A Randomized, Placebo Controlled, Parallel-Group, Double Blind Efficacy and Safety Trial of MK-8931 With a Long Term Double-Blind Extension in Subjects With Mild to Moderate Alzheimer's Disease (Protocol No. MK-8931-017-10)(Also Known as SCH 900931, P07738)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 2,211
- 主要终点
- [Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
研究概览
简要总结
This study consists of two parts, Part I and Part II. The purpose of Part I of the study is to assess the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 78 weeks in the treatment of Alzheimer's Disease (AD). The primary study hypotheses for Part I are that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and that at least one verubecestat dose is superior to placebo at 78 weeks of treatment with respect to change from baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) score. The first approximately 400 participants entering Part I of the study are identified as the Safety Cohort. Participants who complete Part I of the study may choose to participate in Part II, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks.
详细描述
Two substudies are included in Part I of the study: 1) a medical imaging substudy to evaluate changes in brain amyloid protein load using positron emission tomography (PET) and an amyloid tracer ([18F]flutemetamol); and 2) a cerebrospinal fluid (CSF) biomarker substudy to evaluate changes in CSF concentrations of amyloid-β related peptides, total tau, and phosphorylated tau (p-tau). The substudies will be conducted only at designated investigational sites. Participants are not required to take part in a substudy in order to take part in the larger trial.
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
- 55 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of probable AD based on both a) the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria and b) the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) criteria for AD
- •AD is of mild to moderate severity
- •Clear history of cognitive and functional decline over at least one year that is either a) documented in medical records or b) documented by history from an informant who knows the subject well
- •Able to read at a 6th grade level or equivalent, and must have a history of academic achievement and/or employment sufficient to exclude mental retardation
- •If a participant is receiving an acetylcholinesterase inhibitor, memantine, medical food/supplement (e.g., vitamin E) and/or herbal medications for AD, the dose must have been stable for at least three months before Screening, and the participant must be willing to remain on the same dose for the duration of the trial. Participants may need to be on AD treatments in accordance with local requirements
- •Participant must have a reliable and competent trial partner/caregiver who must have a close relationship with the subject
- •Inclusion Criteria for Extension Period (Part II):
- •Tolerated study drug and completed the initial 78-week period of the trial (Part I)
- •Participant must have a reliable and competent trial partner who must have a close relationship with the subject
排除标准
- •History of stroke
- •Evidence of a neurological disorder other than the disease being studied (i.e., probable AD)
- •History of seizures or epilepsy within the last 5 years before Screening
- •Evidence of a clinically relevant or unstable psychiatric disorder, excluding major depression in remission
- •Participant is at imminent risk of self-harm or of harm to others
- •History of alcoholism or drug dependency/abuse within the last 5 years before Screening
- •Participant does not have a magnetic resonance imaging (MRI) scan obtained within 12 months of Screening and is unwilling or not eligible to undergo an MRI scan at the Screening Visit. With Sponsor approval, a head computed tomography (CT) scan may be substituted for MRI scan to evaluate eligibility
- •History of hepatitis or liver disease that has been active within the six months prior to Screening Visit
- •Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of the Screening Visit (e.g., diabetes, hypertension, thyroid or endocrine disease, congestive heart failure, angina, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that participation in the trial would pose a significant medical risk to the subject. Controlled co-morbid conditions are not exclusionary if stable within three months of the Screening Visit
- •History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de pointes
- •History of malignancy occurring within the five years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma; or malignancy which has been treated with potentially curative therapy with no evidence of recurrence for ≥3 year post-therapy
- •Clinically significant vitamin B12 or folate deficiency in the six months before Screening Visit
- •Use of any investigational drugs within 30 days (or longer depending on drug) before Screening or participation in studies involving repeated cognitive testing within 30 days before Screening. Participation in an observational study, such as those involving annual cognitive assessments and/or neuroimaging, may be allowed if approved by Sponsor
- •History of a hypersensitivity reaction to more than three drugs
- •Has tested positive for human immunodeficiency virus (HIV)
- •Close family member (including the caregiver, the spouse or any children) who is among the personnel of the investigational or sponsor staff directly involved with this trial
- •Additional Exclusion Criteria for Safety Cohort:
- •History of an ongoing medical condition that has been poorly controlled within 6 months of the Screening Visit (e.g., hypotension, diabetes, hypertension, cerebrovascular disease, thyroid disease, endocrine disturbance, congestive heart failure, cardiac or gastrointestinal disease, dialysis, or abnormal renal function) other than the condition being studied such that a subject's participation in the trial would pose a significant medical risk
- •History of congestive heart failure (moderate or greater severity), myocardial infarction, heart surgery, syncope, bradycardia, or clinically significant hypotension within one year before Screening
- •Exclusion Criteria for Extension Period (Part II):
- •Participant is at imminent risk of self-harm or of harm to others
- •Has developed a recent or ongoing, uncontrolled, clinically significant medical condition other than AD
- •Has history of or has developed during Part I evidence of long QT syndrome, QTc interval ≥470 milliseconds (for male subjects) or ≥480 milliseconds (for female subjects), or torsades de pointes
- •Has developed a form of dementia that is not AD
研究组 & 干预措施
Arm A. Verubecestat 12 mg [Part I]; 12 mg [Part II]
[Part I] Verubecestat 12 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
干预措施: Verubecestat (Part I and Part II) (Drug)
Arm B. Verubecestat 40 mg [Part I]; 40 mg [Part II]
[Part I] Verubecestat 40 mg once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Verubecestat (Part I and Part II) (Drug)
Arm C. Verubecestat 60mg/40mg [Part I]; 40 mg [Part II]
[Part I] Verubecestat 60 mg once daily until the first IA in Study Part I (Base Study). Following IA, participants in this group were switched to Verubecestat 40 mg once daily, for the remainder of Study Part I (total dosing period: 78 weeks). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Verubecestat (Part I and Part II) (Drug)
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
[Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Placebo (Part I) (Drug)
Arm D. Placebo [Part I]; Verubecestat 40 mg [Part II]
[Part I] Placebo once daily for 78 weeks in Study Part I (Base Study). [Part II] Participants completing Study Part I and continuing to Study Part II (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Verubecestat (Part II) (Drug)
结局指标
主要结局
[Part I (Base Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
时间窗: Baseline and week 78
Least squares mean change from baseline at week 78 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score.
[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
时间窗: Baseline and week 104
Mean change from baseline at week 104 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.
[Part II (Extension Study)] Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) Score
时间窗: Baseline and week 104
Mean change from baseline at week 104 was assessed for the ADCS-ADL score. The ADCS-ADL score measures the performance of activities of daily living, calculated from a 24-question survey. For each of the 24 questions, scores range from 0 (no independence) to (depending on the question) either 2 (1 question), 3 (17 questions), 4 (5 questions), or 5 (1 question), with higher scores indicating greater independence in activity performance. Scores from individual questions are summed into a total ADCS-ADL score, with total scores ranging from 0 to 78. Lower scores indicate less independence in activity performance and, as a result, greater AD severity. Further, increases in AD severity over time would be reflected by decreases in ADCS-ADL score. Per study protocol, the baseline measurement to be used was the baseline measurement obtained in Part I.
[Part I (Base Study)] Number of Participants Who Experienced an Adverse Event
时间窗: Up to week 80 (up to 2 weeks following cessation of study treatment in Part I)
The number of participants experiencing an adverse event (AE) in Part I was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
[Part I (Base Study)] Change From Baseline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) Score
时间窗: Baseline and week 78
Least squares mean change from baseline at week 78 was assessed for the ADAS-Cog score. ADAS-Cog measures cognition by assessing 11 metrics impaired in Alzheimer's Disease (AD): speech; speech comprehension; word finding; word recall; object/finger naming; orientation; obeying commands; ideational praxis; constructional praxis; word recognition; and remembering instruction. For each metric, scores range from 0 (no impairment) to (depending on the metric) either 5 (8 metrics), 8, 10, or 12 (1 metric each); higher scores indicate more severe impairment. Individual scores sum to a total ADAS-Cog score, ranging from 0-70. Higher total scores indicate greater cognitive impairment and AD severity. Further, increases in AD severity over time would be reflected by increases in ADAS-Cog score.
[Part II (Extension Study)] Number of Participants Who Experienced an Adverse Event
时间窗: From week 78 (end of treatment in Part I) up to week 262 of Part II
The number of participants experiencing an adverse event (AE) in Part II was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
[Part I (Base Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
时间窗: Up to week 78
The number of participants discontinuing from study drug due to an AE in Part I was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
[Part II (Extension Study)] Number of Participants Who Discontinued From Study Drug Due to an Adverse Event
时间窗: From week 78 (end of treatment in Part I) up to week 260 of Part II
The number of participants discontinuing from study drug due to an AE in Part II was assessed. An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product is also an AE.
次要结局
- [Part I (Base Study)] Fold Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau(Baseline and week 78)
- [Part I (Base Study)] Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score(Baseline and week 78)
- [Part I (Base Study)] Percent Change From Baseline in Total Hippocampal Volume (THV)(Baseline and week 78)
- [Part I (Base Study)] Change From Baseline in Cortical Amyloid Load Assessed by [18F]Flutemetamol PET Standard Uptake Value Ratio (SUVR)(Baseline and week 78)
- [Part I (Base Study)] Percentage of Participants Achieving Responder Status(Week 78)
- [Part I (Base Study)] Change From Baseline in Neuropsychiatric Inventory (NPI) Score(Baseline and week 78)
- [Part I (Base Study)] Change From Baseline in Mini-Mental State Examination (MMSE) Score(Baseline and week 78)