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)

• Gantenerumab: The amount of fibrillar amyloid deposition as measured by [11C]PiB-PET scans. [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Solanezumab: The concentrations of CSF Aβ species, specifically different treatment effects on free CSF Aβ42 (increase/no change) and free CSF Aβ40 (decrease) with comparable treatment-associated increases in CSF total Aβ42 and total Aβ40. [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]

• Solanezumab Only: Change in amyloid deposition as measured by [11C]PiB-PET mean composite SUVR (Standardized uptake value ratio) [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Gantenerumab Only: Change in Cerebrospinal fluid (CSF) amyloid-beta peptide concentrations. [ Time Frame: Baseline and 2 years ] [ 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 and 2 years ] [ 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 and 2 years ] [ Designated as safety issue: No ]
• Change in 2-[18F] fluoro-2-deoxy-D-glucose (FDG) PET metabolism in specific regions of interest (e.g., precuneus) in treated group as compared to pooled placebo group measured [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]

• Frequency of adverse events during the treatment period [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Nature and severity of adverse events during the treatment period [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Changes in vital signs/physical findings [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Changes in neurological findings [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Changes in laboratory test results [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Changes in ECG findings [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Exploratory Clinical Measures (annual rate of change) [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
  • Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
  • Mini Mental Status Exam (MMSE)
  • Geriatric Depression Scale (GDS)
  • Neuropsychiatric Inventory Questionnaire (NPI-Q)
  • Functional Assessment Questionnaire (FAQ)
• Exploratory Cognitive Measures (annual rate of change) [ Time Frame: Baseline and 2 years ] [ 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)
  • Identification Test (CogState)
  • One Card Learning Test (CogState)
  • Memory Complaint Questionnaire (MAC-Q)
  • Trails A & B
  • 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 to Animals & Vegetables
  • Wechsler Memory Scale Logical Memory I Paragraph Memory (Immediate & Delayed Recall)
  • Rentz Face-Name Association Memory Test (CogState)
  • Stark Pattern Separation Task (CogState)

• Frequency of adverse events during the treatment period [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Nature and severity of adverse events during the treatment period [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Changes in vital signs/physical findings [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Changes in neurological findings [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Changes in laboratory test results [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Changes in ECG findings [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
• Exploratory Clinical Measures (annual rate of change) [ Time Frame: Baseline and 2 years ] [ Designated as safety issue: No ]
  • Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
  • Mini Mental Status Exam (MMSE)
  • Geriatric Depression Scale (GDS)
  • Neuropsychiatric Inventory Questionnaire (NPI-Q)
  • Functional Assessment Questionnaire (FAQ)
• Exploratory Cognitive Measures (annual rate of change) [ Time Frame: Baseline and 2 years ] [ 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)
  • Identification Test (CogState)
  • One Card Learning Test (CogState)
  • Memory and Concerns Questionnaire (MAC-Q)
  • Trails A & B
  • 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 to Animals & Vegetables
  • Wechsler Memory Scale Logical Memory I Paragraph Memory (Immediate & Delayed Recall)
  • Rentz Face-Name Association Memory Test (CogState)
  • Stark Pattern Separation Task (CogState)

The purpose of this study is to assess the safety, tolerability and biomarker efficacy of Gantenerumab and Solanezumab in individuals who have an autosomal dominant Alzheimer's disease (ADAD) mutation.

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 of onset of cognitive changes is relatively consistent within each family, an age of onset is determined for each affected parent as part of the DIAN longitudinal study protocol. Subjects will be eligible for enrollment in the DIAN-TU-001 study when they are between 15 years younger (-15) to 10 years older (+10) than the age of onset of their affected parent.

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 as the primary study endpoints to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest, most subtle cognitive changes will be collected, but will not be primary endpoints as many of these clinically asymptomatic individuals are likely to have minimal changes in cognitive measures during the study. 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.

This study design is possible because the biomarker endpoints are relatively robust. The study design includes a pooled placebo arm shared by all treatment groups. Mutation positive subjects will be randomized to one of the three study arms (placebo, gantenerumab, solanezumab). Mutation negative subjects will all receive placebo, but will be randomized to receive matching placebo for gantenerumab or solanezumab. 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 endpoints will be specified for each treatment arm. Biomarker endpoints will be assessed at least annually. Biomarker data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of action and known effects on the tested biomarkers. At the end of the study period, the Sponsor will consider developing an extension study that would allow subjects enrolled in this study to rollover to a longer therapeutic trial with cognitive endpoints.

• Alzheimers Disease
• Dementia
• Alzheimers Disease, Familial

• Drug: Gantenerumab
  225 mg subcutaneously every 4 weeks
  Other Name: RO4909832
• Drug: Solanezumab
  400 mg intravenous infusion every 4 weeks
  Other Name: LY2062430
• Drug: Matching Placebo (Gantenerumab)
  subcutaneous injection of placebo every 4 weeks
• Drug: Matching Placebo (Solanezumab)
  intravenous infusion of placebo every 4 weeks

• Experimental: Gantenerumab
  Intervention: Drug: Gantenerumab
• Experimental: Solanezumab
  Intervention: Drug: Solanezumab
• Placebo Comparator: Matching placebo (Gantenerumab)
  Intervention: Drug: Matching Placebo (Gantenerumab)
• Placebo Comparator: Matching Placebo (Solanezumab)
  Intervention: Drug: Matching Placebo (Solanezumab)

• Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. Epub 2012 Jul 11.
• Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement. 2012 Jul;8(4):261-71. doi: 10.1016/j.jalz.2011.09.224. Epub 2012 Jun 5.

Inclusion Criteria:

• 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 a 50% chance of having an autosomal dominant Alzheimer's disease (ADAD) mutation (e.g. parent or sibling with a known AD-causing mutation)
• Are within -15 to + 10 years of their parental age of symptom onset
• Cognitively normal or with mild cognitive impairment or mild dementia, Clinical Dementia Rating (CDR) of 0-1 (inclusive)
• 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, subject must agree to use effective contraceptive measures (hormonal contraception, intra-uterine device, sexual abstinence) if partner is not sterilized. Men must agree to use effective contraceptive measures.
• 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, and who signs the necessary consent form if applicable.

Exclusion Criteria:

• History or presence of brain MRI scans indicative of any other significant abnormality
• 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.

• Eli Lilly and Company
• Hoffmann-La Roche
• Alzheimer's Association