Alzheimer's Disease, Mild Cognitive Impairment
Conditions
Brief summary
The main purpose of this study is to assess the ability of a repeated high-frequency site-based computerized cognitive assessment to evaluate the potential treatment effects of donepezil (MK-0000) compared with placebo among participants with mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD). The primary study hypothesis is that the average percentage of correct responses on one card learning (OCL) task will be ≥2 percentage points in participants receiving donepezil compared with participants receiving placebo.
Interventions
DRUGDonepezil
Donepezil 5 mg capsules for a total daily dose of up to 10 mg QD, orally, for Days 1-56.
DRUGPlacebo
Dose matched placebo capsule QD, orally for Days 1-56.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Single-blind (placebo run-in) followed by double-blind
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Has an Mini Mental State Examination (MMSE) score between 18 and 28 (inclusive) at Screening (Visit 1) and Baseline (Visit 2) * Has a diagnosis of mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD) * Has an Modified Hachinski Ischemia Scale (MHIS) score of ≤4 * Must have a reliable and competent study partner/informant who accompanies participant to study visits and participates in assessments * Be willing to provide a blood sample for Apolipoprotein E (APOE) genotyping * Does not have intellectual disability * Be able to speak, read, hear, and understand the language of the study staff and the Informed Consent Form (ICF) * Be able and willing to adhere to the study visit schedule * Have visual acuity, visual function, hearing, and gross and fine motor skills adequate to support study participation * Be capable of performing the Cogstate battery assessments, as demonstrated at the Baseline/Familiarization Visit (Visit 2) * A female participant is eligible to participate if she is a woman of nonchildbearing potential (WONCBP)
Exclusion criteria
* Is at imminent risk of self-harm * Has evidence of a clinically relevant neurological disorder other than AD at screening, including but not limited to: Parkinson's disease, frontotemporal dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, progressive supranuclear palsy, dementia with Lewy bodies, other types of dementia, neurosyphilis or that led to persistent cognitive deficits, or has a history of seizures or epilepsy within the last 5 years before screening * Has a known history of stroke or has a diagnosis of vascular dementia * Has history of multiple episodes of head trauma, or head trauma resulting in protracted loss of consciousness, or serious infectious disease affecting the brain, within the prior 3-5 years * Has evidence of a clinically relevant or unstable psychiatric disorder, based on Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), including schizophrenia or other psychotic disorder, bipolar disorder, major depression, or delirium * Has a recent or ongoing, uncontrolled, clinically significant medical condition within 2 months of the Screening visit * Has a history of cancer * Has a relative contraindication to donepezil including sick sinus syndrome, first, second, or third-degree heart block, bradycardia, active gastrointestinal (GI) bleeding, Zollinger-Ellison syndrome, uncontrolled peptic ulcer disease, or uncontrolled asthma * Has a history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food. Exception: Participants with selected allergies may be enrolled with Sponsor's approval * Is positive for Hepatitis B surface antigen (HBsAg), hepatitis C antibodies or human immunodeficiency virus (HIV) \[participants with a history of chronic hepatitis C virus with a documented cure and/or a positive serologic test for HCV with a negative HCV viral load may be included\] * Has clinically significant vitamin B12 or folate deficiency in the 6 months immediately before screening, or vitamin B12 or folate deficiency in addition to increased serum homocysteine and methylmalonic acid levels at screening * Has prior AD treatment * Has participated in another investigational study within 4 weeks * Has a known history of structural changes on screening magnetic resonance imaging (MRI) scan that are clinically important, including signs indicative of vascular dementia, large infarct, lacunes in critical areas, space-occupying lesions, or extensive white matter disease * Is unwilling to or not eligible to undergo a MRI scan (if a prior MRI scan is not available) * Is pregnant, is attempting to become pregnant, or is nursing children * Has a history of alcoholism or drug dependency/abuse within the last 5 years prior to the Screening visit * Consumes greater than 3 glasses of alcoholic beverages per day * Consumes excessive amounts, defined as greater than 6 servings of coffee, tea, cola, energy drinks, or other caffeinated beverages per day * Is a regular user of cannabis, any illicit drugs or has a history of drug abuse within approximately 5 years. A participant who is a recreational user of cannabis or other drugs within the past 2 years can be enrolled as long as recreational use does not meet the definition of drug abuse and participant agrees to refrain from substance use for duration of study participation * Participants must have a negative urine drug screen (UDS) prior to randomization * Had major surgery within 3 months prior to the Screening visit that would interfere in the participant's ability to fully participate in the study * Has undergone neuropsychological testing (including the MMSE) or cognitive remediation in the past 4 weeks * Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Averaged Correct Response Rate on the One Card Learning Task to Week 8 | Baseline, Up to Week 8 | One Card Learning (OCL) uses a pattern separation paradigm to assess visual memory. The change from baseline of correct responses on the OCL task up to Week 8 is compared in participants receiving donepezil with participants receiving placebo. Change from baseline was the averaged correct response rate at Week 8 minus the correct response rate at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Standard Deviation for Averaged Correct Response Rate on the OCL Task (Arcsine Square Root Transformed) to Week 8 | Baseline, Up to Week 8 | OCL uses a pattern separation paradigm to assess visual memory. Change in standard deviation from baseline for correct response rate on the OCL task up to Week 8 is compared in participants with mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD) receiving donepezil with participants receiving placebo. Change from baseline was the standard deviation for correct response rate at Week 8 minus the standard deviation for correct response rate at baseline. Standard deviations are reported in arcsine square root (sqrt) transformed correct response (CR) rate. |
| Change From Baseline in Averaged Correct Response Rate on the OCL Task to Week 8 in Participants Receiving Donepezil | Baseline, Up to Week 8 | OCL uses a pattern separation paradigm to assess visual memory. The change from baseline of correct responses on the OCL task up to Week 8 in participants receiving donepezil is presented. Change from baseline was the averaged correct response rate at Week 8 minus the correct response rate at baseline. Per protocol, the placebo group was not included in this analysis. |
Countries
Australia, United States
Participant flow
Recruitment details
Treatment-naïve male and female participants with mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD) between the ages of 55 and 85 years (inclusive) will be enrolled in this trial.
Participants by arm
| Arm | Count |
|---|---|
| Donepezil Participants receive donepezil in doses up to 10 mg once daily (QD), orally in a scheduled titration for Days 1-56. The total treatment duration is 56 days. | 29 |
| Placebo Participants receive placebo QD, orally for Days 1-56. The total treatment duration is 56 Days. | 15 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Donepezil |
|---|---|---|---|
| Age, Continuous | 68.4 Years STANDARD_DEVIATION 7.7 | 68.4 Years STANDARD_DEVIATION 7.5 | 68.3 Years STANDARD_DEVIATION 7.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 19 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 25 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 15 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 28 Participants | 19 Participants |
| Sex: Female, Male Female | 12 Participants | 29 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 15 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 15 |
| other Total, other adverse events | 16 / 29 | 4 / 15 |
| serious Total, serious adverse events | 1 / 29 | 0 / 15 |
Outcome results
Primary
Change From Baseline in Averaged Correct Response Rate on the One Card Learning Task to Week 8
One Card Learning (OCL) uses a pattern separation paradigm to assess visual memory. The change from baseline of correct responses on the OCL task up to Week 8 is compared in participants receiving donepezil with participants receiving placebo. Change from baseline was the averaged correct response rate at Week 8 minus the correct response rate at baseline.
Time frame: Baseline, Up to Week 8
Population: All participants who received at least one dose of study medication and yielded at least one measurement for that outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change From Baseline in Averaged Correct Response Rate on the One Card Learning Task to Week 8 | 0.055 Proportion of correct response | Standard Deviation 0.078 |
| Placebo | Change From Baseline in Averaged Correct Response Rate on the One Card Learning Task to Week 8 | 0.034 Proportion of correct response | Standard Deviation 0.091 |
Comparison: There was a threshold of ≥2 percentage points. A posterior probability value \>55% was required to satisfy the primary hypothesis.
Secondary
Change From Baseline in Averaged Correct Response Rate on the OCL Task to Week 8 in Participants Receiving Donepezil
OCL uses a pattern separation paradigm to assess visual memory. The change from baseline of correct responses on the OCL task up to Week 8 in participants receiving donepezil is presented. Change from baseline was the averaged correct response rate at Week 8 minus the correct response rate at baseline. Per protocol, the placebo group was not included in this analysis.
Time frame: Baseline, Up to Week 8
Population: All participants who received at least one dose of donepezil and yielded at least one measurement for that outcome measure. Per protocol, the placebo group was not included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Donepezil | Change From Baseline in Averaged Correct Response Rate on the OCL Task to Week 8 in Participants Receiving Donepezil | 0.055 Proportion of correct response | Standard Deviation 0.078 |
Secondary
Change From Baseline in Standard Deviation for Averaged Correct Response Rate on the OCL Task (Arcsine Square Root Transformed) to Week 8
OCL uses a pattern separation paradigm to assess visual memory. Change in standard deviation from baseline for correct response rate on the OCL task up to Week 8 is compared in participants with mild cognitive impairment (MCI) or mild Alzheimer's Disease (AD) receiving donepezil with participants receiving placebo. Change from baseline was the standard deviation for correct response rate at Week 8 minus the standard deviation for correct response rate at baseline. Standard deviations are reported in arcsine square root (sqrt) transformed correct response (CR) rate.
Time frame: Baseline, Up to Week 8
Population: All participants who received at least one dose of study medication and yielded at least one measurement for that outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Donepezil | Change From Baseline in Standard Deviation for Averaged Correct Response Rate on the OCL Task (Arcsine Square Root Transformed) to Week 8 | MCI | 0.078 Arcsine sqrt transformed proportion CR |
| Donepezil | Change From Baseline in Standard Deviation for Averaged Correct Response Rate on the OCL Task (Arcsine Square Root Transformed) to Week 8 | Mild AD | 0.080 Arcsine sqrt transformed proportion CR |
| Placebo | Change From Baseline in Standard Deviation for Averaged Correct Response Rate on the OCL Task (Arcsine Square Root Transformed) to Week 8 | MCI | 0.074 Arcsine sqrt transformed proportion CR |
| Placebo | Change From Baseline in Standard Deviation for Averaged Correct Response Rate on the OCL Task (Arcsine Square Root Transformed) to Week 8 | Mild AD | 0.097 Arcsine sqrt transformed proportion CR |
Comparison: There was a threshold of ≤ 0.1 for this standard deviation change. A posterior probability value \>70% was required to satisfy this secondary hypothesis.