Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation (DIAN-TU) (DIAN-TU)
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ClinicalTrials.gov Identifier: NCT05269394 |
Recruitment Status :
Recruiting
First Posted : March 8, 2022
Last Update Posted : February 22, 2024
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Tracking Information | |||||||||
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First Submitted Date ICMJE | January 13, 2022 | ||||||||
First Posted Date ICMJE | March 8, 2022 | ||||||||
Last Update Posted Date | February 22, 2024 | ||||||||
Actual Study Start Date ICMJE | December 22, 2021 | ||||||||
Estimated Primary Completion Date | July 2027 (Final data collection date for primary outcome measure) | ||||||||
Current Primary Outcome Measures ICMJE |
The primary end point is the change from Week 24 to Week 104 and Week 208 in tau PET in the Symptomatic Population (Cohort 1). [ Time Frame: Weeks 24, 104, and 208 ] To determine whether E2814 is superior to placebo, when each is concurrently administered with lecanemab, in the change from Week 24 to Week 104 (interim analysis) and Week 208 (final analysis) in tau spread as measured by tau PET in the symptomatic population (Cohort 1).
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Original Primary Outcome Measures ICMJE | Same as current | ||||||||
Change History | |||||||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
Descriptive Information | |||||||||
Brief Title ICMJE | Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation (DIAN-TU) | ||||||||
Official Title ICMJE | A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled Platform Trial of Potential Disease Modifying Therapies Utilizing Biomarker, Cognitive, and Clinical Endpoints in Dominantly Inherited Alzheimer's Disease | ||||||||
Brief Summary | To assess the safety, tolerability, biomarker, cognitive, and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug improves disease-related biomarkers and slows the rate of progression of cognitive or clinical impairment. | ||||||||
Detailed Description | Alzheimer's disease (AD) is characterized pathologically by the presence of accumulation of amyloid plaques and tau-containing neurofibrillary tangles (NFTs) in the brain. Amyloid plaques can be detectable within the brain some years before symptoms manifest whereas tau-mediated toxicity has been hypothesized to appear later during the course of disease. Physiologically, tau is predominantly a neuronal microtubule-associated protein that plays a fundamental role in the stabilization of microtubules. Under pathological conditions however, short motifs in the microtubule binding region (MTBR) domains of tau adopt a beta-sheet conformation, inducing self-assembly with other tau molecules that lead to the formation of insoluble aggregates. Insoluble tau is also a feature of a number of different neurodegenerative diseases collectively termed tauopathies. The accumulation of insoluble deposits has been suggested to result in altered distribution and function of organelles to adversely affect neuronal cell function as well as causing synapse loss, ultimately leading to cell death. In AD, evidence also suggests a direct correlation between the number of NFTs found in the brain at postmortem and the degree of dementia observed in subjects with AD at the time of death. The microtubule-associated protein tau (MAPT) gene is located on chromosome 17 of the human genome. Through alternative splicing, 6 possible tau protein isoforms are expressed from this gene in the adult brain. A number of studies have suggested that pathological forms of tau protein transmit from neuron to neuron in human brain to cause disease, including AD. It has also been reported that tau can form seeds, which when applied extracellularly, can cause the initiation and propagation of intracellular tau aggregation. To form tau seeds, the MTBR of the protein is required. Furthermore, the tau MTBR is important in initiating the tau aggregation process and forming the core of fibrils pathologically associated with disease. Together, these observations suggest that therapeutic intervention with an antibody that binds to the MTBR region of tau in the brain, thereby disrupting tau aggregation may prevent initiation or slow down the neurodegeneration in AD or other tauopathies. Upcoming Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trials are designed to investigate therapies targeting tau in combination with amyloid as pre-specified in the approved and NIH-funded NexGen Prevention Trial grants. As with other amyloid lowering drug trials, clinical benefit was not definitively demonstrated in the symptomatic population after tau pathology has been established. Determining the role of tau in disease biology and progression is critically important. Based on beneficial effects on amyloid, tau, and neurodegeneration markers associated with amyloid removal in the gantenerumab trial arm in DIAN-TU, the DIAN-TU will now implement amyloid removal treatment in mutation carriers and add placebo- controlled tau treatment arms. The platform trial design is exceptionally well-suited for the investigation of treatments used in combination because of ongoing multiple arms in a single trial and operational platform. The current DIAN-TU amyloid removal drug arm has been extended to open-label extension (OLE) periods for prior participants. All enrolled participants who opted-in for OLE were unblinded to genetic status and offered open-label gantenerumab treatment. New treatment- naive mutation positive participants will be started on amyloid removal treatment with genetic counseling and testing. Therefore, all participants will be required to be positive for a dominantly inherited Alzheimer's disease (DIAD) mutation and will receive open-label treatment with lecanemab, an investigational amyloid removal drug, in combination with E2814, an anti-tau drug or placebo. Mutation non-carriers will not be enrolled. Specifically, all E2814 blinded drug arm participants will be treated with the lecanemab and randomized to either active E2814 tau therapy, or placebo. The goal of the study is to investigate potential benefits of anti-tau therapy while anti-amyloid treatment is given as a background therapy. Furthermore, from ethical and participant recruitment perspectives, launching drug trials using amyloid and tau targeting therapies in combination may be essential, as participants and their families have expressed the need to have a drug that changes amyloid disease pathology in addition to being randomized to an investigational anti-tau drug (E2814) with uncertain benefit. This record represents an analysis study portion of the Master Protocol Research Program (MPRP) under NCT01760005 |
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Study Type ICMJE | Interventional | ||||||||
Study Phase ICMJE | Phase 2 Phase 3 |
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Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Interventional Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)Primary Purpose: Treatment |
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Condition ICMJE |
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Intervention ICMJE |
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Study Arms ICMJE |
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Publications * |
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||||||
Recruitment Status ICMJE | Recruiting | ||||||||
Estimated Enrollment ICMJE |
168 | ||||||||
Original Estimated Enrollment ICMJE | Same as current | ||||||||
Estimated Study Completion Date ICMJE | October 2027 | ||||||||
Estimated Primary Completion Date | July 2027 (Final data collection date for primary outcome measure) | ||||||||
Eligibility Criteria ICMJE | Key Inclusion Criteria:
Key Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 18 Years to 80 Years (Adult, Older Adult) | ||||||||
Accepts Healthy Volunteers ICMJE | No | ||||||||
Contacts ICMJE |
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Listed Location Countries ICMJE | Argentina, Australia, Brazil, Canada, Colombia, France, Germany, Ireland, Italy, Japan, Mexico, Netherlands, Puerto Rico, Spain, United Kingdom, United States | ||||||||
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Administrative Information | |||||||||
NCT Number ICMJE | NCT05269394 | ||||||||
Other Study ID Numbers ICMJE | DIAN-TU-001 (E2814) The Alzheimer's Association ( Other Grant/Funding Number: DIAN TTU-12-243040 ) U01AG042791 ( U.S. NIH Grant/Contract ) 2013-000307-17 ( EudraCT Number ) R01AG046179 ( U.S. NIH Grant/Contract ) REec-2014-0817 ( Registry Identifier: Spanish Clinical Studies Registry ) The Alzheimer's Association ( Other Grant/Funding Number: DIAN-TU Tau-15-347219 ) GHR Foundation ( Other Grant/Funding Number: File 4401 ) Alzheimer's Association ( Other Identifier: HDE 18S84914 ) The Alzheimer's Association ( Other Grant/Funding Number: DIAN-TU NG-16-434362 ) R56AG053267 ( U.S. NIH Grant/Contract ) U01AG059798 ( U.S. NIH Grant/Contract ) R01AG053267 ( U.S. NIH Grant/Contract ) R01AG068319 ( U.S. NIH Grant/Contract ) The Alzheimer's Association ( Other Grant/Funding Number: DIAN-TU Tau-21822987 ) The Alzheimer's Association ( Other Identifier: DIAN-TU OLE-21725093 ) |
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Has Data Monitoring Committee | Yes | ||||||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Current Responsible Party | Washington University School of Medicine | ||||||||
Original Responsible Party | Same as current | ||||||||
Current Study Sponsor ICMJE | Washington University School of Medicine | ||||||||
Original Study Sponsor ICMJE | Same as current | ||||||||
Collaborators ICMJE |
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Investigators ICMJE |
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PRS Account | Washington University School of Medicine | ||||||||
Verification Date | February 2024 | ||||||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |