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. Master Protocol DIAN-TU-001
490 patients around the world
Available in Argentina, Puerto Rico, Brazil
This study will recruit participants from the Dominantly Inherited Alzheimer Network
(DIAN) observational study, a multicenter international study supported by the National
Institutes of Health (Grant Number U01-AG032438; RJ Bateman), Dominantly Inherited
Alzheimer Network Trial Units (DIAN-TU) sites, DIAN-TU partner sites, DIAN Expanded
Registry (DIAN-EXR), and families identified by the sites. As part of the DIAN-TU-001
protocol, participants undergo longitudinal assessments that include clinical assessment,
cognitive testing, magnetic resonance imaging (MRI) and amyloid and tau positron emission
tomography (PET) imaging, and analysis of blood and cerebrospinal fluid (CSF).
Participants in DIAN are recruited from families that have at least one member who has
been identified as having a mutation linked to dominantly inherited Alzheimer's disease
(DIAD). 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 enrolls individuals who are either known to have
a disease-causing mutation or who are at risk for such a mutation (the descendant 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 as
part of the DIAN Observational (DIAN-OBS) study protocol. This study will enroll
participants 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) and
predict the age of onset with a high degree of confidence provides a unique opportunity
to assess the efficacy of therapies at asymptomatic and 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 participants 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, when allowable in individual drug arms, 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 these participants to avoid
coercion (e.g., potential participants may be pressured into genetic testing to learn
their genetic status in order to be eligible for the trial) unless the drug-specific
design includes open-label treatment. These mutation negative individuals will be
assigned to the placebo group and data will be used to determine normal ranges of outcome
measures. Participants 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
participants 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.
This is an adaptive platform-based study. 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 (referred to as the mutation positive placebos) which may
be shared by study drug arms. Mutation positive participants will be assigned to a study
drug arm and subsequently randomized within that arm to the active drug to placebo ratio
specified in each drug-specific appendix. When included in individual drug arms, mutation
negative participants will all receive placebo treatment. Participants and study staff
will not be blinded as to which study drug arm each participant has been assigned; they
will be blinded as to whether participants have been randomized to active drug or
placebo.
Biomarker, cognitive, and/or clinical endpoints will be specified for each study drug
arm. Biomarker data will be analyzed for pre-specified endpoints consistent with the
drug's mechanism of action and other AD biomarker outcomes.
Interim analyses of the imaging or fluid biomarker endpoint will assess safety and
whether each study drug engages its biological targets. The clinical and cognitive
assessments are designed to assess subtle cognitive changes that may be detectable before
the onset of dementia as well as cognitive and clinical decline in symptomatic groups.
After the last participant in a study drug arm completes the 4-year treatment period,
participants in that study drug arm may be eligible to receive active study drug in an
open-label extension period.
A cognitive run-in (CRI) period was implemented to allow for enrollment during periods
when study drug arms are not randomizing. This enables the DIAN-TU platform to have
continuous enrollment during periods before or in-between drug arm randomization.
The CRI period of cognitive, clinical, and imaging data collection was designed as part
of the platform study to utilize the time in between enrollment of study drug arms. The
CRI period will enhance study enrollment by identifying eligible participants and
engaging them with the cognitive assessments and can reduce practice effects by allowing
participants to habituate to the testing process. The CRI further provides important
baseline and run-in data that adds control data to the platform and informs about the
effects of tested drugs. The data collected in the CRI period will be used for analysis
in the respective drug arm under which participants are randomized and treated.
Solanezumab and gantenerumab double blind treatment arms: Primary Completion Date= Nov
2019 and Study Completion= March 2020 (NCT04623242)
Gantenerumab open-label extension was discontinued based on findings from an interim
efficacy analysis and the status of the drug program. Primary Completion Date= October 6,
2023; Study final completed visit= November 13, 2023 (NCT06424236)
E2814 treatment arm enrollment complete: Primary Completion Date= April 2028 and Study
Completion= July 2028 (NCT05269394)