Trial Review

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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)
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
Secondary ID [1] 0 0
The Alzheimer's Association
Secondary ID [2] 0 0
DIAN-TU-001 (E2814)
Universal Trial Number (UTN)
Trial acronym
DIAN-TU
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimers Disease 0 0
Dementia 0 0
Alzheimers Disease, Familial 0 0
Condition category
Condition code
Neurological 0 0 0 0
Alzheimer's disease
Neurological 0 0 0 0
Dementias

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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).
Timepoint [1] 0 0
Weeks 24, 104, and 208
Secondary outcome [1] 0 0
Symptomatic Population (Cohort 1): Key Secondary: Change from Week 24 to Week 208 in Clinical Dementia Scale - Sum of Boxes (CDR-SB).
Timepoint [1] 0 0
Weeks 24, 52, 104, 156 and 208
Secondary outcome [2] 0 0
Asymptomatic Population (Cohort 2): Key Secondary: Change from Week 0 to Week 104 and Week 208 in CSF ptau217/total tau
Timepoint [2] 0 0
Weeks 0, 104 and 208
Secondary outcome [3] 0 0
Symptomatic Population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in the cognitive composite score
Timepoint [3] 0 0
Weeks 24, 52, 76, 104, 128, 156, 180 and 208
Secondary outcome [4] 0 0
Symptomatic Population (Cohort 1): Change from Week 0 to Week 24 in amyloid PET
Timepoint [4] 0 0
Week 0 to Week 24
Secondary outcome [5] 0 0
Asymptomatic Population (Cohort 2): Change from Week 0 to Week 52 in CSF ptau217/total tau
Timepoint [5] 0 0
Week 0 to Week 52
Secondary outcome [6] 0 0
Symptomatic population (Cohort 1): Change from Week 24 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
Timepoint [6] 0 0
Weeks 24, 104 and 208
Secondary outcome [7] 0 0
Asymptomatic Population (Cohort 2): Change from Week 52 to Week 104 and Week 208 in CSF neurofilament light chain (NfL)
Timepoint [7] 0 0
Weeks 52, 104 and 208

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.

Key
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
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
Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
22/12/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/10/2027
Actual
Sample size
Target
168
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Neuroscience Research Australia - Randwick
Recruitment hospital [2] 0 0
Mental Health Research Institute - Melbourne
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
3010 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Connecticut
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Indiana
Country [7] 0 0
United States of America
State/province [7] 0 0
Missouri
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
Rhode Island
Country [10] 0 0
United States of America
State/province [10] 0 0
Texas
Country [11] 0 0
United States of America
State/province [11] 0 0
Washington
Country [12] 0 0
Argentina
State/province [12] 0 0
Ciudad Autonoma de Buenos Aire
Country [13] 0 0
Brazil
State/province [13] 0 0
São Paulo
Country [14] 0 0
Canada
State/province [14] 0 0
British Columbia
Country [15] 0 0
Canada
State/province [15] 0 0
Ontario
Country [16] 0 0
Canada
State/province [16] 0 0
Quebec
Country [17] 0 0
Canada
State/province [17] 0 0
Québec
Country [18] 0 0
Colombia
State/province [18] 0 0
Medellín
Country [19] 0 0
France
State/province [19] 0 0
Haute Garonne
Country [20] 0 0
France
State/province [20] 0 0
Nord
Country [21] 0 0
France
State/province [21] 0 0
Paris
Country [22] 0 0
France
State/province [22] 0 0
Rhone
Country [23] 0 0
France
State/province [23] 0 0
Seine Maritime
Country [24] 0 0
Germany
State/province [24] 0 0
Baden Wuerttemberg
Country [25] 0 0
Germany
State/province [25] 0 0
Bayern
Country [26] 0 0
Ireland
State/province [26] 0 0
Dublin
Country [27] 0 0
Italy
State/province [27] 0 0
Brescia
Country [28] 0 0
Italy
State/province [28] 0 0
Firenze
Country [29] 0 0
Japan
State/province [29] 0 0
Niigata-Ken
Country [30] 0 0
Japan
State/province [30] 0 0
Tokyo-To
Country [31] 0 0
Mexico
State/province [31] 0 0
Distrito Federal
Country [32] 0 0
Netherlands
State/province [32] 0 0
Amsterdam
Country [33] 0 0
Puerto Rico
State/province [33] 0 0
San Juan
Country [34] 0 0
Spain
State/province [34] 0 0
Barcelona
Country [35] 0 0
United Kingdom
State/province [35] 0 0
Greater London

Funding & Sponsors
Primary sponsor type
Other
Name
Washington University School of Medicine
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Alzheimer's Association
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Government body
Name [2] 0 0
National Institute on Aging (NIA)
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Accelerating Medicines Partnership (AMP)
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Commercial sector/Industry
Name [4] 0 0
Eisai Inc.
Address [4] 0 0
Country [4] 0 0

Ethics approval
Ethics application status

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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05269394
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.
Public notes

Contacts
Principal investigator
Name 0 0
Randall J Bateman, MD
Address 0 0
Washington University School of Medicine
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Ellen Ziegemeier, MA
Address 0 0
Country 0 0
Phone 0 0
844-DIANEXR (342-6397)
Fax 0 0
Email 0 0
dianexr@wustl.edu
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05269394