A Phase II/III Randomized, Double-Blind, Placebo-Controlled, Cognitive Endpoint, Multi-Center Study of Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 194
- 试验地点
- 25
- 主要终点
- Assess Cognitive Efficacy in Individuals With Mutations Causing Dominantly Inherited AD as Measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE);
研究概览
简要总结
The purpose of this study is to assess the safety, tolerability, biomarker and cognitive efficacy of investigational products in subjects who are known to have an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive impairment and improves disease-related biomarkers.
This is an analysis study for an MPRP: DIAN-TU-001 Master NCT01760005
详细描述
The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with dominantly inherited Alzheimer's disease have very high penetrance (near 100%). This study will target individuals who are either known to have a disease-causing mutation or who are at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status. Because the age at onset of cognitive changes is relatively consistent within each family and with each mutation, an age at onset is determined for each affected parent or mutation. This study will enroll subjects who are either asymptomatic and are within a specific window of time of expected age at onset for their family and/or mutation or who have symptoms of mild Alzheimer's disease.
The ability to identify individuals destined to develop Alzheimer's disease (AD) within the next 10-15 years with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies while individuals are asymptomatic and/or very early stages of dementia. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. These constraints necessitate a specialized study design. Many of the subjects in this study will not yet have any cognitive symptoms of AD; they will be "asymptomatic" carriers of mutations that cause dominantly inherited Alzheimer's disease and would be expected to perform normally on standard cognitive and functional testing. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected. Additionally, because many at-risk individuals decide not to know whether they have the disease-associated mutation or not, some of the at-risk individuals enrolled in this study will not have the disease causing mutations; they will be "mutation negative". It is important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be pressured into genetic testing to learn their genetic status in order to be eligible for the trial). These mutation negative individuals will be assigned to the placebo group; and will not be included in the primary efficacy or futility analyses. Subjects and site study staff will remain blinded as to these individuals' active or placebo group assignment and mutation status. Thus, the study will be double blinded for placebo and for mutation status, except for mutation positive subjects who are aware of their genetic status. There may be exceptional circumstances when required by local regulation or health authorities where enrollment may be restricted to mutation carriers only but such mandates will be thoroughly documented and agreed upon by the governing regulatory agency and sponsor. Several different therapies (each referred to as a study drug arm) will be tested in order to increase the likelihood that an effective treatment will be discovered. The compounds are selected for this trial based on mechanism of action and available data on efficacy and safety profile.
The study design includes a pooled placebo group shared by all study drug arms. Mutation positive subjects will be assigned to a study drug arm and subsequently randomized within that arm in an overall 3:1 ratio to active drug:placebo. Mutation negative subjects will all receive placebo treatment. Importantly, subjects and study staff will not be blinded as to which study drug arm (gantenerumab or solanezumab) each subject has been assigned; they will be blinded as to whether subjects have been randomized to active drug or placebo. Biomarker data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of action and known effects on the tested biomarkers. The primary cognitive endpoint will be the same for all study drug arms. This study is an adaptive platform based study. Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study drug engages its biological targets. This biomarker approach is particularly important in this study as most study subjects will be cognitively normal at baseline and most will remain cognitively normal during the first 2 years of the study. The cognitive composite is designed to assess subtle cognitive changes that may be detectable before the onset of dementia. The cognitive multivariate disease progression model (MDPM) endpoint design will allow for detection of these subtle cognitive changes.
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
- 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 or are unaware of their genetic status and have dominantly inherited Alzheimer's disease (DIAD) mutation in their family.
- •Are within -15 to + 10 years of the predicted or actual age of cognitive symptom onset.
- •Cognitively normal or with mild cognitive impairment or mild dementia, Clinical Dementia Rating (CDR) of 0-1 (inclusive)
- •Fluency in DIAN-TU trial approved language and evidence of adequate premorbid intellectual functioning
- •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
干预措施: Gantenerumab (Drug)
Solanezumab
干预措施: Solanezumab (Drug)
Matching placebo (Gantenerumab)
干预措施: Matching Placebo (Gantenerumab) (Drug)
Matching Placebo (Solanezumab)
干预措施: Matching Placebo (Solanezumab) (Drug)
结局指标
主要结局
Assess Cognitive Efficacy in Individuals With Mutations Causing Dominantly Inherited AD as Measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE);
时间窗: Baseline through Week 260
Multivariate Disease Progression Model adjusted for Estimated Years to Onset (EYO)and includes all timepoints up to treatment discontinuation. The treatment effect is reported relative to the mutation positive placebo arm. Multivariate Cognitive Endpoint comprising: (i) Wechsler Memory Scale-Revised Logical Memory Delayed Recall Test (MEMUNITS), (ii) Wechsler Adult Intelligence Scale Digit Symbol Substitution Test (WAIS), (iii) Mini-Mental State Examination (MMSE), and (iv) International Shopping List Task (ISLT). Measurements for each test were normalized using the mean (SD) at DIAN-TU-001 baseline for mutation negative subjects. Higher scores indicate more favourable cognitive performance.
次要结局
- Solanezumab: Clinical Measures- Functional Assessment Scale (FAS)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Gantenerumab: Rate of Change Over Time- Clinical Dementia Rating Sum of Boxes (CDR-SB)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Gantenerumab: Rate of Change Over Time- Functional Assessment Scale (FAS)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Clinical Measures- CDR Sum of Boxes (CDR-SB)(Baseline and Weeks 52, 104, 156, and 208)
- Solanezumab: Clinical Measures- Mini-Mental Status State Examination (MMSE)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- International Shopping List Task 30-Minute Delayed Recall(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- Groton Maze Learning Test 30 Minute Delayed Recall(Baseline, Week 52, 104, 156, 208 and 260)
- Gantenerumab: Imaging Measures Composite [11C] PiB Partial Volume Corrected Regional Spread Function Standardized Uptake Value Ratio - Composite(Baseline, Weeks 52, 104 and 208)
- Solanezumab: Clinical Measures- Clinical Dementia Rating (CDR)(Baseline and Weeks 52, 104, 156, and 208)
- Solanezumab: Cognitive Measures- Trailmaking Test Part A(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- Raven's Progressive Matrices (Set A)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- WMS-R Logical Memory Delayed Recall Test(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- WMS-R Logical Memory Immediate Recall Test(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Clinical Measures- Geriatric Depression Scale (GDS)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Clinical Measures- Neuropsychiatric Inventory Questionnaire (NPI-Q)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- Trailmaking Test Part B(Baseline, Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- Category Fluency (Animals)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by [11C]PiB-PET Non-partial Volume Corrected(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Imaging Measures- Brain Glucose Metabolism as Measured by Fluorodeoxyglucose (FDG)-PET Non-partial Volume Corrected(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Cognitive Measures- WAIS-R Digit-Symbol Substitution Test(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- Category Fluency (Vegetables)(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Imaging Measures- Brain Atrophy as Measured by Cortical Thickness of Regions of Interest - Precuneus Region(Baseline and Weeks 52, 104, 156 and 208)
- Solanezumab: Imaging Measures- Volumetric MRI Combined Total Volume Corrected for Head Size - Hippocampus Volume(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Imaging Measures- Brain Atrophy as Measured by Whole Brain Volume Corrected for Head Size(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Fluid Biomarker Measures- CSF Aβ 42 Free(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- CSF Tau(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- CSF Aβ 42 Total(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Cognitive Measures- Groton Maze Learning Test Delayed Reversed Recall(Baseline, Week 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- WMS-R Digit Span Backward(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- WMS-R Digit Span Forward(Baseline, Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Cognitive Measures- Composite Including: Alternative Multivariate Composite: (1) Digit Span Backwards; (2) Logical Memory (Immediate); (3) Trailmaking B; (4) Category Fluency (Animals)(Baseline through Week 260)
- Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 Free Change From Baseline(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- Total Plasma Aβ 1-40(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 Total(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by Florbetapir PET(Weeks104 and 208)
- Solanezumab: Imaging Measures- Brain Tau Load as Measured by Flortaucipir PET Non-partial Volume Corrected(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Imaging Measures- Brain Atrophy as Measured by Ventricular Volume (Volumetric MRI) Corrected for Head Size(Baseline and Weeks 52, 104, 156, 208 and 260)
- Solanezumab: Fluid Biomarker Measures- CSF pTau 181(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Change From Baseline Fluid Biomarker Measures- CSF Neurofilament Light Chain (NfL)(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- Plasma Neurofilament Light Chain (NfL)(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- Plasma Anti-drug Antibodies (ADA)(Baseline and Weeks 52, 104 and 208)
- Solanezumab: Fluid Biomarker Measures- Total Plasma Aβ 42(Baseline and Weeks 52, 104 and 208)