A Phase 1b/2, Multicenter, Adaptive, Double-blind, Randomized, Placebo-controlled Study to Assess the Safety, Tolerability, Immunogenicity, and Pharmacodynamic Effects of ACI-24.060 in Subjects With Prodromal Alzheimer's Disease and in Adults With Down Syndrome (ABATE)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- AC Immune SA
- 入组人数
- 304
- 试验地点
- 40
- 主要终点
- Number of participants with Adverse Events (AEs) assessed by intensity (mild, moderate or severe) and causal relationship (unrelated, unlikely, possibly or probably related)
研究概览
简要总结
The purpose of this study is to assess the safety, tolerability, immunogenicity and pharmacodynamic effects of ACI-24.060 in subjects with prodromal Alzheimer's disease and in non-demented adults with Down syndrome.
详细描述
This phase 1b/2 study will be in 2 parts. Study Part 1 will involve subjects with prodromal Alzheimer's disease and is divided into Part 1a and Part 1b. Study Part 2 will involve subjects with Down syndrome.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 35 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Study Part 1a and Part 1b
- •Age ≥50 and ≤85 years at screening.
- •Diagnosis of prodromal AD: MCI due to AD according to National Institute on Aging Alzheimer's Association (NIA-AA) criteria.
- •PET scan at screening consistent with the presence of amyloid pathology.
- •Clinical Dementia Rating (CDR)-Global Score of 0.
- •Subjects either not taking any marketed treatment for AD or receiving a stable dose of an acetylcholinesterase inhibitor (ACHEI) and/or memantine for at least 2 months prior to screening.
- •Study Part 2
- •Age ≥35 and ≤50 years at screening (subjects with DS with age ≥35 and ≤39 years may be considered on the condition that there is prior evidence of amyloid results compatible with AD pathology at PET-scan and/or in biofluids).
- •Male or female subjects with DS with a cytogenetic diagnosis being either trisomy 21 or complete unbalanced translocation of chromosome
- •PET scan at screening consistent with the presence of amyloid pathology.
- •Mild to moderate intellectual disability as per Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classification.
- •Subjects must have a study partner who has direct and regular contact, at least 10 hours per week, with the subject and who is able to provide reliable answers to questions related to the subject, according to the study investigator.
排除标准
- •Any unstable and/or clinically significant medical condition likely to hamper the evaluation of safety and/or efficacy of the study treatment (eg, moderate and/or severe untreated obstructive sleep apnea, clinically significant reduction in serum B12 or folate levels, clinically significant abnormalities of thyroid function, stroke, or other cerebrovascular conditions), as per investigator's judgement.
- •DSM-5 criteria for substance use disorders drug or alcohol abuse or dependence (with the exception of tobacco use disorder) currently met within the past 5 years.
- •History or presence of uncontrolled seizures. If there is a history of seizures, they must be well controlled, with no occurrence of seizures in the 2 years before study screening. The use of antiepileptic medications is permitted.
- •Concomitant or history of clinically significant and/or unstable psychiatric or neurologic disorder other than those considered to be related to AD (eg, head injury with loss of consciousness, symptomatic stroke, Parkinson's disease, severe carotid occlusive disease, transient ischemic attacks, hemorrhagic and/or non-hemorrhagic stroke). Subjects with a history of major depressive disorder may be included if they have been free of major episodes for at least 1 year before screening.
- •History of meningitis or meningoencephalitis.
- •History of moderate or severe traumatic brain injury.
- •History or presence of inflammatory neurological disorders.
- •History or presence of immunological or autoimmune disorders.
- •History of severe allergic reaction (eg, anaphylaxis) including, but not limited to severe allergic reaction to previous vaccines, foods, and/or medications.
- •Significant risk of suicide, defined using the C-SSRS as the subject answering "yes" to suicidal ideation questions 4 or 5 or answering "yes" to suicidal behavior within the past 12 months.
- •MRI scan at screening showing a single area of cerebral vasogenic edema, superficial siderosis, or evidence of a previous macro-hemorrhage or showing more than 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"). Evidence of space occupying lesions other than benign meningioma of less than 1 cm diameter, more than 2 lacunar infarcts, or 1 single infarct larger than 1 cm in diameter. Screening MRI scan showing structural evidence of alternative pathology not consistent with AD and is considered to be at the origin of subject's symptoms.
- •Deviations from normal values for hematologic parameters, liver function tests, and other biochemical measures, judged to be clinically significant by the investigator.
- •Subjects with a positive Human Immunodeficiency Virus (HIV-1 and 2) test at screening.
- •Subjects with clinical or laboratory evidence of active hepatitis B or C at screening (eg, HBV or HCV antigens).
- •Subjects with positive syphilis serology consistent with active syphilis at screening.
- •Subjects with presence of antibody titers related to immunological or autoimmune disorders at screening.
- •MRI examination cannot be done for any reason, including but not limited to metal implants contraindicated for MRI and/or severe claustrophobia.
- •Any contraindication for PET scan imaging.
- •Any contraindication to lumbar puncture in subjects undergoing this procedure (note: lumbar puncture is optional in subjects with DS).
- •Previous treatment with ACI-24 or any other active immunotherapy against AD at any time in the past unless there is firm evidence that the subject received placebo only and the placebo formulation is not expected to induce any specific immune response.
- •Previous treatment with any investigational and/or marketed passive immunotherapy against AD within 6 months before screening or 5 half-lives, whichever is longer, unless there is firm evidence that the subject received placebo only.
- •Ongoing treatment with any approved anti-amyloid passive immunotherapy for Alzheimer's disease.
- •Use of acetylcholinesterase inhibitor or glutamatergic drugs (eg, memantine, topiramate, lamotrigine) if not on stable dose for at least 2 months before screening.
- •Any vaccine, either live or not, including but not limited to influenza or COVID-19 vaccine, received within 4 weeks before randomization.
- •Subjects with treated hypothyroidism not on a stable dose of replacement medication for at least 2 months before screening and having clinically significant abnormal serum T4 and/or thyroid stimulating hormone at screening.
- •Subjects undergoing lumbar puncture and being treated with any anticoagulants or antiplatelet drugs, except aspirin at doses of 100 mg daily or lower.
- •Use of antidepressants (other than selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors at stable dose); typical antipsychotics; γ-aminobutyric acid agonists (eg, gabapentin); or stimulants (eg, methylphenidate, modafinil). Stable doses of atypical antipsychotics or benzodiazepines are only allowed if this is not considered to influence the safety and the efficacy of the study treatment according to the site investigator and the sponsor medical monitor.
- •Chronic use of opioid analgesics. A limited treatment duration for acute conditions until 24 hours before cognitive assessment is allowed.
- •Current use of immunosuppressant or immunomodulating drugs or their use within the 6 months before study screening. Current use of oral steroids or their use within the 3 months before study screening.
- •Additional Exclusion Criteria in Study Part 2
- •The following are exclusion criteria at the time of randomization but will not be considered as exclusionary after treatment assignment:
- •Clinical diagnosis of AD dementia in DS as per International Classification of Diseases 10 (ICD-10).
- •Intelligence quotient score <40 (KBIT-2).
研究组 & 干预措施
Placebo for Study Part 1a (Prodromal AD)
Prodromal AD participants receive placebo at predefined time points over 48 weeks
干预措施: Placebo (Study Part 1a) (Biological)
ACI-24.060 at Dose A in Prodromal AD
Prodromal AD participants receive dose A of ACI-24.060 at predefined time points over 48 weeks
干预措施: ACI-24.060 at Dose A in Study Part 1a (Biological)
ACI-24.060 at Dose B in Prodromal AD
Prodromal AD participants receive dose B of ACI-24.060 at predefined time points over 48 weeks.
干预措施: ACI-24.060 at Dose B in Study Part 1a (Biological)
ACI-24.060 at Dose C in Prodromal AD
Prodromal AD participants receive dose C of ACI-24.060 at predefined time points over 48 weeks.
干预措施: ACI-24.060 at Dose C in Study Part 1a (Biological)
ACI-24.060 with an additional adjuvant at Dose D in Prodromal AD
Prodromal AD participants receive ACI-24.060 with an additional adjuvant at Dose D at predefined time points over 74 weeks.
干预措施: ACI-24.060 with an additional adjuvant at Dose D in Study Part 1b (Biological)
Placebo for Study Part 2 (Down syndrome)
Participants with Down syndrome receive placebo at predefined time points over 74 weeks
干预措施: Placebo (Study Part 2) (Biological)
ACI-24.060 at Dose A in Down syndrome
Participants with Down syndrome receive dose A of ACI-24.060 at predefined time points over 74 weeks. Dose A will be a dose already tested in Study Part 1.
干预措施: ACI-24.060 at Dose A in Study Part 2 (Biological)
ACI-24.060 at Dose B in Down syndrome
Participants with Down syndrome may optionally receive a dose B of ACI-24.060 at predefined time points over 74 weeks.
干预措施: ACI-24.060 at Dose B in Study Part 2 (Biological)
ACI-24.060 at Dose C in Down syndrome
Participants with Down syndrome receive dose C of ACI-24.060 at predefined time points over 74 weeks. Dose C will be a dose already tested in Study Part 1.
干预措施: ACI-24.060 at Dose C in Study Part 2 (Biological)
ACI-24.060 with an additional adjuvant at Dose E in Prodromal AD
Prodromal AD participants receive ACI-24.060 with an additional adjuvant at Dose E at predefined time points over 74 weeks.
干预措施: ACI-24.060 with an additional adjuvant at Dose E in Study Part 1b (Biological)
Placebo for Study Part 1b (Prodromal AD)
Prodromal AD participants receive placebo at predefined time points over 74 weeks
干预措施: Placebo (Study Part 1b) (Biological)
结局指标
主要结局
Number of participants with Adverse Events (AEs) assessed by intensity (mild, moderate or severe) and causal relationship (unrelated, unlikely, possibly or probably related)
时间窗: From Screening to Week 100 (Study Part 2)
Number of participants with abnormal MRI results
时间窗: From Baseline to Week 100 (Study Part 2)
Change from baseline in Anti-Abeta antibody titers in blood
时间窗: From Baseline to Week 100 (Study Part 2)
Number of participants reporting suicidal ideation or behavior using Columbia-Suicide Severity Rating Scale (C-SSRS)
时间窗: From Baseline to Week 100 (Study Part 2)
Number of participants with abnormal physical and neurological examination results
时间窗: From Baseline to Week 100 (Study Part 2)
次要结局
- Change from baseline in Anti-Abeta antibody titers(From Baseline to Week 74 (Study Part 1))
- Change from baseline on brain amyloid levels(From Baseline to W100 (Study Part 2))