A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy And Safety Study of Crenezumab in Patients With Prodromal to Mild Alzheimer's Disease.
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 813
- 试验地点
- 195
- 主要终点
- Change From Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score
研究概览
简要总结
This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The final efficacy and safety assessment will be performed 52 weeks after the last crenezumab dose. Participants will then have the option to enter the Open Label Extension (OLE) study if eligible. Participants who do not enter the OLE study will have additional follow-up visits at 16 and 52 weeks after the last dose, primarily for safety and also for limited efficacy assessments.
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
- •Weight between 40 and 120 kilograms (Kg) inclusive
- •Availability of a person (referred to as the "caregiver") who in the investigator's judgment:
- •Has frequent and sufficient contact with the participant to be able to provide accurate information regarding the participant's cognitive and functional abilities, agrees to provide information at clinic visits (which require partner input for scale completion), signs the necessary consent form, and has sufficient cognitive capacity to accurately report upon the participant's behavior and cognitive and functional abilities
- •Fluency in the language of the tests used at the study site
- •Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
- •Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid (CSF) amyloid beta 1-42 levels as measured on the Elecsys beta-amyloid(1-42) test system or amyloid PET scan by qualitative read by the core/central PET laboratory
- •Demonstrated abnormal memory function at screening (up to 4 weeks before screening begins) or screening (FCSRT cueing index =<0.67 AND free recall =<27)
- •Screening mini mental state examination (MMSE) score of greater than or equal to (>=) 22 points and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0
- •Meets National Institute on Aging/Alzheimer's Association (NIAAA) core clinical criteria for probable AD dementia or prodromal AD (consistent with the NIAAA diagnostic criteria and guidelines for mild cognitive impairment (MCI)
- •If receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening
- •Participant must have completed at least 6 years of formal education after the age of 5 years
排除标准
- •Any evidence of a condition other than AD that may affect cognition such as other dementias, stroke, brain damage, autoimmune disorders (e.g. multiple sclerosis) or infections with neurological sequelae.
- •History of major psychiatric illness such as schizophrenia or major depression (if not considered in remission)
- •At risk of suicide in the opinion of the investigator
- •Any abnormal MRI findings, such as presence of cerebral vascular pathology, cortical stroke, etc or inability to tolerate MRI procedures or contraindication to MRI
- •Unstable or clinically significant cardiovascular (e.g., myocardial infarction), kidney or liver disease
- •Uncontrolled hypertension
- •Screening hemoglobin A1c (HbA1C) >8%
- •Poor peripheral venous access
- •History of cancer except:
- •If considered to be cured or If not being actively treated with anti-cancer therapy or radiotherapy
- •Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins
研究组 & 干预措施
Placebo
Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks.
干预措施: Placebo (Drug)
Crenezumab
Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
干预措施: Crenezumab (Drug)
结局指标
主要结局
Change From Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score
时间窗: Baseline, Week 105
The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region and the use or non-use of anti-dementia medications at baseline were used to estimate the mean change from baseline for this primary endpoint. Data after 29 January 2019 are censored for the primary and secondary efficacy analyses to avoid potential biases due to investigators, participants, raters, etc. being potentially influenced by early closure of the study due to lack of efficacy.
次要结局
- Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 11 (ADAS-Cog-11)(Baseline, Week 105)
- Change From Baseline to Week 105 on Function as Assessed by the ADCS-ADL Total Score(Baseline, Week 105)
- Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 13 (ADAS-Cog-13)(Baseline, Week 105)
- Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS)(Baseline, Week 105)
- Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE)(Baseline, Week 105)
- Change From Baseline to Week 105 on Function as Assessed by the ADCS-instrumental (ADCS-iADL) Subscore(Baseline, Week 105)
- Change From Baseline to Week 105 on a Measure of Dependence Derived From the ADCS-ADL Score(Baseline, Week 105)
- Percentage of Participants With Anti-Crenezumab Antibodies(Baseline up to Week 105)
- Change From Baseline to Week 105 Assessed Using the Neuropsychiatric Inventory Questionnaire (NPI-Q)(Baseline, Week 105)
- Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score(Baseline up to Week 105)
- Plasma Amyloid Beta (Abeta) 40 Concentrations(Week 1 Day 1; Weeks 13, 25, 53, 77 and 105)
- Percentage Change From Baseline to Week 105 in Ventricle Volume as Determined by Magnetic Resonance Imaging (MRI)(Baseline, Week 105)
- Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score(Baseline up to Week 105)
- EQ-5D Questionnaire Domain Score for Caregivers(Baseline up to Week 105)
- Serum Concentration of Crenezumab(Pre-infusion (0 hour), 60-90 minutes post-infusion on Day 1 Week 1 and on Week 25; Weeks 13, 37 (Pre-dose), 53, 77 and 105 (infusion length = as per the Pharmacy Manual))
- EQ-5D Questionnaire Domain Score for Participants(Baseline up to Week 105)
- Percentage of Participants With Adverse Event (AEs) and Serious Adverse Event (SAEs)(Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).)
- Plasma Amyloid Beta (Abeta) 42 Concentrations(Week 1 Day 1; Weeks 13, 25, 53, 77 and 105)
- Percentage Change From Baseline to Week 105 in Whole Brain Volume as Determined by Magnetic Resonance Imaging (MRI)(Baseline, Week 105)
- Percentage Change From Baseline to Week 105 in Hippocampal Volume as Determined by Magnetic Resonance Imaging (MRI)(Baseline, Week 105)