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

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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04308304

Acronym

DDI

Enrollment

Registered

2020-03-16

Start date

2021-02-16

Completion date

2022-05-18

Last updated

2024-08-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer's Disease

Keywords

Alzheimer's Disease, Donepezil

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.

Interventions

DRUGMK-1942

MK-1942 1 mg, 5 mg, and/or 10 mg capsules taken twice daily (BID) by mouth.

DRUGDonepezil

Donepezil 5 mg and/or 10 mg tablets taken once daily (QD) by mouth.

DRUGPlacebo

Placebo capsule matched to MK-1942 taken BID by mouth.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

50 Years to 85 Years

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With ≥1 Adverse Event (AE)	Up to Day 42	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Number of Participants Discontinuing From Study Therapy Due to an Adverse Event (AE)	Up to Day 28	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
Number of Participants With Clinically Significant Abnormalities in 12-Lead Electrocardiogram (ECG) Findings	Up to Day 28	The number of participants with clinically significant 12-lead ECGs is presented. Recordings were made throughout the study, with the participant in a semi-recumbent position having rested in this position for at least 10 minutes beforehand.
Number of Participants With Abnormal (Impaired) Results on Targeted Neurological Exams	Up to 29 days	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.
Number of Participants Who Reported Suicidal Ideation and/or Behavior on Study Based on Responses to the Columbia Suicide Severity Rating Scale (C-SSRS)	Up to 42 days	The number of participants with suicidality using the C-SSRS is 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.
Change From Baseline in Heart Rate (HR)	Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose	The mean change from baseline in HR is presented. Change in HR was determined the first day of treatment with a new dose of MK-1942. A negative value indicates a decrease in HR relative to baseline, and a positive value indicates an increase.
Change From Baseline in Systolic Blood Pressure (SBP)	Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose	The mean change from baseline in SBP is presented. Change in SBP was determined the first day of treatment with a new dose of MK-1942. Negative values represent a decrease in SBP relative to baseline, and positive values represent an increase.
Mean Change From Baseline in Diastolic Blood Pressure (DBP)	Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose	The mean change from baseline in DBP is presented. Change in DBP was determined the first day of treatment with a new dose of MK-1942. Negative values represent a decrease in DBP relative to baseline, and positive values represent an increase.
Number of Participants With Abnormal Clinical Chemistry Test Results Reported as Adverse Events	Up to 42 days	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with abnormal chemistry-related AEs is reported.
Number of Participants With Abnormal Clinical Hematology Test Results Reported as Adverse Events	Up to 42 days	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with abnormal hematology-related AEs is reported.
Number of Participants With Abnormal Urinalysis Results Reported as Adverse Events	Up to 42 days	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with an abnormal urinalysis results AE is reported.

Secondary

Measure	Time frame	Description
Tmax of Donepezil	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Tmax is reported for donepezil 10 mg alone (Day -1) or with MK-1942 50 mg (Day 28).
Ctrough of Donepezil	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Ctrough is reported for donepezil 10 mg alone (Day -1) or with MK-1942 50 mg (Day 28).
Area Under the Plasma Concentration-Time Curve (AUC) From Dosing to 12 Hours Postdose (AUC0-12) of MK-1942	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	AUC0-12 is reported for the first day of treatment of each MK-1942 dose.
AUC From Dosing to 24 Hours Postdose (AUC0-24) of MK-1942	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	AUC0-24 is reported for the first day of treatment of each MK-1942 dose. Due to twice daily dosing, AUC0-24 was calculated as AUC0-24 = AUC0-12 x 2.
Maximum Plasma Concentration (Cmax) of MK-1942	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Cmax is reported for the first day of treatment of each MK-1942 dose.
Trough Plasma Concentration (Ctrough) of MK-1942	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Ctrough is reported for the first day of treatment of each MK-1942 dose. Data from healthy elderly participants used for statistical analyses are unpublished findings from study MK-1942-004.
Time to Reach Maximum Plasma Concentration (Tmax) of MK-1942	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Tmax is reported for the first day of treatment of each MK-1942 dose.
Apparent Terminal Plasma Half-Life (t½) of MK-1942	Day 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	t½ is reported for MK-1942 50 mg.
Apparent Clearance at Steady-state (CLss/F) of MK-1942	Day 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	CLss/F is reported for MK-1942 50 mg.
Apparent Volume of Distribution at Steady State (Vzss/F) of MK-1942	Day 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Vzss/F is reported for MK-1942 50 mg.
AUC0-24 of Donepezil	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	AUC0-24 is reported for donepezil 10 mg alone (Day -1) or with MK-1942 50 mg (Day 28). Due to twice daily dosing, AUC0-24 was calculated as AUC0-12 x 2.
Cmax of Donepezil	Days 1, 7, 14, and 21 (morning dose only): predose and 0.5, 1, 2, 3, 4, 6, and 12 hours postdose	Cmax is reported for donepezil 10 mg alone (Day -1) or with MK-1942 50 mg (Day 28).

Countries

United States

Participant flow

Recruitment details

Male and female adult (≥50 to ≤85 years of age) participants with Alzheimer's disease (AD) and mild-to-moderate cognitive impairment were enrolled at 4 study centers in the United States.

Participants by arm

Arm	Count
MK-1942 AD Participants with AD receive donepezil 10 mg to 15 mg once daily (QD), and MK-1942 twice daily (BID), for 28 days. Doses of MK-1942 were 8 mg (Week 1), 15 mg (Week 2), 30 mg (Week 3) and 50 mg (Week 4).	22
Placebo + Donepezil AD Participants with AD receive donepezil 10 mg to 15 mg QD, and placebo BID, for 28 days.	5
Total	27

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Protocol Violation	1	0
Overall Study	Withdrawal by Subject	4	0

Baseline characteristics

Characteristic	Placebo + Donepezil AD	Total	MK-1942 AD
Age, Continuous	69.4 years STANDARD_DEVIATION 2.6	69.2 years STANDARD_DEVIATION 5	69.1 years STANDARD_DEVIATION 5.5
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	23 Participants	19 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1 Participants	3 Participants	2 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	7 Participants	7 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	5 Participants	20 Participants	15 Participants
Sex: Female, Male Female	2 Participants	12 Participants	10 Participants
Sex: Female, Male Male	3 Participants	15 Participants	12 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 22	0 / 19	0 / 15	0 / 15	0 / 22	0 / 5
other Total, other adverse events	13 / 22	4 / 19	4 / 15	5 / 15	18 / 22	4 / 5
serious Total, serious adverse events	0 / 22	0 / 19	0 / 15	0 / 15	0 / 22	0 / 5

Outcome results

Primary

Change From Baseline in Heart Rate (HR)

The mean change from baseline in HR is presented. Change in HR was determined the first day of treatment with a new dose of MK-1942. A negative value indicates a decrease in HR relative to baseline, and a positive value indicates an increase.

Time frame: Baseline (Day -1) and Days 1, 8, 15, and 22: 2 hours postdose