letter Fluency Test | .003 ± 1.51 | .17 ± 2.52 |
The Delis-Kaplan Executive Function (D-KEFS Trail) Subtest 4: Number-Letter Switching Scaled Score was used to assess executive functioning. Scaled scores range from 1-19. Higher scores represent less impairment (below 8 = low; 8-12 = average; \> 12 = above average). Scores represent seconds to complete the task. Faster performance is better.
| units on a scale | Drug | Placebo |
|---|---|---|
| Change on Trail Making Test - Condition | -1.67 ± 39.45 | -2.3 ± 41.46 |
Measure of visuospatial function requiring matching designs from the Benton Visual Form Discrimination test. Total scores is calculated by adding the number of items correct. Total score ranges from 0-32, higher score is better.
| score on a scale | Drug | Placebo |
|---|---|---|
| Change in Visual Form Discrimination | .92 ± 3.09 | .33 ± 3.94 |
Measure of language / semantic function. This task requires participants to generate words belonging to specific categories within 1 minute. There are three trials. Total scores is computed by obtaining the mean number of words generated across the three trials (fruits/vegetables/animals). Higher score represents better outcome.
| score on a scale | Drug | Placebo |
|---|---|---|
| Change in Category Fluency Test | .17 ± 5.56 | -2.8 ± 4.02 |
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.
| units on a scale | Drug Treatment |
|---|---|
| Instrumental Activities of Daily Living | 6.54 ± 4.23 |
This measure represents the change in the variable longest Digit Span Backwards (LDSB) from baseline to 6 weeks. Score represents the maximum length of number repeated in the backward condition. Score ranges from 0 to 8. Higher scores represent better outcome.
| units on a scale | Drug | Placebo |
|---|---|---|
| Change in Digit Span Backwards | 0.5 ± 0.8 | 0.1 ± 0.75 |
Collected over 6 Months. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Drug | 0/12 (0%) | 0/12 (0%) | 0/12 (0%) |
| Placebo | 0/11 (0%) | 0/11 (0%) | 0/11 (0%) |
| Age, Categorical(Participants) | Drug | Placebo | Total |
|---|---|---|---|
| <=18 years | 0 | 0 | 0 |
| Between 18 and 65 years | 12 | 11 | 23 |
| >=65 years | 0 | 0 | 0 |
| Sex: Female, Male(Participants) | Drug | Placebo | Total |
|---|---|---|---|
| Female | 8 | 7 | 15 |
| Male | 4 | 4 | 8 |
| Race/Ethnicity, Customized(Participants) | Drug | Placebo | Total |
|---|---|---|---|
| Caucasian | 12 | 11 | 23 |
| Region of Enrollment(participants) | Drug | Placebo | Total |
|---|---|---|---|
| United States | 12 | 11 | 23 |
| Mini Mental State Examination (MMSE)(units on a scale) | Drug | Placebo | Total |
|---|---|---|---|
| Mean | 24.3 ± 3.5 | 25.4 ± 1.7 | 24.9 ± 2.6 |
| Dementia Rating Scale (DRS)(units on a scale) | Drug | Placebo | Total |
|---|---|---|---|
| Mean | 119.7 ± 10.4 | 127.1 ± 7.2 | 123.4 ± 8.8 |
| Clinical Dementia Rating Scale (CDRS)(units on a scale) | Drug | Placebo | Total |
|---|---|---|---|
| Mean | 1 ± .4 | 3 ± .4 | 1.9 ± .41 |
| Geriatric Depression Scale (GDS)(units on a scale) | Drug | Placebo | Total |
|---|---|---|---|
| Mean | 6.7 ± 6.2 | 6.5 ± 4.5 | 6.6 ± 5.4 |
12 further baseline measures are reported on the registry.
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