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)

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Clinical Phase

PHASE2/PHASE3

Total Enrollment

197 participants

Study Classification

INTERVENTIONAL

Study Start Date

2021-12-22

Study Completion Date

2028-07-31

Brief Summary

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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

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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

Conditions

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Alzheimers Disease Dementia Alzheimers Disease, Familial

Keywords

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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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Interventional

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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E2814 plus lecanemab

Symptomatic Population (Cohort 1)

At Week 0, participants will receive open-label lecanemab administered intravenously for the full treatment period.

At Week 24, participants randomized to E2814 will receive intravenously in a blinded fashion for the remainder of their treatment period.

Asymptomatic Population (Cohort 2)

At Week 0, participants randomized to E2814 will receive intravenously in a blinded fashion for the full treatment period.

At Week 52, all participants will initiate open-label lecanemab administered intravenously for the remainder of their treatment period.

Group Type EXPERIMENTAL

E2814

Intervention Type DRUG

Administered intravenously in a blinded fashion

Lecanemab

Intervention Type DRUG

Administered intravenously

Matching placebo (E2814) plus lecanemab

Symptomatic Population (Cohort 1)

At Week 0, participants will receive open-label lecanemab administered intravenously for the full treatment period.

At Week 24, participants randomized to E2814 placebo will receive placebo intravenously in a blinded fashion for the remainder of their treatment period.

Asymptomatic Population (Cohort 2)

At Week 0, participants randomized to E2814 placebo will receive placebo intravenously in a blinded fashion for the full treatment period.

At Week 52, all participants will initiate open-label lecanemab administered intravenously for the remainder of their treatment period.

Group Type PLACEBO_COMPARATOR

Lecanemab

Intervention Type DRUG

Administered intravenously

Matching Placebo (E2814)

Intervention Type DRUG

Placebo administered intravenously in a blinded fashion.

Interventions

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E2814

Administered intravenously in a blinded fashion

Intervention Type DRUG

Lecanemab

Administered intravenously

Intervention Type DRUG

Matching Placebo (E2814)

Placebo administered intravenously in a blinded fashion.

Intervention Type DRUG

Other Intervention Names

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BAN2401

Eligibility Criteria

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Inclusion Criteria

* Between 18-80 years of age
* Individuals who know they have an Alzheimer's disease-causing mutation.
* Are within -10 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, participant 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

* Significant neurologic disease (other than AD) or psychiatric disease that may currently or during the course of the study affect cognition or participant's ability to complete the study.
* At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months. Current stable mild depression or current use of antidepressant medications is not exclusionary.
* History or presence of brain MRI scans indicative of any other significant abnormality
* Substance or alcohol use disorder 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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Randall J Bateman, MD

Role: STUDY_DIRECTOR

Washington University School of Medicine

Locations

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University of Alabama in Birmingham

Birmingham, Alabama, United States

Site Status

University of California San Diego Medical Center

La Jolla, California, United States

Site Status

USC Keck School of Medicine

Los Angeles, California, United States

Site Status

Yale University School of Medicine

New Haven, Connecticut, United States

Site Status

Emory University

Atlanta, Georgia, United States

Site Status

Advocate Lutheran General Hospital

Park Ridge, Illinois, United States

Site Status

Indiana University School of Medicine

Indianapolis, Indiana, United States

Site Status

Washington University in St. Louis

St Louis, Missouri, United States

Site Status

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

Site Status

Butler Hospital

Providence, Rhode Island, United States

Site Status

Kerwin Research Center,

Dallas, Texas, United States

Site Status

University of Washington

Seattle, Washington, United States

Site Status

Instituto de Investigaciones Neurologicas Raul Carrea, FLENI

Ciudad Autonoma de Buenos Aire, , Argentina

Site Status

Neuroscience Research Australia

Randwick, New South Wales, Australia

Site Status

Mental Health Research Institute

Melbourne, Victoria, Australia

Site Status

Hospital das Clínicas da Faculdade de Medicina da USP

São Paulo, , Brazil

Site Status

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Site Status

McGill Center for Studies in Aging

Verdun, Quebec, Canada

Site Status

CHU de Quebec - Hôpital de l' Enfant Jésus

Québec, , Canada

Site Status

Grupo de Neurociencias Sede de la Universidad de Antioquia

Medellín, , Colombia

Site Status

CHU de Toulouse - Hôpital Purpan

Toulouse, Haute Garonne, France

Site Status

Hopital Roger Salengro - CHU Lille

Lille, Nord, France

Site Status

Groupe Hospitalier Pitie-Salpetriere

Paris, Paris, France

Site Status

Hopital Neurologique Pierre Wertheimer

Bron, Rhone, France

Site Status

CHU de Rouen - Hôpital Charles Nicolle

Rouen, Seine Maritime, France

Site Status

Universitaetsklinikum Tubingen

Tübingen, Baden-Wurttemberg, Germany

Site Status

LMU-Campus Grosshadern

Munich, Bavaria, Germany

Site Status

St Vincent's University Hospital

Dublin, Dublin, Ireland

Site Status

IRCCS Centro San Giovanni di Dio Fatebenefratelli

Brescia, , Italy

Site Status

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

Site Status

University of Tokyo Hospital

Bunkyō City, Tokyo-To, Japan

Site Status

Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez

Mexico City, Mexico City, Mexico

Site Status

Brain Research Center

Amsterdam, , Netherlands

Site Status

University of Puerto Rico, School of Medicine

San Juan, Puerto Rico, Puerto Rico

Site Status

Hospital Clínic I Provincial de Barcelona

Barcelona, Barcelona, Spain

Site Status

The National Hospital for Neurology and Neurosurgery

London, Greater London, United Kingdom

Site Status

Countries

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United States Argentina Australia Brazil Canada Colombia France Germany Ireland Italy Japan Mexico Netherlands Puerto Rico Spain United Kingdom

References

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