A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled Platform Trial of Potential Disease Modifying Therapies Utilizing Biomarker, Cognitive, and Clinical Endpoints in Dominantly Inherited Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 73
- 试验地点
- 17
- 主要终点
- Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156
研究概览
简要总结
The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers.
详细描述
Alzheimer's disease (AD) is defined by the presence of abnormal accumulations of amyloid protein (plaques) and tau protein (tangles) in the brain. The double-blind arm of DIAN-TU-001 Master protocol (NCT01760005) tested whether gantenerumab provided a clinical benefit by slowing the onset or the worsening of the disease. A clinical benefit was not observed in the double-blind part of the DIAN-TU-001 study. However, gantenerumab was associated with improvements in measures of amyloid and tau and an improvement in an overall measure of neurodegeneration (when nerve cells in the brain lose function over time). It is not known whether these changes may provide future clinical benefits. Based on this information, an exploratory Open Label Extension (OLE) will further study the effect of gantenerumab on these Alzheimer-related proteins and their relationship to disease progression.
After this final evaluation of study treatment with gantenerumab used in the gantenerumab / solanezumab double-blind arm of the Master protocol (NCT01760005), eligible participants from the placebo, solanezumab, and gantenerumab treatment groups in double-blind period were invited to participate in an OLE period to receive active gantenerumab study treatment as part of the DIAN-TU-001 Master protocol. The OLE period of the study planned to provide study treatment with gantenerumab for up to 3 years (36 months).
This study collected brain scans, blood, and spinal fluid tests (also called biomarkers), as well as safety, clinical and cognitive testing. The goal is to determine if gantenerumab has favorable effects on these tests to determine if and how much treatment may prevent or delay the symptoms of AD.
Update:
Based on the results of the completed studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer's disease (DIAD) participants in the DIAN-TU-001 OLE study were substantially clinically benefiting from gantenerumab high-dose treatment before the trial reached completion as the Gant program was being stopped.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Arm is Open-label as noted in the arm description
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Between 18-80 years of age
- •Individuals who know they have an Alzheimer's disease-causing mutation
- •Individuals who have participated in the double-blind period
- •In the opinion of the investigator and sponsor, treatment is not contraindicated for safety
- •Capable of receiving drug and appropriate clinical safety assessment
- •Able to undergo Magnetic Resonance Imaging (MRI), Lumbar Puncture (LP), Positron Emission Tomography (PET), and complete all study related testing and evaluations.
- •For women of childbearing potential, if partner is not sterilized, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence, barrier method with spermicide).
- •Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
- •Has a Study Partner who in the investigator's judgment is able to provide accurate information as to the subject's cognitive and functional abilities, who agrees to provide information at the study visits which require informant input for scale completion.
排除标准
- •History or presence of brain MRI scans indicative of any other significant abnormality
- •Alcohol or drug dependence currently or within the past 1 year
- •Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin or body which would preclude MRI scan.
- •History or presence of clinically significant cardiovascular disease, hepatic/renal disorders, infectious disease or immune disorder, or metabolic/endocrine disorders
- •Anticoagulants except low dose (≤ 325 mg) aspirin.
- •Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the past six months.
- •History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.
- •Positive urine or serum pregnancy test or plans or desires to become pregnant during the course of the trial.
- •Subjects unable to complete all study related testing, including implanted metal that cannot be removed for MRI scanning, required anticoagulation and pregnancy.
研究组 & 干预措施
Gantenerumab Open Label Extension
Gantenerumab: Subcutaneously every 4 weeks, at escalating doses; at target, dosing was every 2 weeks
干预措施: Gantenerumab (Drug)
结局指标
主要结局
Change From Baseline in Composite [11C] Pittsburgh Compound B (PiB)-Positron Emission Tomography (PET) Composite Standardized Uptake Value Ratio (C-SUVR) at Weeks 52, 104 and 156
时间窗: Baseline (Day 1) and Weeks 52, 104 and 156
The composite PiB partial volume corrected C-SUVR was used as the biomarker endpoint for amyloid deposition using PET. The C-SUVR of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex, and temporal cortex of brain regions was analyzed. Higher ratio indicate worse disease stage. Baseline was defined as the last non-missing measurement prior to OLE study drug administration.
次要结局
- Change From Baseline in Clinical Dementia Rating (CDR) - Sum of Boxes Score at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in Clinical Dementia Rating - Global Score at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in Functional Assessment Scale (FAS) at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in Mini-Mental State Examination (MMSE) at Weeks 24, 52, 76, 104, 128 and 156(Baseline (Day 1) and Weeks 24, 52, 76, 104, 128 and 156)
- Change From Baseline in Tau Positron Emission Tomography Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in Phosphorylated Tau (pTau)-181 in Cerebrospinal Fluid (CSF) at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in Neurofilament Light Chain (NfL) in Cerebrospinal Fluid at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in Amyloid Beta1-42/40 Ratio in Cerebrospinal Fluid at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)
- Change From Baseline in DIAN-TU Open Label Extension Cognitive Composite Score at Weeks 52, 104 and 156(Baseline (Day 1) and Weeks 52, 104 and 156)