Alzheimers DiseasePhase 2/3DIAN-TUNCT05269394
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)
A Phase 2/3 study testing E2814 and Lecanemab in people with Alzheimers Disease and Dementia, run by Washington University School of Medicine at 36 sites in 16 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Alzheimers Disease, Dementia, Alzheimers Disease, Familial
- What is being tested?
- E2814 and Lecanemab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 197 participants
- Where
- 36 sitesin 16 countries
- Study dates
- 22 Dec 2021to Jul 2028
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
36 sites in 16 countries.
36 sites in 16 countries
United States12 sites
Emory University
Atlanta, Georgia, 30329
University of Alabama in Birmingham
Birmingham, Alabama, 35294
Kerwin Research Center,
Dallas, Texas, 75231
Indiana University School of Medicine
Indianapolis, Indiana, 46202
University of California San Diego Medical Center
La Jolla, California, 92037
USC Keck School of Medicine
Los Angeles, California, 90033
Yale University School of Medicine
New Haven, Connecticut, 06510
Advocate Lutheran General Hospital
Park Ridge, Illinois, 60068
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
Butler Hospital
Providence, Rhode Island, 02096
University of Washington
Seattle, Washington, 98195
Washington University in St. Louis
St Louis, Missouri, 63110
France5 sites
Hopital Neurologique Pierre Wertheimer
Bron, Rhone, 69677
Hopital Roger Salengro - CHU Lille
Lille, Nord, 59037
Groupe Hospitalier Pitie-Salpetriere
Paris, Paris, 69677
CHU de Rouen - Hôpital Charles Nicolle
Rouen, Seine Maritime, 76031
CHU de Toulouse - Hôpital Purpan
Toulouse, Haute Garonne, 31059
Canada3 sites
CHU de Quebec - Hôpital de l' Enfant Jésus
Québec, G1J 1Z4
Sunnybrook Health Sciences Centre
Toronto, Ontario, M4N 3M5
McGill Center for Studies in Aging
Verdun, Quebec, H4H 1R3
Australia2 sites
Alzheimer's Research Australia
Melbourne, Victoria, 3010
Neuroscience Research Australia
Randwick, New South Wales, 2031
Germany2 sites
LMU-Campus Grosshadern
Munich, Bavaria, 81377
Universitaetsklinikum Tubingen
Tübingen, Baden-Wurttemberg, 72076
Italy2 sites
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Brescia, 25125
Azienda Ospedaliera Universitaria Careggi
Florence, 50134
Argentina1 site
Instituto de Investigaciones Neurologicas Raul Carrea, FLENI
Ciudad Autonoma de Buenos Aire, C1428AQK
Brazil1 site
Hospital das Clínicas da Faculdade de Medicina da USP
São Paulo, 05403-000
Colombia1 site
Grupo de Neurociencias Sede de la Universidad de Antioquia
Medellín
Mexico1 site
Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
Mexico City, Mexico City, 14269
Puerto Rico1 site
University of Puerto Rico, School of Medicine
San Juan, 00936
United Kingdom1 site
The National Hospital for Neurology and Neurosurgery
London, Greater London, WC1B 3BG
About this study
Official title: 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
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.
Read the 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
- Conditions
- Alzheimers Disease, Dementia, Alzheimers Disease, Familial
- Being tested
- E2814, Lecanemab, Matching Placebo (E2814)
- Keywords
- 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
- Medical subject headings
- Alzheimer Disease, Dementia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
E2814Drug
Administered intravenously in a blinded fashion
LecanemabDrug
Also called BAN2401
Administered intravenously
Matching Placebo (E2814)Drug
Placebo administered intravenously in a blinded fashion.
| Study group | Role | What they receive |
|---|---|---|
| E2814 plus lecanemab | Experimental | 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. Receives: Drug: E2814; Drug: Lecanemab |
| Matching placebo (E2814) plus lecanemab | Placebo comparator | 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. Receives: Drug: Lecanemab; Drug: Matching Placebo (E2814) |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
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).
Measured: Weeks 24, 104, and 208
Secondary outcomes (7)
Symptomatic Population (Cohort 1): Key Secondary: Change from Week 24 to Week 208 in Clinical Dementia Scale - Sum of Boxes (CDR-SB).
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
Measured: Weeks 24, 52, 104, 156 and 208
Asymptomatic Population (Cohort 2): Key Secondary: Change from Week 0 to Week 104 and Week 208 in CSF ptau217/total tau
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
Measured: Weeks 0, 104 and 208
Symptomatic Population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in the cognitive composite score
Measured: Weeks 24, 52, 76, 104, 128, 156, 180 and 208
Symptomatic Population (Cohort 1): Change from Week 0 to Week 24 in amyloid PET
Measured: Week 0 to Week 24
Asymptomatic Population (Cohort 2): Change from Week 0 to Week 52 in CSF ptau217/total tau
Measured: Week 0 to Week 52
Symptomatic population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
Measured: Weeks 24, 104 and 208
Asymptomatic Population (Cohort 2): Change from Week 52 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
Measured: Weeks 52, 104 and 208
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Mar 2022
- Study start22 Dec 2021
- Primary completionApr 2028 (estimated)
- Study completionJul 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Alzheimers DiseaseStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Interventional
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 197 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Alzheimer's Association, National Institute on Aging (NIA), Accelerating Medicines Partnership (AMP), Eisai Inc.
- Responsible party
- Sponsor
- Investigators
- Randall J Bateman, MD, Study director, Washington University School of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05269394
- Sponsor's protocol ID
- DIAN-TU-001 (E2814)
- Other IDs
- The Alzheimer's Association, U01AG042791, 2013-000307-17, R01AG046179, REec-2014-0817, The Alzheimer's Association, GHR Foundation, Alzheimer's Association
- Acronym
- DIAN-TU
- Status last verified
- Jul 2026
- First submitted
- 13 Jan 2022
- Last updated
- 27 Jul 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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 \[CAP REF\].
Publications
Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013 Feb;12(2):207-16. doi: 10.1016/S1474-4422(12)70291-0.
PubMed 23332364Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. doi: 10.1038/nature23002. Epub 2017 Jul 5.
PubMed 28678775Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SHW, Goedert M. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140. doi: 10.1038/s41586-018-0454-y. Epub 2018 Aug 29.
PubMed 30158706Kopeikina KJ, Hyman BT, Spires-Jones TL. Soluble forms of tau are toxic in Alzheimer's disease. Transl Neurosci. 2012 Sep;3(3):223-233. doi: 10.2478/s13380-012-0032-y.
PubMed 23029602Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. doi: 10.1007/BF00308809.
PubMed 1759558Goedert M, Spillantini MG. Propagation of Tau aggregates. Mol Brain. 2017 May 30;10(1):18. doi: 10.1186/s13041-017-0298-7.
PubMed 28558799Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Jackson S, O'Neill MJ, Isaacs AM, Hutton ML, Szekeres PG, Goedert M, Bose S. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 2015 Jan 9;290(2):1049-65. doi: 10.1074/jbc.M114.589309. Epub 2014 Nov 18.
PubMed 25406315Barghorn S, Zheng-Fischhofer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. doi: 10.1021/bi000850r.
PubMed 10995239von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5129-34. doi: 10.1073/pnas.97.10.5129.
PubMed 10805776von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem. 2001 Dec 21;276(51):48165-74. doi: 10.1074/jbc.M105196200. Epub 2001 Oct 17.
PubMed 11606569Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, Hitchcock JM, Mills SL, Santacruz AM, Aschenbrenner AJ, Hassenstab J, Benzinger TLS, Gordon BA, Fagan AM, Coalier KA, Cruchaga C, Goate AA, Perrin RJ, Xiong C, Li Y, Morris JC, Snider BJ, Mummery C, Surti GM, Hannequin D, Wallon D, Berman SB, Lah JJ, Jimenez-Velazquez IZ, Roberson ED, van Dyck CH, Honig LS, Sanchez-Valle R, Brooks WS, Gauthier S, Galasko DR, Masters CL, Brosch JR, Hsiung GR, Jayadev S, Formaglio M, Masellis M, Clarnette R, Pariente J, Dubois B, Pasquier F, Jack CR Jr, Koeppe R, Snyder PJ, Aisen PS, Thomas RG, Berry SM, Wendelberger BA, Andersen SW, Holdridge KC, Mintun MA, Yaari R, Sims JR, Baudler M, Delmar P, Doody RS, Fontoura P, Giacobino C, Kerchner GA, Bateman RJ; Dominantly Inherited Alzheimer Network-Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 2021 Jul;27(7):1187-1196. doi: 10.1038/s41591-021-01369-8. Epub 2021 Jun 21.
PubMed 34155411Sandusky-Beltran LA, Sigurdsson EM. Tau immunotherapies: Lessons learned, current status and future considerations. Neuropharmacology. 2020 Sep 15;175:108104. doi: 10.1016/j.neuropharm.2020.108104. Epub 2020 Apr 28.
PubMed 32360477
Study at a glance
From the registry record, last updated by the sponsor on 27 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT05269394
- Acronym / sponsor ID
- DIAN-TU / DIAN-TU-001 (E2814)
- Conditions
- Alzheimers Disease, Dementia, Alzheimers Disease, Familial
- Keywords
- Alzheimer's, Alzheimer's Disease, Dementia, Mutation, Genetic Mutation, Dominantly Inherited Alzheimer's Disease, Dominantly Inherited Alzheimer Network, Autosomal Dominant Alzheimer's Disease
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 197 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- Alzheimer's Association, National Institute on Aging (NIA), Accelerating Medicines Partnership (AMP), Eisai Inc.
- Study start
- 22 Dec 2021 (actual)
- Primary completion
- Apr 2028 (estimated)
- Study completion
- Jul 2028 (estimated)
- First posted
- 8 Mar 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Interventional
| Arm | Type | Receives |
|---|---|---|
| E2814 plus lecanemab | Experimental | Drug: E2814, Drug: LecanemabSymptomatic 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 lecanemab | Placebo comparator | Drug: Lecanemab, Drug: Matching 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. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| E2814Administered intravenously in a blinded fashion | Drug | E2814 plus lecanemab |
| LecanemabAlso: BAN2401Administered intravenously | Drug | E2814 plus lecanemab, Matching placebo (E2814) plus lecanemab |
| Matching Placebo (E2814)Placebo administered intravenously in a blinded fashion. | Drug | Matching placebo (E2814) plus lecanemab |
Primary outcome
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).
7 secondary outcomes
Symptomatic Population (Cohort 1): Key Secondary: Change from Week 24 to Week 208 in Clinical Dementia Scale - Sum of Boxes (CDR-SB).
Time frame: Weeks 24, 52, 104, 156 and 208
Asymptomatic Population (Cohort 2): Key Secondary: Change from Week 0 to Week 104 and Week 208 in CSF ptau217/total tau
Time frame: Weeks 0, 104 and 208
Symptomatic Population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in the cognitive composite score
Time frame: Weeks 24, 52, 76, 104, 128, 156, 180 and 208
Symptomatic Population (Cohort 1): Change from Week 0 to Week 24 in amyloid PET
Time frame: Week 0 to Week 24
Asymptomatic Population (Cohort 2): Change from Week 0 to Week 52 in CSF ptau217/total tau
Time frame: Week 0 to Week 52
Symptomatic population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
Time frame: Weeks 24, 104 and 208
Asymptomatic Population (Cohort 2): Change from Week 52 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
Time frame: Weeks 52, 104 and 208
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jul 2026.
- Background: PubMed 23332364Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD, Lesnick TG, Pankratz VS, Donohue MC, Trojanowski JQ. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013 Feb;12(2):207-16. doi: 10.1016/S1474-4422(12)70291-0.
- Background: PubMed 28678775Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. doi: 10.1038/nature23002. Epub 2017 Jul 5.
- Background: PubMed 30158706Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SHW, Goedert M. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140. doi: 10.1038/s41586-018-0454-y. Epub 2018 Aug 29.
- Background: PubMed 23029602Kopeikina KJ, Hyman BT, Spires-Jones TL. Soluble forms of tau are toxic in Alzheimer's disease. Transl Neurosci. 2012 Sep;3(3):223-233. doi: 10.2478/s13380-012-0032-y.
- Background: PubMed 1759558Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. doi: 10.1007/BF00308809.
- Background: PubMed 28558799Goedert M, Spillantini MG. Propagation of Tau aggregates. Mol Brain. 2017 May 30;10(1):18. doi: 10.1186/s13041-017-0298-7.
- Background: PubMed 25406315Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Jackson S, O'Neill MJ, Isaacs AM, Hutton ML, Szekeres PG, Goedert M, Bose S. Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem. 2015 Jan 9;290(2):1049-65. doi: 10.1074/jbc.M114.589309. Epub 2014 Nov 18.
- Background: PubMed 10995239Barghorn S, Zheng-Fischhofer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. doi: 10.1021/bi000850r.
- Background: PubMed 10805776von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5129-34. doi: 10.1073/pnas.97.10.5129.
- Background: PubMed 11606569von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem. 2001 Dec 21;276(51):48165-74. doi: 10.1074/jbc.M105196200. Epub 2001 Oct 17.
- Background: PubMed 34155411Salloway S, Farlow M, McDade E, Clifford DB, Wang G, Llibre-Guerra JJ, Hitchcock JM, Mills SL, Santacruz AM, Aschenbrenner AJ, Hassenstab J, Benzinger TLS, Gordon BA, Fagan AM, Coalier KA, Cruchaga C, Goate AA, Perrin RJ, Xiong C, Li Y, Morris JC, Snider BJ, Mummery C, Surti GM, Hannequin D, Wallon D, Berman SB, Lah JJ, Jimenez-Velazquez IZ, Roberson ED, van Dyck CH, Honig LS, Sanchez-Valle R, Brooks WS, Gauthier S, Galasko DR, Masters CL, Brosch JR, Hsiung GR, Jayadev S, Formaglio M, Masellis M, Clarnette R, Pariente J, Dubois B, Pasquier F, Jack CR Jr, Koeppe R, Snyder PJ, Aisen PS, Thomas RG, Berry SM, Wendelberger BA, Andersen SW, Holdridge KC, Mintun MA, Yaari R, Sims JR, Baudler M, Delmar P, Doody RS, Fontoura P, Giacobino C, Kerchner GA, Bateman RJ; Dominantly Inherited Alzheimer Network-Trials Unit. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 2021 Jul;27(7):1187-1196. doi: 10.1038/s41591-021-01369-8. Epub 2021 Jun 21.
- Background: PubMed 32360477Sandusky-Beltran LA, Sigurdsson EM. Tau immunotherapies: Lessons learned, current status and future considerations. Neuropharmacology. 2020 Sep 15;175:108104. doi: 10.1016/j.neuropharm.2020.108104. Epub 2020 Apr 28.
- Expanded registryLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Randall J Bateman, MD study director
Washington University School of Medicine
36 sites in 16 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing E2814 and Lecanemab in people with Alzheimers Disease and Dementia, run by Washington University School of Medicine at 36 sites in 16 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 27 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 36 sites in United States, France, Canada, Australia, Germany and 11 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05269394, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Jul 2026.