Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia: A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer's Disease Caused by a Genetic Mutation
- Conditions
- Alzheimers Disease, FamilialDementiaAlzheimers Disease
- Interventions
- Registration Number
- NCT06424236
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
The purpose of this study is 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 slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers.
- Detailed Description
Alzheimer's disease (AD) is defined by the presence of abnormal accumulations of amyloid protein (plaques) and tau protein (tangles) in the brain. The double-blind arm of DIAN-TU-001 Master protocol (NCT01760005) tested whether gantenerumab provided a clinical benefit by slowing the onset or the worsening of the disease. A clinical benefit was not observed in the double-blind part of the DIAN-TU-001 study. However, gantenerumab was associated with improvements in measures of amyloid and tau and an improvement in an overall measure of neurodegeneration (when nerve cells in the brain lose function over time). It is not known whether these changes may provide future clinical benefits. Based on this information, an exploratory Open Label Extension (OLE) will further study the effect of gantenerumab on these Alzheimer-related proteins and their relationship to disease progression.
After this final evaluation of study treatment with gantenerumab used in the gantenerumab / solanezumab double-blind arm of the Master protocol (NCT01760005), participants from the double-blind arm known to carry the genetic mutation for AD have been invited to participate in an OLE period to receive active gantenerumab study treatment as part of the DIAN-TU-001 Master protocol. The OLE period of the study planned to provide study treatment with gantenerumab for up to 3 years (36 months).
This study will continue to collect brain scans, blood, and spinal fluid tests (also called biomarkers), as well as cognitive testing. The idea is to determine if gantenerumab has favorable effects on these tests as it may prevent or delay the symptoms of AD.
Update:
Based on the completed studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer's disease (DIAD) participants in the DIAN-TU-001 OLE study were benefiting from gantenerumab high-dose treatment.
After evaluation, it was decided to discontinue the DIAN-TU-001 gantenerumab OLE.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 73
- Between 18-80 years of age
- Individuals who know they have an Alzheimer's disease-causing mutation
- Individuals who have participated in the double-blind period
- In the opinion of the investigator and sponsor, treatment is not contraindicated for safety
- Capable of receiving drug and appropriate clinical safety assessment
- 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, subject 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.
- History or presence of brain MRI scans indicative of any other significant abnormality
- Alcohol or drug dependence 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
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Gantenerumab Open Label Extension Gantenerumab Gantenerumab: Subcutaneously every 4 weeks, at escalating doses
- Primary Outcome Measures
Name Time Method Change in amyloid load as measured by [11C]PiB-PET composite standardized uptake value ration (C-SUVR) Week 0 and Weeks 48, 104, and 156 The composite PiB partial volume corrected standardized uptake value ratio is used as the biomarker endpoint for amyloid deposition. Corresponding analyses based on conversion of SUVR to centiloid will be performed by Washington University.
- Secondary Outcome Measures
Name Time Method Annual Rate of change in Clinical Dementia Rating (CDR) Sum of Boxes Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the CDR Sum of Boxes. Minimum score 0; maximum score 18. Higher score indicates worse performance.
Annual Rate of change in Tau PET Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR) Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Tau PET Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR)
Annual Rate of change in Cerebrospinal Fluid (CSF) phosphorylated Tau (pTau)-181 Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Cerebrospinal Fluid (CSF) phosphorylated Tau (pTau)-181
Annual Rate of change in DIAN-TU Open Label Extension Cognitive Composite Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the DIAN-TU OLE Cognitive Composite. The Cognitive Composite is calculated using the WMS-R Digit Span Backward Recall (Minimum score 0; Maximum score 7. Lower indicates worse performance.), the Category Fluency (Animals) value (Minimum score 0; Maximum score Unlimited. Lower score indicates worse performance.), the Wechsler Adult Intelligence Scale Digit Symbol Substitution test (Minimum score 0; Maximum score 93. Lower score indicates worse performance.) , and the Mini Mental State Examination (Minimum score 0; Maximum score 30. Lower score indicates worse performance).
Annual Rate of change in Clinical Dementia Rating (CDR) Global Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the CDR Global. Minimum score 0; maximum score 3. Higher score indicates worse performance.
Annual Rate of change in Mini-Mental State Examination (MMSE) Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Mini-Mental State Examination (MMSE). Minimum score 0; maximum score 30. Lower score indicates worse performance.
Annual Rate of change in Neurofilament Light chain (NfL) in CSF (CSF NfL) Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Neurofilament Light chain (NfL) in CSF (CSF NfL)
Annual Rate of change in Functional Assessment Scale (FAS) Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Functional Assessment Scale (FAS). Higher score indicates worse performance.
Annual Rate of change in Cerebrospinal Fluid (CSF) Amyloid Beta1-42/40 Week 0 and Weeks 48, 104, and 156 Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in CSF Amyloid Beta1-42/40
Trial Locations
- Locations (22)
Hopital Roger Salengro - CHU Lille
🇫🇷Lille, Nord, France
Neuroscience Research Australia
🇦🇺Randwick, New South Wales, Australia
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
Mental Health Research Institute
🇦🇺Melbourne, Victoria, Australia
Groupe Hospitalier Pitie-Salpetriere
🇫🇷Paris cedex 13, Paris, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷Rouen, Seine Maritime, France
St Vincent's University Hospital
🇮🇪Dublin, Ireland
Emory University
🇺🇸Atlanta, Georgia, United States
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
University of Washington
🇺🇸Seattle, Washington, United States
CHU de Toulouse - Hôpital Purpan
🇫🇷Toulouse, Haute Garonne, France
University of Puerto Rico, School of Medicine
🇵🇷San Juan, Puerto Rico
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Hospital Clínic I Provincial de Barcelona
🇪🇸Barcelona, Spain
Hopital Neurologique Pierre Wertheimer
🇫🇷Bron cedex, Rhone, France
The National Hospital for Neurology and Neurosurgery
🇬🇧London, Greater London, United Kingdom
UBC Hospital
🇨🇦Vancouver, British Columbia, Canada
University of California San Diego Medical Center
🇺🇸La Jolla, California, United States
Washington University in St. Louis
🇺🇸Saint Louis, Missouri, United States
Butler Hospital
🇺🇸Providence, Rhode Island, United States
The McCuster Foundation of Alzheimer's Disease Research
🇦🇺Nedlands, Western Australia, Australia
University of Alabama in Birmingham
🇺🇸Birmingham, Alabama, United States