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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)

Phase 2
Active, not recruiting
Conditions
Alzheimers Disease
Dementia
Alzheimers Disease, Familial
Interventions
Drug: E2814
Drug: Matching Placebo (E2814)
Drug: Lecanemab
Registration Number
NCT05269394
Lead Sponsor
Washington University School of Medicine
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

Recruitment & Eligibility

Status
ACTIVE_NOT_RECRUITING
Sex
All
Target Recruitment
197
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.

Key

Read More
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.
Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
PARALLEL
Arm && Interventions
GroupInterventionDescription
E2814 plus lecanemabE2814Symptomatic 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.
Matching placebo (E2814) plus lecanemabMatching Placebo (E2814)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.
E2814 plus lecanemabLecanemabSymptomatic 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.
Matching placebo (E2814) plus lecanemabLecanemabSymptomatic 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.
Primary Outcome Measures
NameTimeMethod
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).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).

Secondary Outcome Measures
NameTimeMethod
Symptomatic population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)Weeks 24, 104 and 208
Symptomatic Population (Cohort 1): Key Secondary: Change from Week 24 to Week 208 in Clinical Dementia Scale - Sum of Boxes (CDR-SB).Weeks 24, 52, 104, 156 and 208

To determine whether E2814 is superior to placebo, when each is concurrently administered with lecanemab, in change from Week 24 to Week 208 in CDR-SB

Scores range from 0-18 with lower scores showing better outcomes

Symptomatic Population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in the cognitive composite scoreWeeks 24, 52, 76, 104, 128, 156, 180 and 208
Asymptomatic Population (Cohort 2): Key Secondary: Change from Week 0 to Week 104 and Week 208 in CSF ptau217/total tauWeeks 0, 104 and 208

To determine whether E2814 is superior to placebo, when each is administered alone and then concurrently with lecanemab, in change from Week 0 to Week 104 (interim analysis) and Week 208 (final analysis) in cerebrospinal fluid (CSF) phosphorylated tau (ptau217)/total tau

Symptomatic Population (Cohort 1): Change from Week 0 to Week 24 in amyloid PETWeek 0 to Week 24
Asymptomatic Population (Cohort 2): Change from Week 0 to Week 52 in CSF ptau217/total tauWeek 0 to Week 52
Asymptomatic Population (Cohort 2): Change from Week 52 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)Weeks 52, 104 and 208

Trial Locations

Locations (38)

Emory University

🇺🇸

Atlanta, Georgia, United States

USC Keck School of Medicine

🇺🇸

Los Angeles, California, United States

Grupo de Neurociencias Sede de la Universidad de Antioquia

🇨🇴

Medellín, Colombia

St Vincent's University Hospital

🇮🇪

Dublin, Ireland

University of Pittsburgh

🇺🇸

Pittsburgh, Pennsylvania, United States

Mental Health Research Institute

🇦🇺

Melbourne, Victoria, Australia

UBC Hospital

🇨🇦

Vancouver, British Columbia, Canada

Hopital Roger Salengro - CHU Lille

🇫🇷

Lille, Nord, France

Neuroscience Research Australia

🇦🇺

Randwick, New South Wales, Australia

University of California San Diego Medical Center

🇺🇸

La Jolla, California, United States

Indiana University School of Medicine

🇺🇸

Indianapolis, Indiana, United States

Washington University in St. Louis

🇺🇸

Saint Louis, Missouri, United States

University of Washington

🇺🇸

Seattle, Washington, United States

Butler Hospital

🇺🇸

Providence, Rhode Island, United States

Instituto de Investigaciones Neurologicas Raul Carrea, FLENI

🇦🇷

Ciudad Autonoma de Buenos Aire, Argentina

Hospital das Clínicas da Faculdade de Medicina da USP

🇧🇷

São Paulo, Brazil

Sunnybrook Health Sciences Centre

🇨🇦

Toronto, Ontario, Canada

McGill Center for Studies in Aging

🇨🇦

Verdun, Quebec, Canada

CHU de Quebec - Hôpital de l' Enfant Jésus

🇨🇦

Québec, Canada

CHU de Toulouse - Hôpital Purpan

🇫🇷

Toulouse, Haute Garonne, France

Groupe Hospitalier Pitie-Salpetriere

🇫🇷

Paris cedex 13, Paris, France

Hopital Neurologique Pierre Wertheimer

🇫🇷

Bron cedex, Rhone, France

Universitaetsklinikum Tubingen

🇩🇪

Tübingen, Baden Wuerttemberg, Germany

CHU de Rouen - Hôpital Charles Nicolle

🇫🇷

Rouen, Seine Maritime, France

LMU-Campus Grosshadern

🇩🇪

Muenchen, Bayern, Germany

Brain Research Center

🇳🇱

Amsterdam, Netherlands

Azienda Ospedaliera Universitaria Careggi

🇮🇹

Firenze, Italy

IRCCS Centro San Giovanni di Dio Fatebenefratelli

🇮🇹

Brescia, Italy

Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez

🇲🇽

Mexico, Distrito Federal, Mexico

Niigata University Medical & Dental Hospital

🇯🇵

Niigata-shi, Niigata-Ken, Japan

Hospital Clínic I Provincial de Barcelona

🇪🇸

Barcelona, Spain

University of Puerto Rico, School of Medicine

🇵🇷

San Juan, Puerto Rico

The National Hospital for Neurology and Neurosurgery

🇬🇧

London, Greater London, United Kingdom

Advocate Lutheran General Hospital

🇺🇸

Park Ridge, Illinois, United States

University of Tokyo Hospital

🇯🇵

Bunkyō-Ku, Tokyo-To, Japan

Kerwin Research Center,

🇺🇸

Dallas, Texas, United States

University of Alabama in Birmingham

🇺🇸

Birmingham, Alabama, United States

Yale University School of Medicine

🇺🇸

New Haven, Connecticut, United States

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