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.
- Registration Number
- NCT04623242
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
The purpose of this study is to assess the safety, tolerability, biomarker and cognitive efficacy of investigational products in subjects who are known to have an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive impairment and improves disease-related biomarkers.
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- Detailed Description
The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with dominantly inherited Alzheimer's disease have very high penetrance (near 100%). This study will target individuals who are either known to have a disease-causing mutation or who are at risk for such a mutation (the child or sibling of a pr...
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 194
- Between 18-80 years of age
- Individuals who know they have an Alzheimer's disease-causing mutation or are unaware of their genetic status and have dominantly inherited Alzheimer's disease (DIAD) mutation in their family.
- Are within -15 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, 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
- PARALLEL
- Arm && Interventions
Group Intervention Description Matching placebo (Gantenerumab) Matching Placebo (Gantenerumab) - Matching Placebo (Solanezumab) Matching Placebo (Solanezumab) - Solanezumab Solanezumab - Gantenerumab Gantenerumab -
- Primary Outcome Measures
Name Time Method Assess Cognitive Efficacy in Individuals With Mutations Causing Dominantly Inherited AD as Measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE); Baseline through Week 260 Multivariate Disease Progression Model adjusted for Estimated Years to Onset (EYO)and includes all timepoints up to treatment discontinuation. The treatment effect is reported relative to the mutation positive placebo arm.
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- Secondary Outcome Measures
Name Time Method Solanezumab: Clinical Measures- Functional Assessment Scale (FAS) Baseline and Weeks 52, 104, 156, 208 and 260 The Functional Assessment Scale is to be administered and completed by the study partner about subjects for whom they care. This scale measures instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS is to assess change in an individual's functional activities, relative to previously atta...
Gantenerumab: Rate of Change Over Time- Clinical Dementia Rating Sum of Boxes (CDR-SB) Baseline and Weeks 52, 104, 156, 208 and 260 CDR-SB score is considered a more detailed quantitative general index of cognition and function, and provides more information than the global CDR score in patients with mild dementia
Scores range from 0-18 with lower scores showing more favorable cognitive function.Gantenerumab: Rate of Change Over Time- Functional Assessment Scale (FAS) Baseline and Weeks 52, 104, 156, 208 and 260 The Functional Assessment Scale is to be administered and completed by the study partner about subjects for whom they care. This scale measures instrumental activities of daily living such as preparing balanced meals and managing personal finances. The intent of the FAS is to assess change in an individual's functional activities, relative to previously atta...
Solanezumab: Clinical Measures- CDR Sum of Boxes (CDR-SB) Baseline and Weeks 52, 104, 156, and 208 CDR-SB score is considered a more detailed quantitative general index and provides more information than the global CDR score in patients with mild dementia
Scores range from 0-18 with lower scores showing more favorable cognitive function.Solanezumab: Clinical Measures- Mini-Mental Status State Examination (MMSE) Baseline and Weeks 52, 104, 156, 208 and 260 MMSE is a brief, quantitative measure of cognitive status in adults used to screen for cognitive impairment, to estimate the severity of cognitive impairment at a given point in time, to follow the course of cognitive changes in an individual over time, and to document an individual's response to treatment.
...Solanezumab: Cognitive Measures- International Shopping List Task 30-Minute Delayed Recall Baseline and Weeks 52, 104, 156, 208 and 260 Classic list-learning test that measures verbal learning \& memory.
Scores range from 0-12 with higher scores indicating more favorable cognitive performance.Solanezumab: Cognitive Measures- Groton Maze Learning Test 30 Minute Delayed Recall Baseline, Week 52, 104, 156, 208 and 260 The Groton Maze Learning Test 30 minute delayed recall measures episodic memory. The primary outcome is the number of errors made during recall of the previously memorized pathway from the Groton Maze Learning Test. The minimum score is 0 errors and the max is 999. Lower scores indicate better cognitive performance.
Gantenerumab: Imaging Measures Composite [11C] PiB Partial Volume Corrected Regional Spread Function Standardized Uptake Value Ratio - Composite Baseline, Weeks 52, 104 and 208 In vivo quantification of β-amyloid deposition using positron emission tomography. This measure is a composite of brain regions. Higher scores indicate worse disease stage.
Solanezumab: Clinical Measures- Clinical Dementia Rating (CDR) Baseline and Weeks 52, 104, 156, and 208 Clinical Dementia Rating - Global Score - Number of Subjects with an Increase from Baseline by Visit
Solanezumab: Cognitive Measures- Trailmaking Test Part A Baseline and Weeks 52, 104, 156, 208 and 260 Trail Making test taps attention, processing speed, and executive function. Part A consists of 25 circles numbered 1 through 25 distributed over a white sheet of standard document-sized paper. The subject is instructed to connect the circles with a drawn line as quickly as possible in ascending numerical order without lifting their pen.
...Solanezumab: Cognitive Measures- Raven's Progressive Matrices (Set A) Baseline and Weeks 52, 104, 156, 208 and 260 This is a measure of fluid intelligence. This test is used to get an estimate of the subjects IQ at baseline. Subjects are asked to complete a visual pattern by circling one of six response choices.
Scores range from 0-12 with higher scores indicating more favorable cognitive performance.Solanezumab: Cognitive Measures- WMS-R Logical Memory Delayed Recall Test Baseline and Weeks 52, 104, 156, 208 and 260 Measure of delayed recall (episodic memory) of a story read to the subject at the beginning of the testing session and subject is asked to relay the story 20 minutes later.
Scores range from 0-25 with higher scores indicating more favorable cognitive performance.Solanezumab: Cognitive Measures- WMS-R Logical Memory Immediate Recall Test Baseline and Weeks 52, 104, 156, 208 and 260 This test assesses the ability to recall a short story. The subject is read a short story and immediately after hearing the story, the subject is asked to retell the story from memory.
Scores range from 0-25 with higher scores indicating more favorable cognitive performance.Solanezumab: Clinical Measures- Geriatric Depression Scale (GDS) Baseline and Weeks 52, 104, 156, 208 and 260 The Geriatric Depression Scale (GDS) is a self-report measure of depression in older adults. Users respond in a "Yes/No" format. Of the 15 items, 10 indicate the presence of depression when answered positively while the other 5 are indicative of depression when answered negatively.
...Solanezumab: Clinical Measures- Neuropsychiatric Inventory Questionnaire (NPI-Q) Baseline and Weeks 52, 104, 156, 208 and 260 The questionnaire is to be administered and completed by the study partner about patients for whom they care. Each of the 12 NPI-Q domains contains a survey question that reflects cardinal symptoms of that domain. Initial responses to each domain question are "Yes"(present) or "No" (absent). If the response to the domain question is "No", the study partner g...
Solanezumab: Cognitive Measures- Trailmaking Test Part B Baseline, Weeks 52, 104, 156, 208 and 260 This test taps attention, processing speed, and executive function and depends on visuo-motor and perceptual-scanning skills and also requires considerable cognitive flexibility in shifting from number to letter sets under time pressure. Part B consists of 25 circles, but these circles contain either numbers (1 through 13) or letters (A through L). The subje...
Solanezumab: Cognitive Measures- Category Fluency (Animals) Baseline and Weeks 52, 104, 156, 208 and 260 Category Fluency is a widely used measure of semantic memory (verbal fluency, language). The subject is asked to name different exemplars of a given semantic category (animals), and the number of unique exemplars named is scored.
Higher scores indicate more favorable cognitive function.Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by [11C]PiB-PET Non-partial Volume Corrected Baseline and Weeks 52, 104 and 208 PiB Standardized Uptake Value Ratio (\[11C\]PiB SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions dervived via automated segmentation using FreeSurfer) with respect to a reference region. In amyloi...
Solanezumab: Imaging Measures- Brain Glucose Metabolism as Measured by Fluorodeoxyglucose (FDG)-PET Non-partial Volume Corrected Baseline and Weeks 52, 104 and 208 FDG Standardized Uptake Value Ratio (\[18F\]FDG SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions derivved via automated segmentation using FreeSurfer) with respect to a reference region. In amyloi...
Solanezumab: Cognitive Measures- WAIS-R Digit-Symbol Substitution Test Baseline and Weeks 52, 104, 156, 208 and 260 This test engages multiple cognitive abilities, including attention, psychomotor speed, complex scanning, visual tracking, and immediate memory.
Scores range from 0-93 with higher scores indicate more favorable cognitive function.Solanezumab: Cognitive Measures- Category Fluency (Vegetables) Baseline and Weeks 52, 104, 156, 208 and 260 Category Fluency is a widely used measure of semantic memory (verbal fluency, language). The subject is asked to name different exemplars of a given semantic category (vegetables), and the number of unique exemplars named is scored.
Higher scores indicate more favorable cognitive function.Solanezumab: Imaging Measures- Brain Atrophy as Measured by Cortical Thickness of Regions of Interest - Precuneus Region Baseline and Weeks 52, 104, 156 and 208 Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. For the clinical trial we examined cortical thickness values ...
Solanezumab: Imaging Measures- Volumetric MRI Combined Total Volume Corrected for Head Size - Hippocampus Volume Baseline and Weeks 52, 104, 156, 208 and 260 Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. For the clinical trial we examined volume values in prespecif...
Solanezumab: Imaging Measures- Brain Atrophy as Measured by Whole Brain Volume Corrected for Head Size Baseline and Weeks 52, 104, 156, 208 and 260 Brain atrophy was defined by structural magnetic resonance imaging (MRI) A Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequence was processed using the Freesurfer software suite. This package provides volumes and thickness values for cortical regions and volumes for subcortical regions. A whole brain volume measure was generated to represent globa...
Solanezumab: Fluid Biomarker Measures- CSF Aβ 42 Free Baseline and Weeks 52, 104 and 208 Measured concentration of the total soluble Aβ 1-42 peptide in cerebrospinal fluid using ELISA
Solanezumab: Fluid Biomarker Measures- CSF Tau Baseline and Weeks 52, 104 and 208 Measured concentration of the soluble Tau peptide in cerebrospinal fluid
Solanezumab: Fluid Biomarker Measures- CSF Aβ 42 Total Baseline and Weeks 52, 104 and 208 Measured concentration of the total soluble Aβ1-42 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)
Solanezumab: Cognitive Measures- Groton Maze Learning Test Delayed Reversed Recall Baseline, Week 52, 104, 156, 208 and 260 The Groton Maze Learning Test measures executive function using a maze learning paradigm. A 10 x 10 grid of tiles is presented to the participant on the screen. A 28-step pathway is hidden among these tiles. A blue tile indicates the start and a tile with red circles indicates the finish. The participant must move one step at a time from the start toward the...
Solanezumab: Cognitive Measures- WMS-R Digit Span Backward Baseline and Weeks 52, 104, 156, 208 and 260 Widely used measure of working memory (or attention) in which the subject is read number sequences of increasing length and then asked to repeat each sequence backward. The primary measure of performance is the number of digit sequences correctly reversed.
...Solanezumab: Cognitive Measures- WMS-R Digit Span Forward Baseline, Weeks 52, 104, 156, 208 and 260 This is a widely-used test of working memory in which the subject is read number sequences of increasing length and asked to repeat them. The total score is the number of sequences correctly repeated.
The unit of measure is number of digit sequences correctly recalled and ranges from 0-12. Higher scores indicate more favorable cognitive function.Solanezumab: Cognitive Measures- Composite Including: Alternative Multivariate Composite: (1) Digit Span Backwards; (2) Logical Memory (Immediate); (3) Trailmaking B; (4) Category Fluency (Animals) Baseline through Week 260 Multivariate Disease Progression Model adjusted for estimated years from symptom onset (EYO) and includes all time points up to treatment discontinuation. The treatment effect for Solanezumab is reported relative to the mutation positive placebo arm.
...Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 Free Change From Baseline Baseline and Weeks 52, 104 and 208 Measured concentration of the drug bound and free soluble Aβ1-40 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)
Solanezumab: Fluid Biomarker Measures- Total Plasma Aβ 1-40 Baseline and Weeks 52, 104 and 208 Measured concentration of the total soluble Aβ 1-40 peptide in cerebrospinal fluid using ELISA
Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 Total Baseline and Weeks 52, 104 and 208 Measured concentration of the total soluble Aβ1-40 peptide in cerebrospinal fluid using enzyme-linked immunosorbent assay (ELISA)
Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by Florbetapir PET Weeks104 and 208 Florbetapir Standardized Uptake Value Ratio (\[18F\]AV-45 SUVR) is the most common quantitative method used to make regional comparisons within a subject as well as between subjects and computed as the degree of radiotracer uptake in a target region of interest (regions derivved via automated segmentation using FreeSurfer) with respect to a reference region....
Solanezumab: Imaging Measures- Brain Tau Load as Measured by Flortaucipir PET Non-partial Volume Corrected Baseline and Weeks 52, 104 and 208 This variable represents how much neurofibrillary tau pathology is present in brain as assessed using positron emission tomography (PET). Scans were conducted using \[F18\] Flortaucipir, a commonly used tracer in the field.
Solanezumab: Imaging Measures- Brain Atrophy as Measured by Ventricular Volume (Volumetric MRI) Corrected for Head Size Baseline and Weeks 52, 104, 156, 208 and 260 Rather than looking at how tissue in the brain changes, it is also possible to quantify how the ventricles, fluid filled spaces in the brain, change. Increasing ventricular volume represents greater amounts of cerebral spinal fluid which suggests atrophy of the brain. Magnetization Prepared - RApid Gradient Echo) (MPRAGE) sequences were processed using the F...
Solanezumab: Fluid Biomarker Measures- CSF pTau 181 Baseline and Weeks 52, 104 and 208 Measured concentration of phosphorylated tau at threonine-181 in cerebrospinal fluid
Solanezumab: Change From Baseline Fluid Biomarker Measures- CSF Neurofilament Light Chain (NfL) Baseline and Weeks 52, 104 and 208 Measured concentration of neurofilament light chain in cerebrospinal fluid using SIMO
Solanezumab: Fluid Biomarker Measures- Plasma Neurofilament Light Chain (NfL) Baseline and Weeks 52, 104 and 208 Measured concentration of neurofilamnet light chain in plasma using Single Molecule Array (SIMOA)
Solanezumab: Fluid Biomarker Measures- Plasma Anti-drug Antibodies (ADA) Baseline and Weeks 52, 104 and 208 Measurement of the presence or absence of anti-drug antibodies in serum
Note: Mutation Negative Placebo subjects are not displayed as anti-drug antibody testing was not to be evaluated for these subjects.
...Solanezumab: Fluid Biomarker Measures- Total Plasma Aβ 42 Baseline and Weeks 52, 104 and 208 Measured concentration of the total soluble Aβ 1-42 peptide in cerebrospinal fluid using ELISA
Trial Locations
- Locations (25)
University of California San Diego Medical Center
🇺🇸La Jolla, California, United States
Washington University in St. Louis
🇺🇸Saint Louis, Missouri, United States
Columbia University
🇺🇸New York, New York, United States
Butler Hospital
🇺🇸Providence, Rhode Island, United States
UBC Hospital
🇨🇦Vancouver, British Columbia, Canada
The McCuster Foundation of Alzheimer's Disease Research
🇦🇺Nedlands, Western Australia, Australia
CHU de Toulouse - Hôpital Purpan
🇫🇷Toulouse, Haute Garonne, France
McGill Center for Studies in Aging
🇨🇦Verdun, Quebec, Canada
Hopital Roger Salengro - CHU Lille
🇫🇷Lille, Nord, France
St Vincent's University Hospital
🇮🇪Dublin, Ireland
Hopital Neurologique Pierre Wertheimer
🇫🇷Bron cedex, Rhone, France
CHU de Rouen - Hôpital Charles Nicolle
🇫🇷Rouen, Seine Maritime, France
University of Puerto Rico, School of Medicine
🇵🇷San Juan, Puerto Rico
Hospital Clínic I Provincial de Barcelona
🇪🇸Barcelona, Spain
The National Hospital for Neurology and Neurosurgery
🇬🇧London, Greater London, United Kingdom
University of Alabama in Birmingham
🇺🇸Birmingham, Alabama, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Indiana University School of Medicine
🇺🇸Indianapolis, Indiana, United States
University of Washington
🇺🇸Seattle, Washington, United States
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Yale University School of Medicine
🇺🇸New Haven, Connecticut, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Mental Health Research Institute
🇦🇺Melbourne, Victoria, Australia
Groupe Hospitalier Pitie-Salpetriere
🇫🇷Paris cedex 13, Paris, France
Neuroscience Research Australia
🇦🇺Randwick, New South Wales, Australia