Effect of γ-Secretase Inhibition on the Progression of Alzheimer's Disease: LY450139 Versus Placebo
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 1,537
- 试验地点
- 1
- 主要终点
- Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks
研究概览
简要总结
Alzheimer's disease (AD) is a fatal degenerative disease of the brain for which there is no cure. AD causes brain cells to die. AD is thought to be caused by an excess of beta-amyloid (β-amyloid), a sticky protein in the brain that forms amyloid plaques. At autopsy, AD patients are required to have these amyloid plaques in the brain in order to have a definitive diagnosis of AD. Inhibiting the enzyme gamma-secretase (γ-secretase) lowers the production of β-amyloid. Semagacestat (LY450139) is a functional γ-secretase inhibitor and was shown to lower β-amyloid in blood and spinal fluid in humans tested thus far and in blood, spinal fluid, and brain in animals tested thus far. This study used several different tests to measure the effect of semagacestat on both β-amyloid and amyloid plaques for some participants. The build-up of amyloid plaques was measured by a brain scan that takes a picture of amyloid plaques in the brain. Other tests measured the overall function of the brain and brain size in some participants. In this trial, participants who initially received placebo (inactive sugar pill) were, at a certain point in the study, switched over to active drug, semagacestat. In other words, all participants could eventually receive active drug. Participation could last approximately 2 years. Participants taking approved AD medications were permitted to participate in this study and continue taking these medications during the study. All participants who completed this study had the option to continue receiving semagacestat by participating in an open-label study.
Preliminary results from this study (H6L-MC-LFAN [LFAN]) and another similar study (H6L-MC-LFBC [LFBC; NCT00762411]) showed semagacestat did not slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Study drug was stopped in all studies. Studies LFAN, LFBC, and open-label H6L-MC-LFBF (LFBF; NCT01035138) were amended to continue collecting safety data, including cognitive scores, for at least 7 months. The Clinical Trial Registry (CTR) will reflect results of analyses from the original LFAN protocol in addition to those from the amended LFAN protocol.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meets criteria for mild to moderate Alzheimer's disease (AD) with Mini-Mental State Examination (MMSE) score of 16-26 at Visit 1
- •Modified Hachinski Ischemia Scale score of less than or equal to 4
- •Geriatric Depression Scale score of less than or equal to 6
- •A magnetic resonance imaging (MRI) or computerized tomography (CT) scan in the last 2 years with no findings inconsistent with a diagnosis of AD
- •If female, must be without menstruation for at least 12 consecutive months or have had both ovaries removed
排除标准
- •Is not capable of swallowing whole oral medication
- •Has serious or unstable illnesses
- •Does not have a reliable caregiver
- •Chronic alcohol or drug abuse within the past 5 years
- •Has ever had active vaccination for AD
研究组 & 干预措施
Placebo
Participants received placebo orally once daily for the first 76 weeks. At the end of 76 weeks, placebo arm participants received LY450139 titrated up to 140 milligrams (mg) orally once daily until Week 88.
干预措施: Placebo (Drug)
100 mg LY450139
Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily until Week 88.
干预措施: LY450139 (Drug)
140 mg LY450139
Participants received 60 mg LY450139 orally once daily for 2 weeks, followed by 100 mg LY450139 orally once daily for 2 weeks, then 140 mg LY450139 orally once daily until Week 88.
干预措施: LY450139 (Drug)
结局指标
主要结局
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 76 Weeks
时间窗: Baseline (randomization), 76 weeks
ADAS-Cog11 was used as a primary efficacy measure. It consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 76 Weeks
时间窗: Baseline (randomization), 76 weeks
ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog11) Score at 16 Weeks After Cessation of Study Drug
时间窗: Baseline (randomization), 16 weeks following treatment cessation
ADAS-Cog11 consists of 11 items assessing areas of function most typically impaired in Alzheimer's disease (AD): orientation, verbal memory, language, and praxis. The scale ranges from 0 to 70, with higher scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
Change From Baseline in Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Score at 16 Weeks After Cessation of Study Drug
时间窗: Baseline (randomization), 16 weeks following treatment cessation
ADCS-ADL is a 23-item inventory developed as a Rater-administered questionnaire answered by the participant's caregiver. It measures performance of basic and instrumental activities of daily living by participants. The total score ranges from 0 to 78, with lower scores indicating greater disease severity. Least Squares (LS) Mean value was controlled for baseline value, age, investigator, visit, and concomitant standard of care (SOC) medication.
次要结局
- Percent Change From Baseline in Amyloid Beta (Aβ) 1-42 Plasma Concentration at 52 Weeks(Baseline (randomization), 52 weeks)
- Change From Baseline in Amyloid Imaging Positron Emission Tomography (AV-45 PET) up to 76 Weeks(Baseline (randomization), up to 76 weeks)
- Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) at 4 Weeks After Cessation of Study Drug(Baseline (randomization), 4 weeks following treatment cessation)
- Change From Baseline in Amyloid Beta (Aβ) 1-42 Concentration in Spinal Fluid up to 76 Weeks(Baseline (randomization), up to 76 weeks)
- LY450139 Population Pharmacokinetics: Volume of Distribution of LY450139(6 weeks, 12 weeks, and 52 weeks)
- Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in Resource Utilization in Dementia-Lite (RUD-Lite) Score (Number of Hospitalizations) up to 76 Weeks(Baseline (randomization), up to 76 weeks)
- Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 16 Weeks After Cessation of Study Drug(Baseline (randomization), 16 weeks following treatment cessation)
- Change From Baseline in Mini Mental State Examination (MMSE) Score at 4 Weeks After Cessation of Study Drug(Baseline (randomization), 4 weeks following treatment cessation)
- Change From Baseline in Phosphorylated-Tau (P-Tau) Concentration in Spinal Fluid(Baseline (randomization), up to 76 weeks)
- Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) Score at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in Mini Mental State Examination (MMSE) Score at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in Hippocampal Volume Using Volumetric Magnetic Resonance Imaging (vMRI) up to 76 Weeks(Baseline (randomization), up to 76 weeks)
- LY450139 Population Pharmacokinetics: Clearance of LY450139(6 weeks, 12 weeks, and 52 weeks)
- Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in Positron Emission Tomography (PET) Using Fluorine-18 Fluorodeoxyglucose (18F-FDG) at 76 Weeks(Baseline (randomization), 76 weeks)
- Change From Baseline in Tau Concentration in Spinal Fluid up to 76 Weeks(Baseline (randomization), up to 76 weeks)
- Change From Baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score at 4 Weeks After Cessation of Study Drug(Baseline (randomization), 4 weeks following treatment cessation)
- Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) Score at 16 Weeks After Cessation of Study Drug(Baseline (randomization), 16 weeks following treatment cessation)
- Change From Baseline in Neuropsychiatric Inventory (NPI) Score at 4 Weeks After Cessation of Study Drug(Baseline (randomization), 4 weeks following treatment cessation)
- Change From Baseline in EuroQol 5-Dimensional Health-Related Quality of Life Scale Proxy Version (EQ-5D Proxy) Visual Analog Scale (VAS) Score at 4 Weeks After Cessation of Study Drug(Baseline (randomization), 4 weeks following treatment cessation)