Clinical trial NCT04308304: MK-1942/Donepezil Interactions in Participants With Alzheimer's Disease (MK-1942-005)
Official title: A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Pharmacokinetics of MK-1942 Administered to Alzheimer's Disease Patients Receiving Donepezil Treatment.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Alzheimer's Disease
Keywords: Alzheimer's Disease
Donepezil
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-03-16
Enrollment: 27
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study investigated 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 were to determine if the combination of MK-1942 with donepezil increases the incidence or severity of adverse events (AEs) previously reported for these agents alone, or results in unanticipated AEs in the patient population targeted for MK-1942 treatment. In addition, changes in the PK parameters of either MK-1942 or donepezil as a result of co-administration were assessed.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With ≥1 Adverse Event (AE)
timeFrame: Up to Day 42
measure: Number of Participants Discontinuing From Study Therapy Due to an Adverse Event (AE)
timeFrame: Up to Day 28
measure: Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG) Findings
timeFrame: Up to Day 28
measure: Number of Participants With Abnormal (Impaired) Results on Targeted Neurological Exams
timeFrame: Up to 29 days
measure: Number of Participants Who Reported Suicidal Ideation and/or Behavior on Study Based on Responses to the Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: Up to 42 days
measure: Change From Baseline in Heart Rate (HR)
timeFrame: Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose
measure: Change From Baseline in Systolic Blood Pressure (SBP)
timeFrame: Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose
measure: Mean Change From Baseline in Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose
measure: Number of Participants With Abnormal Clinical Chemistry Test Results Reported as Adverse Events
timeFrame: Up to 42 days
measure: Number of Participants With Abnormal Clinical Hematology Test Results Reported as Adverse Events
timeFrame: Up to 42 days
measure: Number of Participants With Abnormal Urinalysis Results Reported as Adverse Events
timeFrame: Up to 42 days
Secondary outcomes:
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Dosing to 12 Hours Postdose (AUC0-12) of MK-1942
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: AUC From Dosing to 24 Hours Postdose (AUC0-24) of MK-1942
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Maximum Plasma Concentration (Cmax) of MK-1942
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Trough Plasma Concentration (Ctrough) of MK-1942
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Time to Reach Maximum Plasma Concentration (Tmax) of MK-1942
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Apparent Terminal Plasma Half-Life (t½) of MK-1942
timeFrame: Day 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Apparent Clearance at Steady-state (CLss/F) of MK-1942
timeFrame: Day 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Apparent Volume of Distribution at Steady State (Vzss/F) of MK-1942
timeFrame: Day 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: AUC0-24 of Donepezil
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Cmax of Donepezil
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Ctrough of Donepezil
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
measure: Tmax of Donepezil
timeFrame: Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose
Other outcomes:
Locations:
city: Rogers
country: United States
facility: Woodland Research Northwest, LLC ( Site 0004)
state: Arkansas
city: Hallandale Beach
country: United States
facility: Velocity Clinical Research, Hallandale Beach ( Site 0002)
state: Florida
city: Decatur
country: United States
facility: iResearch Atlanta ( Site 0005)
state: Georgia
city: Salt Lake City
country: United States
facility: ICON ( Site 0003)
state: Utah
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: