Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation. (DIAN-TU)

• Assess cognitive efficacy of gantenerumab and solanezumab in individuals with mutations causing dominantly inherited AD as measured by change in the DIAN-TU cognitive composite score. Comparisons will not be made between the two drug treatments. [ Time Frame: Baseline and Week 52, 104, 156, and 208 ] [ Designated as safety issue: No ]
  

• Gantenerumab: Cerebral amyloid imaging using [11C]PiB-PET. [ Time Frame: Baseline and Weeks 52, 104, and 208 ] [ Designated as safety issue: No ]
  
• Solanezumab: Total Abeta 1-42 (Aβ42) in CSF. [ Time Frame: Baseline, Week 104 ] [ Designated as safety issue: No ]
  
• Change in amyloid deposition as measured by [11C]PiB-PET-C-SUVR [when not the biomarker endpoint] [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
  
• Change in CSF amyloid-beta peptide concentrations [when not the biomarker endpoint] [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
  
• Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
  
• Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI) [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
  
• Change in FDG-PET metabolism in specific regions of interest (e.g., precuneus) in treated group as compared to pooled placebo group measured [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
  

• Change from Baseline in Clinical Measures [ Time Frame: Baseline, week 208 ] [ Designated as safety issue: No ]
  • Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
  • Geriatric Depression Scale (GDS)
  • Neuropsychiatric Inventory Questionnaire (NPI-Q)
  • Functional Assessment Questionnaire (FAQ)
  • Mini Mental Status Exam (MMSE)
  • Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
  • Geriatric Depression Scale (GDS)
  • Neuropsychiatric Inventory Questionnaire (NPI-Q)
  • Functional Assessment Questionnaire (FAQ)
  • Mini Mental Status Exam (MMSE)
  
  
• Change from Baseline in Cognitive Measures [ Time Frame: Baseline, week 208 ] [ Designated as safety issue: No ]
  • International Shopping List Test (12-Item Word List Learning): 3 learning trials, Immediate Recall, 30-min Delayed Recall (CogState)
  • Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-min Delayed Recall (CogState)
  • Cogstate Detection Task
  • Cogstate Identification Test
  • Cogstate One Card Learning Test
  • Cogstate One-Back (OBK) Task
  • Stark Pattern Separation Task
  • Memory Complaint Questionnaire (MAC-Q)
  • Trails A & B [baseline, week 208]
  • Wechsler Memory Scale - Revised (WMS-R) Digit Span
  • Wechsler Adult Intelligence Scale - Revised (WAIS-R) Digit-Symbol Substitution Test
  • Raven's Progressive Matrices (Set A)
  • Category Fluency (Animals & Vegetables)
  • Wechsler Memory Scale Logical Memory I Paragraph Memory (Immediate & Delayed Recall)
  
  
• Exploratory Biomarker Measures [ Time Frame: Baseline, week 208 ] [ Designated as safety issue: No ]
  Symptomatic (CDR > 0) and asymptomatic (CDR=0)
  
  
• Safety and Tolerability Outcome Measures [ Time Frame: 4 Years ] [ Designated as safety issue: Yes ]
  • Frequency of adverse events during the treatment period
  • Nature and severity of adverse events during the treatment period
  
  
• Safety and Tolerability Outcome Measures [ Time Frame: Baseline, week 208 ] [ Designated as safety issue: No ]
  • Vital signs/physical findings
  • Neurological findings
  • Laboratory test results
  • ECG findings
  
  

The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with autosomal dominant 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 (Ryman et al., 2014), 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 of 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 at asymptomatic and very early stages of dementia. Although there are differences between dominantly inherited AD and the more common age-associated sporadic disease, the results of the early intervention in this study will have implications for future studies and treatments in sporadic AD. 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 Autosomal Dominant 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; 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. Two different therapies will be tested in order to increase the likelihood that an effective treatment will be discovered. They were selected for this trial based on mechanism of action and available data on efficacy and safety profile.

The study design includes a pooled placebo arm shared by all treatment groups. Mutation positive subjects will be randomized to one of the four study arms (gantenerumab:gantenerumab placebo:solanezumab:solanezumab placebo) in an overall 3:1:3:1 ratio for active drug:placebo. Mutation negative subjects will all receive placebo. Importantly, subjects and study staff will not be blinded as to which treatment group each subject has been assigned; they will be blinded as to whether subjects have been randomized to active drug or placebo arms. Biomarker data will be analyzed for prespecified 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 both treatment arms. 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 the time of enrollment 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 four year cognitive endpoint will allow for analysis of these subtle cognitive changes.