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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT05269394
Registration number
NCT05269394
Ethics application status
Date submitted
13/01/2022
Date registered
8/03/2022
Date last updated
22/02/2024
Titles & IDs
Public title
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)
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Scientific 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
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Secondary ID [1]
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The Alzheimer's Association
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Secondary ID [2]
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DIAN-TU-001 (E2814)
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Universal Trial Number (UTN)
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Trial acronym
DIAN-TU
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Alzheimers Disease
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Dementia
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Alzheimers Disease, Familial
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Condition category
Condition code
Neurological
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Alzheimer's disease
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Neurological
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Dementias
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - E2814
Treatment: Drugs - Lecanemab
Treatment: Drugs - Matching Placebo (E2814)
Experimental: 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.
Placebo Comparator: 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.
Treatment: Drugs: E2814
Administered intravenously in a blinded fashion
Treatment: Drugs: Lecanemab
Administered intravenously
Treatment: Drugs: Matching Placebo (E2814)
Placebo administered intravenously in a blinded fashion.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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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).
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Assessment method [1]
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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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Timepoint [1]
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Weeks 24, 104, and 208
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Secondary outcome [1]
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Symptomatic Population (Cohort 1): Key Secondary: Change from Week 24 to Week 208 in Clinical Dementia Scale - Sum of Boxes (CDR-SB).
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Assessment method [1]
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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
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Timepoint [1]
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Weeks 24, 52, 104, 156 and 208
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Secondary outcome [2]
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Asymptomatic Population (Cohort 2): Key Secondary: Change from Week 0 to Week 104 and Week 208 in CSF ptau217/total tau
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Assessment method [2]
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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
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Timepoint [2]
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Weeks 0, 104 and 208
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Secondary outcome [3]
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Symptomatic Population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in the cognitive composite score
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Assessment method [3]
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Timepoint [3]
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Weeks 24, 52, 76, 104, 128, 156, 180 and 208
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Secondary outcome [4]
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Symptomatic Population (Cohort 1): Change from Week 0 to Week 24 in amyloid PET
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Assessment method [4]
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Timepoint [4]
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Week 0 to Week 24
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Secondary outcome [5]
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Asymptomatic Population (Cohort 2): Change from Week 0 to Week 52 in CSF ptau217/total tau
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Assessment method [5]
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Timepoint [5]
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Week 0 to Week 52
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Secondary outcome [6]
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Symptomatic population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
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Assessment method [6]
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Timepoint [6]
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Weeks 24, 104 and 208
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Secondary outcome [7]
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Asymptomatic Population (Cohort 2): Change from Week 52 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
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Assessment method [7]
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Timepoint [7]
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Weeks 52, 104 and 208
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Eligibility
Key inclusion criteria
Key
- 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.
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Minimum age
18
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Maximum age
80
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2/Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
22/12/2021
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
1/10/2027
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Actual
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Sample size
Target
168
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,VIC
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Recruitment hospital [1]
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Neuroscience Research Australia - Randwick
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Recruitment hospital [2]
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Mental Health Research Institute - Melbourne
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Recruitment postcode(s) [1]
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2031 - Randwick
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Recruitment postcode(s) [2]
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3010 - Melbourne
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Recruitment outside Australia
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United States of America
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Alabama
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California
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United States of America
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Connecticut
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United States of America
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Georgia
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United States of America
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Illinois
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United States of America
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Indiana
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United States of America
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Missouri
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United States of America
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Pennsylvania
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Texas
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United States of America
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Washington
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Argentina
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Ciudad Autonoma de Buenos Aire
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Brazil
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São Paulo
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Canada
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British Columbia
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Canada
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Ontario
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Canada
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Quebec
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Canada
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Québec
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Colombia
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Medellín
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France
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Haute Garonne
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France
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Nord
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France
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Paris
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France
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France
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Seine Maritime
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Germany
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Baden Wuerttemberg
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Germany
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Bayern
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Ireland
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Dublin
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Italy
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Brescia
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Italy
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Firenze
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Japan
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Niigata-Ken
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Japan
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Tokyo-To
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Mexico
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Distrito Federal
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Netherlands
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Amsterdam
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Puerto Rico
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San Juan
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Spain
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Barcelona
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United Kingdom
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Greater London
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Funding & Sponsors
Primary sponsor type
Other
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Name
Washington University School of Medicine
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Address
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Other collaborator category [1]
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Other
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Name [1]
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Alzheimer's Association
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Government body
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National Institute on Aging (NIA)
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Other
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Accelerating Medicines Partnership (AMP)
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Commercial sector/Industry
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Eisai Inc.
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT05269394
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Trial related presentations / 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.
Fitzpatrick 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.
Falcon 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.
Kopeikina 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.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. doi: 10.1007/BF00308809.
Goedert M, Spillantini MG. Propagation of Tau aggregates. Mol Brain. 2017 May 30;10(1):18. doi: 10.1186/s13041-017-0298-7.
Falcon 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.
Barghorn 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.
von 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.
von 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.
Salloway 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.
Sandusky-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.
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Public notes
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Contacts
Principal investigator
Name
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Randall J Bateman, MD
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Address
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Washington University School of Medicine
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Email
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Contact person for public queries
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Ellen Ziegemeier, MA
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Phone
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844-DIANEXR (342-6397)
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Email
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT05269394
Download to PDF