A Study of a Potential Disease Modifying Treatment in Individuals at Risk for or With a Type of Early Onset AD Caused by a Genetic Mutation
Start Date
11/22/2024
Completion Date
8/1/2034
Summary
The purpose of this research study is to test the study drug, referred to as remternetug, to determine its effectiveness for the study treatment of asymptomatic (at risk) Alzheimer disease in individuals with AD-causing mutations. This study will also investigate the effects of remternetug on biomarkers (measures of the disease including brain scans, blood and spinal fluid tests), examine safety data to identify any potential benefits or risks, and examine how well participants can tolerate remternetug. Stage 1 will determine if treatment with the study drug prevents or reverses amyloid beta (Aβ) accumulation compared with placebo in participants with dominantly inherited Alzheimer's disease (DIAD). Stage 2 will evaluate the effect of early anti-amyloid treatment on downstream biomarkers of AD in treated participants compared to external control groups.
Detailed Description
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive decline in cognitive function and the ability to perform activities of daily living. The amyloid hypothesis of AD postulates that the accumulation of amyloid beta (Aβ) is an early and necessary event in the pathogenesis of AD. This hypothesis suggests that interventions that slow the accumulation of Aβ plaque in the brain or increase clearance of Aβ may be able to slow the progression of the AD clinical syndrome. AD occurs on a continuum from asymptomatic (preclinical) to mild cognitive impairment (MCI), and then to dementia in mild, moderate, and severe stages. Evidence from both genetic at-risk and age at-risk cohorts, such as in dominantly inherited AD (DIAD) suggests that the pathophysiological process of AD begins well more than a decade before the clinical stage now recognized as AD dementia, and that neurodegeneration is already apparent on MRI by the stage of mild cognitive impairment. Recent clinical trial data suggest that treating AD during the earlier stages could have the greatest potential benefit on the disease by slowing progression The ability to identify individuals destined to develop Alzheimer's disease (AD) with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies at asymptomatic and very early stages of dementia. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. Participants in this study will not yet have developed any clinical symptoms of AD; they will be "asymptomatic" carriers of mutations that cause DIAD and would be expected to perform normally on standard cognitive and functional testing. Further, most mutation carriers will have levels of AD-associated amyloid beta (Aβ) and non-Aβ biomarkers that are the same as non-carriers. Amyloid beta is a protein that accumulates in the brain of people with AD. Although we do not understand exactly what causes AD, the abnormal accumulation of amyloid beta protein in the brain is thought to play an important role in the symptoms of AD. Recent research studies indicate that amyloid beta may start building up in the brain 15 years or more before the onset of memory loss. Imaging and fluid biomarkers will be used to demonstrate that the treatment compounds have engaged their therapeutic targets. A set of cognitive measures designed to assess the very earliest and most subtle cognitive changes will be collected. The overall objectives of this study are to evaluate the biomarker effect, safety, and tolerability of investigational study drugs in participants who are known to have an AD-causing mutation. The primary objective of Stage 1 is to determine if treatment with the study drug prevents or slows the rate of Aβ pathological disease accumulation demonstrated by Aβ PiB positron emission tomography (PET) imaging. The primary objective of Stage 2 is to evaluate the effect of early anti-amyloid treatment on disease progression by assessing downstream non-Aβ biomarkers of AD (e.g., CSF total tau, NfL, MRI volume) compared to a control group from the DIAN Obs natural history study and the DIAN-TU-001 placebo-treated participants. Remternetug is a monoclonal antibody. The mechanism of action of remternetug is to target and remove aggregated amyloid plaque, a key pathological hallmark of AD, via microglial-mediated clearance. Remternetug has demonstrated the ability to reduce brain amyloid plaque. The remternetug arm is part of Master Protocol DIAN-TU-002 (NCT05552157)
Eligibility Criteria
Age Range: 18 years to No maximum
Interventions
Remternetug
Matching Placebo (Remternetug)
Conditions
Locations
University of Alabama in Birmingham
Birmingham, Alabama 35294
United States
University of California San Diego Medical Center
La Jolla, California 92037
United States
University of Southern Califonria
Los Angeles, California 90089
United States
Yale University School of Medicine
New Haven, Connecticut 06510
United States
Emory University
Atlanta, Georgia 30329
United States
Advocate Lutheran General Hospital
Park Ridge, Illinois 60068
United States
Indiana University School of Medicine
Indianapolis, Indiana 46202
United States
Washington University in St. Louis
St Louis, Missouri 63110
United States
New York University Medical Center
New York, New York 10016
United States
University of Pittsburgh
Pittsburgh, Pennsylvania 15213
United States
Butler Hospital
Providence, Rhode Island 02096
United States
Kerwin Research and Memory Center
Dallas, Texas 75231
United States
University of Washington
Seattle, Washington 98195
United States
Instituto de Investigaciones Neurologicas Raul Carrea, FLENI
Ciudad Autonoma de Buenos Aire, C1428AQK
Argentina
Neuroscience Research Australia
Randwick, New South Wales 2031
Australia
Alzheimer's Research Australia
Melbourne, Victoria 3010
Australia
UBC Hospital
Vancouver, British Columbia V6T 2B5
Canada
Sunnybrook Health Sciences Centre
Toronto, Ontario M4N 3M5
Canada
McGill Center for Studies in Aging
Verdun, Quebec H4H 1R3
Canada
CHU de Quebec - Hôpital de l' Enfant Jésus
Québec, G1J 1Z4
Canada
Grupo de Neurociencias Sede de la Universidad de Antioquia
Medellín,
Colombia
CHU de Toulouse - Hôpital Purpan
Toulouse, Haute Garonne 31059
France
Hopital Roger Salengro - CHU Lille
Lille, Nord 59037
France
Groupe Hospitalier Pitie-Salpetriere
Paris, Paris 69677
France
Hopital Neurologique Pierre Wertheimer
Bron, Rhone 69677
France
CHU de Rouen - Hôpital Charles Nicolle
Rouen, Seine Maritime 76031
France
Universitaetsklinikum Tubingen
Tübingen, Baden-Wurttemberg 72076
Germany
LMU-Campus Grosshadern
Munich, Bavaria 81377
Germany
IRCCS Centro San Giovanni di Dio Fatebenefratelli
Brescia, 25125
Italy
Azienda Ospedaliera Universitaria Careggi
Florence, 50134
Italy
Instituto Nacional de Neurologia y Neurocirugia Manuel Velasco Suarez
Mexico City, Mexico City 14269
Mexico
Brain Research Center
Amsterdam, 1081 GM
Netherlands
New Zealand Brain Research Institute
Christchurch, 8011
New Zealand
University of Puerto Rico, School of Medicine
San Juan, 00936
Puerto Rico
Asan Medical Center
Seoul,
South Korea
Hospital Clínic I Provincial de Barcelona
Barcelona, 8036
Spain
The National Hospital for Neurology and Neurosurgery
London, Greater London WC1B 3BG
United Kingdom