Clinical trial NCT06384573: DIAN-TU Amyloid Removal Trial (ART) in Dominantly Inherited Alzheimer's Disease
Official title: The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) Amyloid Removal Trial (ART): A Phase IIIb/IV Open-Label Study of Lecanemab to Evaluate Prevention and Progression of Dominantly Inherited Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Alzheimer's Disease
Dementia
Alzheimer's 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
Early Onset Alzheimer's Disease
DIAN
DIAN-TU
DIAD
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Alzheimer's Association
name: Eisai Inc.
First posted: 2024-04-25
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open label study to treat dominantly inherited Alzheimer's disease (DIAD) mutation carrier participants from the DIAN-TU-001 gantenerumab Open Label Extension (OLE) period with lecanemab to determine the effects of amyloid removal on age of onset and clinical progression compared to external controls, if amyloid plaque as measured by amyloid PET can be fully removed in DIAD, and the effects of amyloid removal on biomarkers of disease progression.

Detailed description: The Dominantly Inherited Alzheimer Network (DIAN) and the DIAN Trials Unit (DIAN-TU) have established a global network that has increased understanding of Alzheimer's disease (AD) and identified a reliable cohort of individuals available for clinical trials. Over the past 12 years, the DIAN-TU has conducted a trial with the monoclonal antibody gantenerumab (DIAN-TU-001), providing the longest treatment period for individuals with amyloid removing immunotherapies (trial launched in December 2012, double-blind readout in 2019, currently completing the open-label extension \[OLE\] in 2024). Notably, efficacy and safety outcomes of the DIAN-TU and other trials with dominantly inherited AD (DIAD) populations have predicted and were concordant with sporadic AD (sAD) trials in several programs.

The DIAN-TU-001 gantenerumab OLE period has reached the end of participation and there is an urgent need to launch a trial that will allow for the continued amyloid removal treatment and monitoring of these uniquely informative individuals. The range of exposure duration in these individuals to gantenerumab is large: 2 to 10 years. Because there are a substantial number of participants that are approaching the estimated age that AD symptoms develop, it is critical to continue to monitor and treat these individuals to identify whether robust amyloid reduction prior to symptom onset can provide significant delay in disease progression.

In summary, the main reason for conducting this study is to gather key data to answer important outstanding scientific and clinical care questions for dominantly inherited AD and sporadic AD. These include improved insights into efficacy-related questions regarding drug dose and duration, mechanism of action, target population, and target disease stage that results in optimal benefit to patients. An evaluation of the long-term effects of amyloid removal on disease progression in DIAD could provide the first proof of concept that removing amyloid years before symptom onset could have major effects in delaying symptom onset by years, and to provide estimates for the relative effect sizes by years to symptom onset. Additionally, this study could provide the first evidence that patients can be treated with mechanistically different amyloid removing drugs to achieve full amyloid removal. Together these insights could offer guidance as to how clinicians can use lecanemab, a monoclonal antibody passive immunotherapy, in the era of multiple available amyloid removing treatments.

Participants in this trial will be co-enrolled in the DIAN Observational Study (DIAN Obs, NCT00869817). DIAN Obs represents a unique translational study in AD research that has provided transformational, data-driven models of the sequence of biomarkers abnormalities in preclinical DIAD. DIAN Obs is the largest longitudinal, multi-national study tracking DIAD families using a uniform protocol. To maximize the efficiency and utility of the DIAN Obs, the study introduced several efficiencies including 1) harmonizing protocols with the DIAN-TU, 2) applying International Conference on Harmonization Good Clinical Practice (ICH GCP) standards and a global unique identifier (GUID) at all performance sites to facilitate data sharing between all DIAN studies. Annual assessments will be performed for this population to collect clinical and cognitive data, amyloid and tau PET imaging, and cerebrospinal fluid (CSF) and plasma biomarkers for primary and secondary outcomes.

Eligibility criteria: Key Inclusion Criteria:

* Previously participated in the DIAN-TU-001 gantenerumab OLE period.
* Willing to participate in ongoing anti-amyloid therapy with informed consent by participant or legally authorized representative.
* People of childbearing potential (POCBP), if partner is not sterilized, must agree to use highly effective contraceptive measures (e.g., hormonal contraception, intra-uterine device, sexual abstinence, vasectomized partner) from Consent (V1) until five (5) halflives after last dose of any study drug. Refer to the study procedures manual for acceptable methods of contraception.
* Co-enrollment in the DIAN Observational Study (DIAN Obs, NCT00869817) and is willing to complete DIAN Obs procedures and assessments.
* Able to undergo safety MRI scans as required.
* Vascular access adequate for study drug administration and safety monitoring.

Key Exclusion Criteria:

* Has any significantly increased risks associated with amyloid-related imaging abnormalities characterized by edema/effusion (ARIA-E), ARIA characterized by microhemorrhage (ARIA-H MCH) or superficial siderosis (ARIA-H SS) and vascular factors reviewed by the medical monitoring team. Risks to be reviewed include:

  1. History of recurrent ARIA-E (2 or more episodes regardless of location).
  2. More than 20 ARIA-H MCH.
  3. More than one area of ARIA-H SS.
  4. More than 2 lacunar infarcts or stroke involving a major vascular territory.
* Requiring full anticoagulation or on high dose or dual antiplatelet therapy (daily aspirin 325 mg or less allowed).
* History of macrohemorrhages \>1 cm.
* Intolerance for lecanemab.
* Pregnancy.
* Breastfeeding.
* Uncontrolled medical condition that is life threatening or precludes interpretation of AD.
* Uncontrolled blood pressure including mean arterial pressure exceeding 97 mm Hg.
* Uncontrolled seizure disorder.
* Ongoing auto-immune condition, bleeding diathesis, or neutropenia (platelets lower than 50,000) major depression or psychiatric condition.
* Exposure to other AD investigational agents within the past six months, or five half-lives from Visit 2 (Entry Visit) whichever is longer.
* Active cancer/malignancy that could interfere with study evaluations.

Primary outcomes:
measure: The primary endpoint for the final analysis is the time to recurrent progression of Clinical Dementia Rating - Sum of Boxes (CDR-SB).
timeFrame: Week 0, Week 52, Week 104, Week 156, Week 208, Week 260, Week 312, Week 364
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama in Birmingham
state: Alabama
city: Indianapolis
country: United States
facility: Indiana University School of Medicine
state: Indiana
city: Saint Louis
country: United States
facility: Washington University in St. Louis
state: Missouri
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Randwick
country: Australia
facility: Neuroscience Research Australia
state: New South Wales
city: London
country: United Kingdom
facility: The National Hospital for Neurology and Neurosurgery
state: Greater London
Study officials:
affiliation: Washington University School of Medicine
name: Randall J Bateman, MD
role: STUDY_DIRECTOR
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