A Phase III, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Clinical Trial to Study the Efficacy and Safety of MK-8931 (SCH 900931) in Subjects With Amnestic Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal AD)
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 1,454
- 主要终点
- Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130
研究概览
简要总结
This study consists of two parts, Part 1 and Part 2. Part 1 assesses the efficacy and safety of verubecestat (MK-8931) compared with placebo administered for 104 weeks in the treatment of amnestic mild cognitive impairment (aMCI) due to Alzheimer's Disease (AD), also known as prodromal AD. Participants are randomized to receive placebo, or 12 mg or 40 mg verubecestat, once daily. The primary study hypothesis for Part 1 is that ≥1 verubecestat dose is superior to placebo with respect to the change from baseline in the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) score at 104 weeks. Participants completing Part 1 may choose to participate in Part 2, which is a long term double-blind extension to assess efficacy and safety of verubecestat administered for up to an additional 260 weeks. In Part 2, all participants receive either 12 mg or 40 mg verubecestat, once daily.
详细描述
As a result of protocol amendment, Study Part 2 will contain a Positron Emission Tomography (PET) imaging substudy to assess regional neurofibrillary tangle (NFT) expression.
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
- Triple (Participant, Investigator, Outcomes Assessor)
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
- •Diagnosis of prodromal AD, including the following:
- •History of subjective memory decline with gradual onset and slow progression for at least one year corroborated by an informant,
- •Objective impairment in episodic memory by memory test performed at Screening,
- •Does not meet criteria for dementia, AND
- •Positive Screening amyloid imaging PET scan using [18F]flutametamol tracer or positive Screening CSF tau:amyloid-β42 (Aβ42) ratio (Participants with a prior positive amyloid imaging PET scan or a Screening PET scan with florbetaben or florbetapir may be enrolled without a Screening flutemetamol scan with Sponsor approval)
- •Able to read at a 6th grade level or equivalent
- •If participant is receiving an acetylcholinesterase inhibitor or memantine, the dose must have been stable for at least three months before Screening
- •Must have a reliable and competent trial partner/informant who has a close relationship with the participant and is willing to accompany the participant to all required trial visits, and to monitor compliance of the administration of the trial medication
- •Inclusion Criteria for Extension Period (Part 2):
- •Tolerated study drug and completed the initial 104-week period of the trial (Part 1)
- •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 clinically relevant neurological disorder other than the disease being studied (i.e., prodromal AD)
- •History of seizures or epilepsy within the last 5 years
- •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 6 months prior to Screening
- •Recent or ongoing, uncontrolled, clinically significant medical condition within 3 months of Screening
- •History of malignancy occurring within the 5 years before Screening, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or localized prostate carcinoma
- •Clinically significant vitamin B12 or folate deficiency in the 6 months before Screening
- •Use of any investigational drugs or participation in clinical trials within the 30 days before Screening
- •History of a hypersensitivity reaction to more than three drugs
- •Has human immunodeficiency virus (HIV) by medical history
- •Participant is unwilling or has a contraindication to undergo PET scanning including but not limited to claustrophobia, excessive weight or girth
- •History or current evidence of long QT syndrome, corrected QT (QTc) interval ≥470 milliseconds (for male participants) or ≥480 milliseconds (for female participants), or torsades de pointes
- •Close family member (including the trial partner, spouse or children) who is among the personnel of the investigational or sponsor staff directly involved with this trial
- •Exclusion Criteria for Extension Period (Part 2):
- •Participant is at imminent risk of self-harm or of harm to others
- •Has developed a recent or ongoing, uncontrolled, clinically significant medical or psychiatric condition
- •Results of safety assessments (e.g., laboratory tests) performed in participant at end of Part 1 that are clinically unacceptable to the Investigator
- •Has developed a form of dementia that is not AD
- •Has progressed to dementia due to AD per investigator diagnosis in the initial 104-week study (Part 1).
- •Exclusion Criteria for NFT PET Substudy (Part 2):
- •Had one or two PET scans with MK-6240 in the initial 104-week study.
研究组 & 干预措施
Arm A. Verubecestat 12 mg (Part 1); 12 mg (Part 2)
[Part 1] Verubecestat 12 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 12 mg once daily for an additional 260 weeks.
干预措施: Verubecestat 12 mg (Parts 1 and 2) (Drug)
Arm B. Verubecestat 40 mg (Part 1); 40 mg (Part 2)
[Part 1] Verubecestat 40 mg once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Verubecestat 40 mg (Parts 1 and 2) (Drug)
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
[Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Verubecestat 40 mg (Parts 1 and 2) (Drug)
Arm C. Placebo (Part 1); Verubecestat 40 mg (Part 2)
[Part 1] Placebo once daily for 104 weeks in Part 1 (Base Study). [Part 2] Participants completing Part 1 and continuing to Part 2 (Extension Study) receive Verubecestat 40 mg once daily for an additional 260 weeks.
干预措施: Placebo (Part 1) (Other)
结局指标
主要结局
Part 2 (Extension Study). Mean Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 130
时间窗: Baseline and Week 130 (i.e., Week 26 of Part 2)
Mean change from baseline at week 130 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score. Per protocol, baseline refers to the baseline measurement obtained in Part 1.
Part 2 (Extension Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
时间窗: From Week 104 (start of treatment in Part 2) up to Week 210 (up to 2 weeks following cessation of study treatment in Part 2)
The percentage of participants experiencing an AE in Part 2 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 2 (Extension Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
时间窗: From Week 104 (start of treatment in Part 2) up to Week 208 (i.e., up to Week 104 in Part 2)
The percentage of participants who discontinued from study drug due to an AE in Part 2 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 1 (Base Study). Percentage of Participants Who Experienced ≥1 Adverse Event (AE)
时间窗: Up to Week 106 (up to 2 weeks following cessation of study treatment in Part 1)
The percentage of participants experiencing an AE in Part 1 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 1 (Base Study). Least Squares Mean (LSM) Change From Baseline in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 104
时间窗: Baseline and Week 104 in Part 1
LSM change from baseline at week 104 was assessed for CDR-SB score, a clinical rating of global cognitive function, comprised of 6 domains: memory; orientation; judgment and problem solving; community affairs; home and hobbies; and personal care. For each domain, the degree of impairment is assessed by a semi-structured interview of the participant as well as the participant's caregiver. For each domain, potential scores range from 0 (no impairment) to 3 (severe impairment). Individual domain scores are summed to a total CDR-SB score (range: 0-18). Higher scores indicate more severe cognitive impairment. Further, increases in cognitive impairment would be reflected by increases in CDR-SB score.
Part 1 (Base Study). Percentage of Participants Who Discontinued From Study Drug Due to an Adverse Event (AE)
时间窗: Up to Week 104 in Part 1
The percentage of participants who discontinued from study drug due to an AE in Part 1 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 1 (Base Study). Event-Rate Per 100 Participant Years for Progression to a Clinical Diagnosis of Probable AD Dementia(Up to Week 104 in Part 1)
- Part 1 (Base Study). Least Squares Mean Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL MCI) Score at Week 104(Baseline and Week 104 in Part 1)
- Part 1 (Base Study). Least Squares Mean Change From Baseline in the 3-Domain Composite Cognition Score (CCS-3D) at Week 104(Baseline and Week 104 in Part 1)
- Part 1 (Base Study). Least Squares Mean Percent Change From Baseline in Total Hippocampal Volume (THV) at Week 104(Baseline and Week 104 in Part 1)
- Part 1 (Base Study). Least Squares Mean Change From Baseline in Composite Cortical Amyloid Standard Uptake Value Ratio (SUVR) Assessed With Amyloid Tracer [18F]Flutemetamol Using Positron Emission Tomography (PET) Imaging at Week 104(Baseline and Week 104 in Part 1)
- Part 1 (Base Study). Estimated Least Squares Mean Difference Between the Last (Week 104) and First (Week 13) Post-dose CDR-SB Assessment(Week 13 and Week 104 in Part 1)
- Part 1 (Base Study). Mean Percent Change From Baseline in Cerebrospinal Fluid (CSF) Total Tau Concentration at Week 104(Baseline and Week 104 in Part 1)