MK-1942/Donepezil Interactions in Participants With Alzheimer's Disease (MK-1942-005)

Study Overview
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Brief Summary
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The study will investigate the effects on safety and pharmacokinetics (PK) of MK-1942 and donepezil when co-administered to participants with Alzheimer's Disease with mild-to-moderate cognitive impairment stably treated with donepezil. The objectives of this study include determining if the combination of MK-1942 with donepezil increases the incidence or severity of adverse events (AEs) previously reported for these agents, or results in unanticipated AEs in the patient population targeted for MK-1942 treatment. In addition, any changes in the PK parameters of either MK-1942 or donepezil as a result of co-administration will be assessed.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Pharmacokinetics of MK-1942 Administered to Alzheimer's Disease Patients Receiving Donepezil Treatment.

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: MK-1942
* Drug: Donepezil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) ≥18 and ≤35 kg/m^2, inclusive. Is in good health based on medical history, physical examination, vital sign measures and electrocardiogram performed prior to randomization. Have a negative urine drug screen prior to randomization. Have a history of cognitive and functional decline with gradual onset and slow progression for at least one year before screening that is either corroborated or well-documented. Be receiving donepezil (maximum dose: ≥10-mg, ≤15-mg) for symptomatic treatment of cognitive impairment associated with Alzheimer's dementia. The dose level must be stable for at least 1 month prior to screening. Have a reliable and competent trial partner/caregiver who has a close relationship with the subject, has face-to-face contact at least three days a week for a minimum of six waking hours a week, and is willing to accompany the participant, if desired, to trial visits. The trial partner/caregiver should understand the nature of the trial and adhere to trial requirements (e.g., dosing, visit schedules, and nature and number of evaluations). Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Male participants must refrain from donating sperm PLUS agree to study guidelines regarding abstinent and/or contraception during the intervention period and for at least an additional 90 days (a spermatogenesis cycle) after the last dose of study intervention: A female participant is eligible to participate if she is a women of nonchildbearing potential by study criteria. Exclusion Criteria: Is positive for hepatitis B surface antigen, hepatitis C antibodies or human immunodeficiency virus (HIV). Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia-Suicide Severity Rating Scale (CSSRS), or of harm to others in the opinion of the investigator. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4 weeks prior to the pretrial (screening) visit. Has a history of uncontrolled, clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. Candidates should not have a history of asthma, chronic obstructive pulmonary disease, urinary obstructions or gastrointestinal bleeding. Has a history of cancer (malignancy) exceptions for (1) Adequately treated non-melanomatous skin carcinoma or carcinoma in situ of the cervix or; (2) Other malignancies which have been successfully treated with appropriate follow up and therefore unlikely to recur for the duration of the study. Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex allergy), or has had an anaphylactic reaction or significant intolerability (i.e., systemic allergic reaction) to prescription or non-prescription drugs or food. Has evidence of a clinically relevant or unstable psychiatric disorder, based on The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, including schizophrenia or other psychotic disorder, bipolar disorder, or delirium at the time of the pre-study (screening) visit, or has a history of clinically significant psychiatric disorder of the last 5 years. Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the pre-study (screening) visit.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-1942<br>Dose Level 1: 8-mg MK-1942 twice daily (BID) x 7 days (7D), Day 1 to Day 7; Dose Level 2: 15-mg MK-1942 BID x 7D, Day 8 to Day 14; Dose Level 3: 30-mg MK-1942 BID x 7D, Day 15 to Day 21; Dose Level 4: ≤50-mg MK-1942 BID x 7D (Provisional Dose Level), Day 22 to Day 28 All participants to receive Donepezil once daily. | Drug: MK-1942<br>* MK-1942, oral, 1-mg, 5-mg and/or 10-mg capsules, BID dosing up to 28 days<br>Drug: Donepezil<br>* Donepezil, oral, 5-mg and/or 10-mg tablet (maximum dose 15 mg QD), QD dosing for up to 28 days<br>|
| Placebo Comparator: Placebo<br>Placebo to MK-1942 BID x 21 [28] D All participants to receive Donepezil once daily. | Drug: Donepezil<br>* Donepezil, oral, 5-mg and/or 10-mg tablet (maximum dose 15 mg QD), QD dosing for up to 28 days<br>Drug: Placebo<br>* Placebo to MK-1942, oral, capsule, all dosage levels, BID dosing for up to 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing an Adverse Event (AE) | The number of participants experiencing an AE will be presented. An adverse event (AE) is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to Day 42 (post-study visit) | 
| Number of Participants Discontinuing Study Medication due to an Adverse Event | The number of participants discontinuing study medication due to an AE will be presented. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. | Up to Day 28 (last day of treatment) | 
| Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG) Findings | The number of participants with clinically significant 12-lead ECGs will be presented. Twelve lead ECGs will be obtained during the study using an ECG machine that automatically measured ECG parameters of PR, QRS, QT, and QT corrected by Bazett's formula (QTcB), QT corrected by Fridericia's formula (QTcF) intervals. Twelve lead ECGs will be performed with the participant in a semi-recumbent position having rested in this position for at least 10 minutes beforehand. Measurements that deviate substantially from previous readings will be repeated immediately. | Baseline Up to Day 42 | 
| Number of Participants with Abnormal (Impaired) Results on Targeted Neurological Exams | The number of participants with abnormal (impaired) results on targeted neurological exams will be presented. The targeted neurological exam contains Modules 1, 2 and 5 of the general examination, focusing on arousal, cranial nerve function, and gait and will be administered several times throughout the treatment period starting on Day 1 up until Day 29. The number of participants with abnormal (impaired) results on targeted neurological exams will be reported. Each exam will be graded as Normal or Impaired with the abnormality described. | Baseline Up to Day 29 | 
| Number of Participants Who Reported Suicidal Ideation and/or Behavior on Study Based on Responses to the Columbia Suicide Severity Rating Scale (C-SSRS) | The number of participants with suicidality using the C-SSRS will be presented. The C-SSR will be used in this study only for the purpose of safety monitoring by measuring the incidence of different types of suicidality categories during treatment. C-SSRS assessment will be based upon a clinician's interpretation of the participant's responses to the C-SSRS questions, not by a numbered scale. Suicidal ideation and/or behaviors identified on the C-SSRS may not be considered an adverse event, based on the investigator's judgment. Participants who report at least one occurrence of suicidal behavior or suicidal ideation will be counted as having experienced suicidality. Suicidal behavior includes suicide attempt, aborted attempt, interrupted attempt, or preparatory behavior. Suicidal ideation include a wish to die or active suicidal thought with or without method, intent or plan. | From the first day of study treatment through study follow-up (Up to Day 42) | 
| Percent Change from Baseline in Heart Rate at Day 42 | Baseline will be Day 1. Change from Baseline will be calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Day 42 will be presented. | Baseline and Day 42 | 
| Percent Change from Baseline in Systolic Blood Pressure at Day 42 | Baseline will be Day 1. Change from Baseline will be calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Day 42 will be presented. | Baseline and Day 42 | 
| Percent Change from Baseline in Diastolic Blood Pressure at Day 42 | Baseline will be Day 1. Change from Baseline will be calculated by subtracting Baseline values from individual post-Baseline values. Mean change from Baseline up to Day 42 will be presented. | Baseline and Day 42 | 
| Number of Participants with Abnormal Clinical Chemistry Test Results Reported as Adverse Events | The number of participants with abnormal clinical chemistry results reported as adverse events will be presented. | Up to Day 42 | 
| Number of Participants with Abnormal Clinical Hematology Test Results Reported as Adverse Events | The number of participants with abnormal clinical hematology results reported as adverse events will be presented. | Up to Day 42 | 
| Number of Participants With Abnormal Urinalysis Results Reported as Adverse Events | The number of participants with abnormal urinalysis results reported as adverse events will be presented. | Up to Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Amount of Drug in the Plasma (Cmax) of MK-1942 | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| Amount of Drug in the Plasma from the Dose to Hour 12 (AUC0-12) of MK-1942 | AUC0-12 is a measure of the total amount of drug in the plasma from the dose to Hour 12. Samples for PK on Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| Amount of Drug in the Plasma from the Dose to Hour 24 (AUC0-24) of MK-1942 | AUC0-24 is a measure of the total amount of drug in the plasma from the dose to Hour 24. Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| Trough plasma concentration (Ctrough) of MK-1942 | Trough plasma concentration (Ctrough, measured concentration at the end of a dosing interval at steady state [taken directly before next administration]). Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. On Days 2, 4, 8, 9, 11, 15,16, 18, 22, 23, and 25 a sample will be taken before the AM dose (Ctrough). | Days 1, 7, 14, 21, and 28 | 
| Time to Reach the Maximum Concentration in the Plasma after the Drug Dose (Tmax) of MK-1942 | Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| Apparent Terminal t1/2 of MK-1942 | Apparent Terminal T1/2 is the time required for a given drug concentration in the plasma to decrease by 50%. Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| Apparent Clearance at Steady-state (CLss/F) of MK-1942 | The rate and extent of absorption of MK-1942 will be performed by assessment of the apparent plasma clearance following dosing (CLss/F). Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| The Apparent Volume of Distribution at Steady State (Vzss/F) of MK-1942 | Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state. Days 1, 7, 14, 21, and 28 are intense PK sampling days. Blood samples will be taken predose, and at 0.5, 1, 2, 3, 4, 6, and 12 hours post AM dose. On Day 28 (or last day of dosing), administer the AM dose only and sample predose, 0.5, 1, 2, 3, 4, 6, 12, 24, 48, and 72 hours post-dose. | Days 1, 7, 14, 21, and 28 | 
| Amount of Drug in the Plasma from the Dose to Hour 24 (AUC0-24) of Donepezil | AUC0-24 is a measure of the total amount of drug in the plasma from the dose to Hour 24. Days -1 and 28 are intense PK sampling days. Samples to be taken pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose. On Day -1 time points are relative to the morning donepezil dose. If Dose Level 4 is not given, Day 21 will be the second intense PK sampling day instead of Day 28. | Days -1 and 28 | 
| Maximum Amount of Drug in the Plasma (Cmax) of Donepezil | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Days -1 and 28; intense PK sampling days. Samples to be taken pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose. On Day -1 time points are relative to the morning donepezil dose. If Dose Level 4 is not given, Day 21 will be the second intense PK sampling day instead of Day 28. | Days -1 and 28 | 
| Trough plasma concentration (Ctrough) of Donepezil | Trough plasma concentration (Ctrough, measured concentration at the end of a dosing interval at steady state [taken directly before next administration]). Days -1 and 28 are intense PK sampling days. Samples to be taken pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose. On Day -1 time points are relative to the morning donepezil dose. If Dose Level 4 is not given, Day 21 will be the second intense PK sampling day instead of Day 28. | Days -1 and 28 | 
| Time to Reach the Maximum Concentration in the Plasma after the Drug Dose (Tmax) of Donepezil | Tmax is a measure of the time to reach the maximum concentration in the plasma after the drug dose. Days -1 and 28 are intense PK sampling days. Samples to be taken pre-dose and 0.5, 1, 2, 3, 4, 6, 12 and 24 hours post-dose. On Day -1 time points are relative to the morning donepezil dose. If Dose Level 4 is not given, Day 21 will be the second intense PK sampling day instead of Day 28. | Days -1 and 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Donepezil