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)

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.

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

Eli Lilly and Company, Hoffmann-La Roche, Alzheimer's Association, National Institute on Aging (NIA), Avid Radiopharmaceuticals, Accelerating Medicines Partnership (AMP)

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

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.

Alzheimer's, Alzheimer's Disease, Dementia, Mutation, Genetic Mutation, Dominantly Inherited Alzheimer's Disease, Dominantly Inherited Alzheimer Network, Autosomal Dominant Alzheimer's Disease, Early Onset Alzheimer's Disease, DIAN, DIAN-TU, DIAN TU, DIAD

Assess Cognitive Efficacy in Individuals With Mutations Causing Dominantly Inherited AD as Measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE);

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.

CDR-SB score is considered a more detailed quantitative general index of cognition and function, and provides more information than the global CDR score in patients with mild dementia Scores range from 0-18 with lower scores showing more favorable cognitive function.

The Functional Assessment Scale is to be administered and completed by the study partner about subjects for whom they care. This scale measures instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS is to assess change in an individual's functional activities, relative to previously attained abilities, that are caused by cognitive dysfunction. If the study partner indicates that the subject no longer performs a particular task, it is reasonable to probe further and ask if they think the subject could still do the task. This will help tease out the relevant cognitive impairment

Gantenerumab: Imaging Measures Composite [11C] PiB Partial Volume Corrected Regional Spread Function Standardized Uptake Value Ratio - Composite

In vivo quantification of β-amyloid deposition using positron emission tomography. This measure is a composite of brain regions. Higher scores indicate worse disease stage.

CDR-SB score is considered a more detailed quantitative general index and provides more information than the global CDR score in patients with mild dementia Scores range from 0-18 with lower scores showing more favorable cognitive function.

The Geriatric Depression Scale (GDS) is a self-report measure of depression in older adults. Users respond in a "Yes/No" format. Of the 15 items, 10 indicate the presence of depression when answered positively while the other 5 are indicative of depression when answered negatively. Scores range from 0-15 for completed questionnaires. A score of 88 is recorded for participants unable to complete the test. Lower scores show more favorable outcome.

The questionnaire is to be administered and completed by the study partner about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are "Yes"(present) or "No" (absent). If the response to the domain question is "No", the study partner goes to the next question. If "Yes", the study partner then rates both the Severity of the symptoms present within the last month on a 3-point scale and the associated impact of the symptom manifestations on them (i.e. Caregiver Distress) using a 5-point scale. The NPI-Q provides symptom 'Severity' and 'Distress' ratings for each symptom reported, and total 'Severity' and 'Distress' scores reflecting the sum of individual domain scores. Scores range from 0-36 with lower scores indicating more favorable cognitive function.

The Functional Assessment Scale is to be administered and completed by the study partner about subjects for whom they care. This scale measures instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS is to assess change in an individual's functional activities, relative to previously attained abilities, that are caused by cognitive dysfunction. If the study partner indicates that the subject no longer performs a particular task, it is reasonable to probe further and ask if they think the subject could still do the task. This will help tease out the relevant cognitive impairment Scores range from 0-30 with lower scores indicate more favorable cognitive performance

MMSE is a brief, quantitative measure of cognitive status in adults used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual's response to treatment. Scores range from 0-30 and higher scores indicate more favorable cognitive function.

Classic list-learning test that measures verbal learning & memory. Scores range from 0-12 with higher scores indicating more favorable cognitive performance.

The Groton Maze Learning Test 30 minute delayed recall measures episodic memory. The primary outcome is the number of errors made during recall of the previously memorized pathway from the Groton Maze Learning Test. The minimum score is 0 errors and the max is 999. Lower scores indicate better cognitive performance.

The Groton Maze Learning Test measures executive function using a maze learning paradigm. A 10 x 10 grid of tiles is presented to the participant on the screen. A 28-step pathway is hidden among these tiles. A blue tile indicates the start and a tile with red circles indicates the finish. The participant must move one step at a time from the start toward the end by touching a tile next to their current location. If the correct move is made a green checkmark appears and if the move is incorrect a red cross is revealed. Once completed, they are returned to the start location to repeat the test and must try to remember the pathway they have just completed. "Delayed Reverse Recall" measures spatial working memory. The outcome is the number of errors made with the range of 0-999. Lower scores indicate better cognitive performance.

Trail Making test taps attention, processing speed, and executive function. Part A consists of 25 circles numbered 1 through 25 distributed over a white sheet of standard document-sized paper. The subject is instructed to connect the circles with a drawn line as quickly as possible in ascending numerical order without lifting their pen. The subject's performance is judged in terms of the time, in seconds, required to complete each trail (Max time 150 seconds). Lower scores indicate more favorable cognitive function.

This test taps attention, processing speed, and executive function and depends on visuo-motor and perceptual-scanning skills and also requires considerable cognitive flexibility in shifting from number to letter sets under time pressure. Part B consists of 25 circles, but these circles contain either numbers (1 through 13) or letters (A through L). The subject must connect the circles while alternating between numbers and letters in an ascending order (e.g., A to 1; 1 to B; B to 2; 2 to C). The subject's performance is judged in terms of the time, in seconds, required to complete each Trail (Max of 300 seconds). Lower scores indicate more favorable cognitive function.

This test engages multiple cognitive abilities, including attention, psychomotor speed, complex scanning, visual tracking, and immediate memory. Scores range from 0-93 with higher scores indicate more favorable cognitive function.

Widely used measure of working memory (or attention) in which the subject is read number sequences of increasing length and then asked to repeat each sequence backward. The primary measure of performance is the number of digit sequences correctly reversed. The unit of measure is number of digit sequences correctly recalled and ranges from 0-12. Higher scores indicate more favorable cognitive function.

This is a widely-used test of working memory in which the subject is read number sequences of increasing length and asked to repeat them. The total score is the number of sequences correctly repeated. The unit of measure is number of digit sequences correctly recalled and ranges from 0-12. Higher scores indicate more favorable cognitive function.

This is a measure of fluid intelligence. This test is used to get an estimate of the subjects IQ at baseline. Subjects are asked to complete a visual pattern by circling one of six response choices. Scores range from 0-12 with higher scores indicating more favorable cognitive performance.

Category Fluency is a widely used measure of semantic memory (verbal fluency, language). The subject is asked to name different exemplars of a given semantic category (animals), and the number of unique exemplars named is scored. Higher scores indicate more favorable cognitive function.

Category Fluency is a widely used measure of semantic memory (verbal fluency, language). The subject is asked to name different exemplars of a given semantic category (vegetables), and the number of unique exemplars named is scored. Higher scores indicate more favorable cognitive function.

Measure of delayed recall (episodic memory) of a story read to the subject at the beginning of the testing session and subject is asked to relay the story 20 minutes later. Scores range from 0-25 with higher scores indicating more favorable cognitive performance.

This test assesses the ability to recall a short story. The subject is read a short story and immediately after hearing the story, the subject is asked to retell the story from memory. Scores range from 0-25 with higher scores indicating more favorable cognitive performance.

Solanezumab: Cognitive Measures- Composite Including: Alternative Multivariate Composite: (1) Digit Span Backwards; (2) Logical Memory (Immediate); (3) Trailmaking B; (4) Category Fluency (Animals)

Multivariate Disease Progression Model adjusted for estimated years from symptom onset (EYO) and includes all time points up to treatment discontinuation. The treatment effect for Solanezumab is reported relative to the mutation positive placebo arm. This alternative multivariate endpoint includes four tests: Logical Memory Immediate Recall, Digit Span Backward Recall, Category Fluency (Animals), Trailmaking Test Part B. Measurements for each test will be normalized using the mean (SD) at DIAN-TU-001 baseline among mutation negative subjects before being analyzed. For the Trailmaking Test B, the scores will be multiplied by -1 as higher scores indicate worse performance; whereas for the other three, lower scores indicate worse performance. Therefore, on the standardized endpoints, lower scores indicate worse performance.

Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by [11C]PiB-PET Non-partial Volume Corrected

PiB Standardized Uptake Value Ratio ([11C]PiB SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions dervived via automated segmentation using FreeSurfer) with respect to a reference region. In amyloid and tau imaging, SUVR is typically generated using some portion or the entire cerebellum as a reference because cerebellum is not affected until late in the progression of AD.

Florbetapir Standardized Uptake Value Ratio ([18F]AV-45 SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions derivved via automated segmentation using FreeSurfer) with respect to a reference region. In amyloid and tau imaging, SUVR is typically generated using some portion or the entire cerebellum as a reference because cerebellum is not affected until late in the progression of AD.

Solanezumab: Imaging Measures- Brain Glucose Metabolism as Measured by Fluorodeoxyglucose (FDG)-PET Non-partial Volume Corrected

FDG Standardized Uptake Value Ratio ([18F]FDG SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions derivved via automated segmentation using FreeSurfer) with respect to a reference region. In amyloid and tau imaging, SUVR is typically generated using some portion or the entire cerebellum as a reference because cerebellum is not affected until late in the progression of AD.

Solanezumab: Imaging Measures- Brain Atrophy as Measured by Cortical Thickness of Regions of Interest - Precuneus Region

Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. For the clinical trial we examined cortical thickness values in prespecified regions of interest known to show atrophy in autosomal dominant Alzheimer Disease. Higher measurements are more favorable.

Solanezumab: Imaging Measures- Volumetric MRI Combined Total Volume Corrected for Head Size - Hippocampus Volume

Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. For the clinical trial we examined volume values in prespecified regions of interest known to show atrophy in autosomal dominant Alzheimer Disease.

Solanezumab: Imaging Measures- Brain Tau Load as Measured by Flortaucipir PET Non-partial Volume Corrected

This variable represents how much neurofibrillary tau pathology is present in brain as assessed using positron emission tomography (PET). Scans were conducted using [F18] Flortaucipir, a commonly used tracer in the field.

Solanezumab: Imaging Measures- Brain Atrophy as Measured by Whole Brain Volume Corrected for Head Size

Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. A whole brain volume measure was generated to represent global atrophy across the cortical and subcortical regions.

Solanezumab: Imaging Measures- Brain Atrophy as Measured by Ventricular Volume (Volumetric MRI) Corrected for Head Size

Rather than looking at how tissue in the brain changes, it is also possible to quantify how the ventricles, fluid filled spaces in the brain, change. Increasing ventricular volume represents greater amounts of cerebral spinal fluid which suggests atrophy of the brain. Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequences were processed using the Freesurfer software suite. Total ventricular volume was calculated from the ventricular volumes generated by this program.

Measured concentration of the drug bound and free soluble Aβ1-40 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)

Measurement of the presence or absence of anti-drug antibodies in serum Note: Mutation Negative Placebo subjects are not displayed as anti-drug antibody testing was not to be evaluated for these subjects. Note: Treatment Emergent Anti-Drug Antibody Positive subjects are defined as those with either (a) a baseline status of ADA Not Present and at least one post-baseline ADA present with a titer >= 1:20 or (b) both a baseline and post-baseline status of ADA Present with the post-baseline titer being 2 dilutions (4-fold) greater than the baseline titer. Note: Treatment Emergent Anti-Drug Antibody Inconclusive subjects are defined as those for whom >=20% of the subject's post-baseline ADA results are ADA Inconclusive and all remaining post-baseline samples are ADA Not Present. Note: Treatment Emergent Anti-Drug Antibody Negative subjects are defined as those who are evaluable for TE ADA but are neither TE ADA Positive nor TE ADA Inconclusive.

Measured concentration of the total soluble Aβ1-42 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)

Measured concentration of the total soluble Aβ1-40 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)

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 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. Exclusion Criteria: 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.

Access to DIAN-TU trial data will follow the DIAN-TU data access policy, which complies with the guidelines established by the Collaboration for Alzheimer's Prevention [CAP REF].

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