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)

Sponsor

Washington University School of Medicine (Other)

Overall Status

Recruiting

CT.gov ID

NCT05269394

Collaborator

Alzheimer's Association (Other), National Institute on Aging (NIA) (NIH), Accelerating Medicines Partnership (AMP) (Other), Eisai Inc. (Industry)

168

Enrollment

Locations

Arms

69.3

Anticipated Duration (Months)

4.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimers Disease Dementia Alzheimers Disease, Familial	Drug: E2814 Drug: Lecanemab Drug: Matching Placebo (E2814)	Phase 2/Phase 3

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

Study Type:

Interventional

Anticipated Enrollment :

168 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

InterventionalInterventional

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 22, 2021

Anticipated Primary Completion Date :

Jul 1, 2027

Anticipated Study Completion Date :

Oct 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
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.	Drug: E2814 Administered intravenously in a blinded fashion Drug: Lecanemab Administered intravenously Other Names: BAN2401
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.	Drug: Lecanemab Administered intravenously Other Names: BAN2401 Drug: Matching Placebo (E2814) Placebo administered intravenously in a blinded fashion.

Arm

Intervention/Treatment

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.

Drug: E2814

Administered intravenously in a blinded fashion

Drug: Lecanemab

Administered intravenously

Other Names:

BAN2401

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.

Drug: Lecanemab

Administered intravenously

Other Names:

BAN2401

Drug: Matching Placebo (E2814)

Placebo administered intravenously in a blinded fashion.

Outcome Measures

Primary Outcome Measures

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

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
Asymptomatic Population (Cohort 2): Key Secondary: Change from Week 0 to Week 104 and Week 208 in CSF ptau217/total tau [Weeks 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 24 to Week 104 and Week 208 in the cognitive composite score [Weeks 24, 52, 76, 104, 128, 156, 180 and 208]
Symptomatic Population (Cohort 1): Change from Week 0 to Week 24 in amyloid PET [Week 0 to Week 24]
Asymptomatic Population (Cohort 2): Change from Week 0 to Week 52 in CSF ptau217/total tau [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) [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) [Weeks 52, 104 and 208]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Key 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 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama in Birmingham	Birmingham	Alabama	United States	35294
2	University of California San Diego Medical Center	La Jolla	California	United States	92037
3	USC Keck School of Medicine	Los Angeles	California	United States	90033
4	Yale University School of Medicine	New Haven	Connecticut	United States	06510
5	Emory University	Atlanta	Georgia	United States	30329
6	Advocate Lutheran General Hospital	Park Ridge	Illinois	United States	60068
7	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202
8	Washington University in St. Louis	Saint Louis	Missouri	United States	63110
9	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
10	Butler Hospital	Providence	Rhode Island	United States	02096
11	Kerwin Research Center,	Dallas	Texas	United States	75231
12	University of Washington	Seattle	Washington	United States	98195
13	Instituto de Investigaciones Neurologicas Raul Carrea, FLENI	Ciudad Autonoma de Buenos Aire		Argentina	C1428AQK
14	Neuroscience Research Australia	Randwick	New South Wales	Australia	2031
15	Mental Health Research Institute	Melbourne	Victoria	Australia	3010
16	The McCuster Foundation of Alzheimer's Disease Research	Nedlands	Western Australia	Australia	6009
17	Hospital das Clínicas da Faculdade de Medicina da USP	São Paulo		Brazil	05403-000
18	UBC Hospital	Vancouver	British Columbia	Canada	V6T 2B5
19	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
20	McGill Center for Studies in Aging	Verdun	Quebec	Canada	H4H 1R3
21	CHU de Quebec - Hôpital de l' Enfant Jésus	Québec		Canada	G1J 1Z4
22	Grupo de Neurociencias Sede de la Universidad de Antioquia	Medellín		Colombia
23	CHU de Toulouse - Hôpital Purpan	Toulouse	Haute Garonne	France	31059
24	Hopital Roger Salengro - CHU Lille	Lille	Nord	France	59037
25	Groupe Hospitalier Pitie-Salpetriere	Paris cedex 13	Paris	France	69677
26	Hopital Neurologique Pierre Wertheimer	Bron cedex	Rhone	France	69677
27	CHU de Rouen - Hôpital Charles Nicolle	Rouen	Seine Maritime	France	76031
28	Universitaetsklinikum Tubingen	Tübingen	Baden Wuerttemberg	Germany	72076
29	LMU-Campus Grosshadern	Muenchen	Bayern	Germany	81377
30	St Vincent's University Hospital	Dublin		Ireland	DUBLIN 4
31	IRCCS Centro San Giovanni di Dio Fatebenefratelli	Brescia		Italy	25125
32	Azienda Ospedaliera Universitaria Careggi	Firenze		Italy	50134
33	Niigata University Medical & Dental Hospital	Niigata-shi	Niigata-Ken	Japan	951-8520
34	Osaka City University Hospital Clinical Research Center of Dementia	Osaka-shi	Osaka-Fu	Japan	545-8586
35	University of Tokyo Hospital	Bunkyō-Ku	Tokyo-To	Japan	113-8655
36	Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez	Mexico	Distrito Federal	Mexico	14269
37	Brain Research Center	Amsterdam		Netherlands	1081 GM
38	University of Puerto Rico, School of Medicine	San Juan		Puerto Rico	00936
39	Hospital Clínic I Provincial de Barcelona	Barcelona		Spain	8036
40	The National Hospital for Neurology and Neurosurgery	London	Greater London	United Kingdom	WC1B 3BG