Clinical trial NCT04623242: 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.
Official title: A Phase II/III Randomized, Double-Blind, Placebo-Controlled, Cognitive Endpoint, Multi-Center Study of Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Alzheimers Disease
Dementia
Alzheimers 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
DIAN TU
DIAD
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Eli Lilly and Company
name: Hoffmann-La Roche
name: Alzheimer's Association
name: National Institute on Aging (NIA)
name: Avid Radiopharmaceuticals
name: Accelerating Medicines Partnership (AMP)
First posted: 2020-11-10
Enrollment: 194
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Interventional
Primary purpose: TREATMENT

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.

This is an analysis study for an MPRP: DIAN-TU-001 Master NCT01760005

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 proband with a known mutation) and unaware of their genetic status. Because the age at onset of cognitive changes is relatively consistent within each family and with each mutation, an age at onset is determined for each affected parent or mutation. This study will enroll subjects who are either asymptomatic and are within a specific window of time of expected age at onset for their family and/or mutation or who have symptoms of mild Alzheimer's disease.

The ability to identify individuals destined to develop Alzheimer's disease (AD) within the next 10-15 years with a high degree of confidence provides a unique opportunity to assess the efficacy of therapies while individuals are asymptomatic and/or very early stages of dementia. Families with known disease-causing mutations are extremely rare and are geographically dispersed throughout the world. These constraints necessitate a specialized study design. Many of the subjects in this study will not yet have any cognitive symptoms of AD; they will be "asymptomatic" carriers of mutations that cause dominantly inherited Alzheimer's disease and would be expected to perform normally on standard cognitive and functional testing. 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. Additionally, because many at-risk individuals decide not to know whether they have the disease-associated mutation or not, some of the at-risk individuals enrolled in this study will not have the disease causing mutations; they will be "mutation negative". It is important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects may be pressured into genetic testing to learn their genetic status in order to be eligible for the trial). These mutation negative individuals will be assigned to the placebo group; and will not be included in the primary efficacy or futility analyses. Subjects and site study staff will remain blinded as to these individuals' active or placebo group assignment and mutation status. Thus, the study will be double blinded for placebo and for mutation status, except for mutation positive subjects who are aware of their genetic status. There may be exceptional circumstances when required by local regulation or health authorities where enrollment may be restricted to mutation carriers only but such mandates will be thoroughly documented and agreed upon by the governing regulatory agency and sponsor. Several different therapies (each referred to as a study drug arm) will be tested in order to increase the likelihood that an effective treatment will be discovered. The compounds are selected for this trial based on mechanism of action and available data on efficacy and safety profile.

The study design includes a pooled placebo group shared by all study drug arms. Mutation positive subjects will be assigned to a study drug arm and subsequently randomized within that arm in an overall 3:1 ratio to active drug:placebo. Mutation negative subjects will all receive placebo treatment. Importantly, subjects and study staff will not be blinded as to which study drug arm (gantenerumab or solanezumab) each subject has been assigned; they will be blinded as to whether subjects have been randomized to active drug or placebo. Biomarker data will be analyzed for pre-specified endpoints consistent with the drug's mechanism of action and known effects on the tested biomarkers. The primary cognitive endpoint will be the same for all study drug arms. This study is an adaptive platform based study. Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each study drug engages its biological targets. This biomarker approach is particularly important in this study as most study subjects will be cognitively normal at baseline and most will remain cognitively normal during the first 2 years of the study. The cognitive composite is designed to assess subtle cognitive changes that may be detectable before the onset of dementia. The cognitive multivariate disease progression model (MDPM) endpoint design will allow for detection of these subtle cognitive changes.

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Assess Cognitive Efficacy in Individuals With Mutations Causing Dominantly Inherited AD as Measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE);
timeFrame: Baseline through Week 260
Secondary outcomes:
measure: Gantenerumab: Rate of Change Over Time- Clinical Dementia Rating Sum of Boxes (CDR-SB)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Gantenerumab: Rate of Change Over Time- Functional Assessment Scale (FAS)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Gantenerumab: Imaging Measures Composite [11C] PiB Partial Volume Corrected Regional Spread Function Standardized Uptake Value Ratio - Composite
timeFrame: Baseline, Weeks 52, 104 and 208
measure: Solanezumab: Clinical Measures- Clinical Dementia Rating (CDR)
timeFrame: Baseline and Weeks 52, 104, 156, and 208
measure: Solanezumab: Clinical Measures- CDR Sum of Boxes (CDR-SB)
timeFrame: Baseline and Weeks 52, 104, 156, and 208
measure: Solanezumab: Clinical Measures- Geriatric Depression Scale (GDS)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Clinical Measures- Neuropsychiatric Inventory Questionnaire (NPI-Q)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Clinical Measures- Functional Assessment Scale (FAS)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Clinical Measures- Mini-Mental Status State Examination (MMSE)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- International Shopping List Task 30-Minute Delayed Recall
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Groton Maze Learning Test 30 Minute Delayed Recall
timeFrame: Baseline, Week 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Groton Maze Learning Test Delayed Reversed Recall
timeFrame: Baseline, Week 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Trailmaking Test Part A
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Trailmaking Test Part B
timeFrame: Baseline, Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- WAIS-R Digit-Symbol Substitution Test
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- WMS-R Digit Span Backward
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- WMS-R Digit Span Forward
timeFrame: Baseline, Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Raven's Progressive Matrices (Set A)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Category Fluency (Animals)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Category Fluency (Vegetables)
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- WMS-R Logical Memory Delayed Recall Test
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- WMS-R Logical Memory Immediate Recall Test
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Cognitive Measures- Composite Including: Alternative Multivariate Composite: (1) Digit Span Backwards; (2) Logical Memory (Immediate); (3) Trailmaking B; (4) Category Fluency (Animals)
timeFrame: Baseline through Week 260
measure: Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by [11C]PiB-PET Non-partial Volume Corrected
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Imaging Measures- Brain Amyloid Load as Measured by Florbetapir PET
timeFrame: Weeks104 and 208
measure: Solanezumab: Imaging Measures- Brain Glucose Metabolism as Measured by Fluorodeoxyglucose (FDG)-PET Non-partial Volume Corrected
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Imaging Measures- Brain Atrophy as Measured by Cortical Thickness of Regions of Interest - Precuneus Region
timeFrame: Baseline and Weeks 52, 104, 156 and 208
measure: Solanezumab: Imaging Measures- Volumetric MRI Combined Total Volume Corrected for Head Size - Hippocampus Volume
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Imaging Measures- Brain Tau Load as Measured by Flortaucipir PET Non-partial Volume Corrected
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Imaging Measures- Brain Atrophy as Measured by Whole Brain Volume Corrected for Head Size
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Imaging Measures- Brain Atrophy as Measured by Ventricular Volume (Volumetric MRI) Corrected for Head Size
timeFrame: Baseline and Weeks 52, 104, 156, 208 and 260
measure: Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 Free Change From Baseline
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- CSF Aβ 42 Free
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- CSF Tau
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- CSF pTau 181
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Change From Baseline Fluid Biomarker Measures- CSF Neurofilament Light Chain (NfL)
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- Plasma Neurofilament Light Chain (NfL)
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- Plasma Anti-drug Antibodies (ADA)
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- Total Plasma Aβ 1-40
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- Total Plasma Aβ 42
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- CSF Aβ 42 Total
timeFrame: Baseline and Weeks 52, 104 and 208
measure: Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 Total
timeFrame: Baseline and Weeks 52, 104 and 208
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama in Birmingham
state: Alabama
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Atlanta
country: United States
facility: Emory University
state: Georgia
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: New York
country: United States
facility: Columbia University
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Butler Hospital
state: Rhode Island
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Randwick
country: Australia
facility: Neuroscience Research Australia
state: New South Wales
city: Melbourne
country: Australia
facility: Mental Health Research Institute
state: Victoria
city: Nedlands
country: Australia
facility: The McCuster Foundation of Alzheimer's Disease Research
state: Western Australia
city: Vancouver
country: Canada
facility: UBC Hospital
state: British Columbia
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Verdun
country: Canada
facility: McGill Center for Studies in Aging
state: Quebec
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital Purpan
state: Haute Garonne
city: Lille
country: France
facility: Hopital Roger Salengro - CHU Lille
state: Nord
city: Paris cedex 13
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
state: Paris
city: Bron cedex
country: France
facility: Hopital Neurologique Pierre Wertheimer
state: Rhone
city: Rouen
country: France
facility: CHU de Rouen - Hôpital Charles Nicolle
state: Seine Maritime
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico, School of Medicine
city: Barcelona
country: Spain
facility: Hospital Clínic I Provincial de Barcelona
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
References:
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citation: Grill JD, Bateman RJ, Buckles V, Oliver A, Morris JC, Masters CL, Klunk WE, Ringman JM; Dominantly Inherited Alzheimer's Network. A survey of attitudes toward clinical trials and genetic disclosure in autosomal dominant Alzheimer's disease. Alzheimers Res Ther. 2015 Jul 22;7(1):50. doi: 10.1186/s13195-015-0135-0. eCollection 2015.
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