A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Pharmacokinetics of MK-1942 Administered to Alzheimer's Disease Patients Receiving Donepezil Treatment.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 27
- 试验地点
- 4
- 主要终点
- Number of Participants With ≥1 Adverse Event (AE)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Donepezil
Participants receive 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.
干预措施: MK-1942 (Drug)
Donepezil
Participants receive 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.
干预措施: Donepezil (Drug)
Placebo
Placebo to MK-1942 BID x 21 [28] D All participants to receive Donepezil once daily.
干预措施: Donepezil (Drug)
Placebo
Placebo to MK-1942 BID x 21 [28] D All participants to receive Donepezil once daily.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Participants With ≥1 Adverse Event (AE)
时间窗: 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.
Change From Baseline in Heart Rate (HR)
时间窗: 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.
Number of Participants Discontinuing From Study Therapy Due to an Adverse Event (AE)
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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 Systolic Blood Pressure (SBP)
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)