Exploratory PLatform Trial on Anti-Inflammatory Agents in Alzheimer's Disease (EXPLAIN-AD): A Randomized, Placebo-controlled, Multicenter Platform Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Various Anti-inflammatory Agents in Patients With Mild Cognitive Impairment Due to Alzheimer's Disease and Mild Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 34
- 试验地点
- 3
- 主要终点
- Change From Baseline in Cognition as Measured by the Neuropsychological Test Battery (NTB) Z-scores
研究概览
简要总结
The purpose of this platform study was to evaluate the effect of anti-inflammatory agents on cognition in early Alzheimer's disease. Additionally, the safety and tolerability and their effects on central and peripheral inflammation were evaluated. Due to early termination only a single agent could be studied.
详细描述
This was a randomized, placebo-controlled, participant- and investigator-blinded study in participants with either mild cognitive impairment or mild Alzheimer's disease with evidence of peripheral inflammation.
This study was originally planned as a platform study, designed to investigate different agents in a continuous manner. However, due to early termination of the study only one experimental arm was enrolled.
The study included a screening period (Day -60 to Day -8), followed by a baseline period of 7 days (Day -7 to Day -1), a treatment period of 20 weeks (Day 1 to Day 141), a study completion evaluation (EOC1) approximately 30 days after the last agent administration (Day 171) and a second end of cohort visit (EOC2) approximately 140 days after the last agent administration (Day 281).
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
- 45 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, age ≥ 45 years and ≤ 90 years at the time of signing the informed consent;
- •Participant has a reliable study partner or caregiver can accompany the participant to all visits;
- •A diagnosis of probable MCI due to AD or mild AD according to the National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria;
- •Confirmed amyloid and tau positivity via CSF sampling performed at screening;
- •Mini-Mental State Examination (MMSE) total score of 20 to 24 (inclusive) at screening; OR, MMSE total score of 25-30 (inclusive) plus a DSST score at least 0.5 standard deviation (SD) below normative data at screening.
排除标准
- •Use of an investigational agent or an approved product with the intent to modulate inflammation or modulate the course of AD (e.g., Tau ASOs, gene therapy, amyloid or tau vaccine):
- •Previous use of small molecules is allowed if discontinued for at least five half-lives, or at least 30 days from when the expected pharmacodynamic effect has returned to baseline prior to screening, whichever is longer
- •Previous use of monoclonal or polyclonal antibodies or other biologics is allowed if discontinued for at least five half-lives prior to screening
- •Current medical or neurological condition that might impact cognition or performance on cognitive assessments, e.g., MCI not due to AD, non-Alzheimer dementia, Huntington's disease, Parkinson's disease, stroke, schizophrenia, bipolar disorder, active major depression, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), active seizure disorder, or history of traumatic brain injury associated with loss of consciousness and ongoing residual transient or permanent neurological signs/symptoms including cognitive deficits, and/or associated with skull fracture;
- •Diagnosis of vascular dementia prior to screening (e.g., modified Hachinski Ischaemic Scale score > 6 or those who meet the NINDS AIREN criteria for vascular dementia);
研究组 & 干预措施
Canakinumab
Canakinumab 150 mg SC once every 4 weeks for the first 2 doses followed by 300 mg SC once every 4 weeks for the subsequent 4 doses.
干预措施: Canakinumab (Biological)
Placebo
Matching placebo sub-cutaneous injections
干预措施: Placebo (Other)
结局指标
主要结局
Change From Baseline in Cognition as Measured by the Neuropsychological Test Battery (NTB) Z-scores
时间窗: Baseline and day 171
NTB is a composite of multiple neuropsychological tests that provide a thorough assessment of the cognitive domains affected by early Alzheimer's Disease (AD), in particular, memory, executive function, attention and verbal fluency. 5 out of 9 NTB components were administered in the study, Rey Auditory Verbal Learning Test (RAVLT) immediate and delayed scores, Wechsler Memory Scale Digit Span, Controlled Word Association Test (COWAT) and Category Fluency Test (CFT). For each component a raw score was converted to z-score that indicates the number of standard deviations away from the mean. Total Z-score was derived by averaging all resulting z-scores. A change from baseline was calculated as post-baseline z-score minus pre-treatment z-score. A zero Z-score means no cognitive change, a negative value indicates decline, and a positive value means improvement.
次要结局
- Change From Baseline in Memory as Measured by the Total Composite NTB Memory Z-score(Baseline and day 171)
- Change From Baseline in Executive Function as Measured by the Total Composite NTB Executive Function Z-score(Baseline and day 171)
- Change From Baseline in Digit Symbol Substitution Test (DSST) Score - CANTAB(Baseline and day 171)
- Change From Baseline in Neuropsychiatric Symptoms as Measured by the Neuropsychiatric Inventory (NPI) Total Score(Baseline and day 171)
- Change From Baseline in Neuropsychiatric Symptoms Associated Distress as Measured by the Neuropsychiatric Inventory Caregiver Distress (NPI-D) Score(Baseline and day 171)
- Change From Baseline in Mean eNeuropsychiatric at Home Caregiver Assessment Score(Baseline, day 85)
- Change From Baseline in Everyday Cognition Scale (ECog) Total Score(Baseline and day 171)
- Change From Baseline in eCognitive Testing Scores - SWM Between Errors(Baseline, day 85)
- Change From Baseline in eCognitive Testing Scores - SWM Strategy(Baseline, day 85)
- Change From Baseline in eCognitive Testing Scores - MTS Proportional Slowing 8-2 Patterns(Baseline, day 85)
- Change From Baseline in eCognitive Testing Scores - PAL First Attempt Memory Score(Baseline, day 85)
- Change From Baseline in Microglia Activation as Measured by Positron-Emission Tomography-Translocator Protein 18kDa - Microglia Activation(Baseline and day 85)
- Serum Pharmacokinetic Concentrations of Canakinumab(Baseline, day29, day 57, day 85, day 141, day 171)
- Total Target (IL-1 Beta) Concentration in Serum and CSF(Baseline, day 29, day 57, day 85, day 141, day 171 for serum concentrations and Baseline and day 85 for CSF concentrations)
- Number of Participants With Anti-agent Antibodies in Serum(Baseline, day 85, day 171)
- Number of Participants Who Experience Adverse Events and Serious Adverse Events(From first dose up to approximately 140 days post last dose (day 281))