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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. Master Protocol DIAN-TU001 (DIAN-TU)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01760005
Recruitment Status : Recruiting
First Posted : January 3, 2013
Last Update Posted : June 25, 2021
Eli Lilly and Company
Hoffmann-La Roche
Alzheimer's Association
National Institute on Aging (NIA)
Avid Radiopharmaceuticals
Accelerating Medicines Partnership (AMP)
Information provided by (Responsible Party):
Washington University School of Medicine

Tracking Information
First Submitted Date  ICMJE December 26, 2012
First Posted Date  ICMJE January 3, 2013
Last Update Posted Date June 25, 2021
Actual Study Start Date  ICMJE December 2012
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
Assess cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by the change from baseline in the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
The DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) consists of 4 cognitive measures: Wechsler Memory Scale-Revised Logical Memory Delayed Recall Test, Wechsler Adult Intelligence Sale Digit Symbol Substitution Test (WAIS), International Shopping List Task (ISLT), Mini-Mental State Examination (MMSE)
Original Primary Outcome Measures  ICMJE
 (submitted: December 31, 2012)
  • Gantenerumab: The amount of fibrillar amyloid deposition as measured by [11C]PiB-PET scans. [ Time Frame: Baseline and 2 years ]
  • Solanezumab: The concentrations of CSF Aβ species, specifically different treatment effects on free CSF Aβ42 (increase/no change) and free CSF Aβ40 (decrease) with comparable treatment-associated increases in CSF total Aβ42 and total Aβ40. [ Time Frame: Baseline and 2 years ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: December 31, 2012)
  • Solanezumab Only: Change in amyloid deposition as measured by [11C]PiB-PET mean composite SUVR (Standardized uptake value ratio) [ Time Frame: Baseline and 2 years ]
  • Gantenerumab Only: Change in Cerebrospinal fluid (CSF) amyloid-beta peptide concentrations. [ Time Frame: Baseline and 2 years ]
  • Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group [ Time Frame: Baseline and 2 years ]
  • Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI) [ Time Frame: Baseline and 2 years ]
  • Change in 2-[18F] fluoro-2-deoxy-D-glucose (FDG) PET metabolism in specific regions of interest (e.g., precuneus) in treated group as compared to pooled placebo group measured [ Time Frame: Baseline and 2 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: December 31, 2012)
  • Frequency of adverse events during the treatment period [ Time Frame: 2 years ]
  • Nature and severity of adverse events during the treatment period [ Time Frame: 2 years ]
  • Changes in vital signs/physical findings [ Time Frame: Baseline and 2 years ]
  • Changes in neurological findings [ Time Frame: Baseline and 2 years ]
  • Changes in laboratory test results [ Time Frame: Baseline and 2 years ]
  • Changes in ECG findings [ Time Frame: Baseline and 2 years ]
  • Exploratory Clinical Measures (annual rate of change) [ Time Frame: Baseline and 2 years ]
    • Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
    • Mini Mental Status Exam (MMSE)
    • Geriatric Depression Scale (GDS)
    • Neuropsychiatric Inventory Questionnaire (NPI-Q)
    • Functional Assessment Questionnaire (FAQ)
  • Exploratory Cognitive Measures (annual rate of change) [ Time Frame: Baseline and 2 years ]
    • International Shopping List Test (12-Item Word List Learning): 3 learning trials, Immediate Recall, 30-min Delayed Recall (CogState)
    • Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-min Delayed Recall (CogState)
    • Identification Test (CogState)
    • One Card Learning Test (CogState)
    • Memory and Concerns Questionnaire (MAC-Q)
    • Trails A & B
    • Wechsler Memory Scale - Revised (WMS-R) Digit Span
    • Wechsler Adult Intelligence Scale - Revised (WAIS-R) Digit-Symbol Substitution Test
    • Raven's Progressive Matrices (Set A)
    • Category Fluency to Animals & Vegetables
    • Wechsler Memory Scale Logical Memory I Paragraph Memory (Immediate & Delayed Recall)
    • Rentz Face-Name Association Memory Test (CogState)
    • Stark Pattern Separation Task (CogState)
Descriptive Information
Brief Title  ICMJE 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. Master Protocol DIAN-TU001
Official Title  ICMJE 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
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.
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 (Ryman, Acosta-Baena et al. 2014), 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.

A cognitive run-in (CRI) period may open for recruitment if no study drug arm is available for immediate enrollment, or if a treatment arm is stopped prior to the planned completion (e.g., at biomarker interim, drug toxicity). The CRI period will enhance study enrollment by identifying eligible subjects and engaging them with the cognitive process, and can reduce fluctuations in practice effects by allowing subjects to become accustomed to the testing process.

For the solanezumab and gantenerumab double blind treatment arms: Primary Completion Date= Nov 2019 and Study Completion= March 2020 (NCT04623242)

An open-label extension for gantenerumab is enrolling by invitation under this protocol.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Interventional with a non-interventional run-in component (Future interventions to be added)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
One arm is Open-label as noted in the arm descriptions
Primary Purpose: Treatment
Condition  ICMJE
  • Alzheimers Disease
  • Dementia
  • Alzheimers Disease, Familial
Intervention  ICMJE
  • Drug: Gantenerumab
    Subcutaneously every 4 weeks at escalating doses
    Other Name: RO4909832
  • Drug: Solanezumab
    Intravenous infusion every 4 weeks at escalating doses
    Other Name: LY2062430
  • Drug: Matching Placebo (Gantenerumab)
    Subcutaneous injection of placebo every 4 weeks
  • Drug: Matching Placebo (Solanezumab)
    Intravenous infusion of placebo every 4 weeks
  • Drug: Gantenerumab
    Open-label administered Subcutaneously every 4 weeks at escalating doses
    Other Name: RO4909832
Study Arms  ICMJE
  • Experimental: Gantenerumab
    Intervention: Drug: Gantenerumab
  • Experimental: Solanezumab
    Intervention: Drug: Solanezumab
  • Placebo Comparator: Matching placebo (Gantenerumab)
    Intervention: Drug: Matching Placebo (Gantenerumab)
  • Placebo Comparator: Matching Placebo (Solanezumab)
    Intervention: Drug: Matching Placebo (Solanezumab)
  • No Intervention: Cognitive Run-in
  • Active Comparator: Gantenerumab Open Label Extension
    Subcutaneously every 4 weeks at escalating doses
    Intervention: Drug: Gantenerumab
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 19, 2020)
Original Estimated Enrollment  ICMJE
 (submitted: December 31, 2012)
Estimated Study Completion Date  ICMJE July 2022
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. For Cognitive Run-In (CRI): includes participants who are younger than 15 years prior to the expected age of cognitive symptom onset, in addition to those 15 years younger and no more than 10 years older than expected 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Ellen Ziegemeier, MA 844-DIANEXR (342-6397)
Contact: Jennifer Petranek 844-DIANEXR (342-6397)
Listed Location Countries  ICMJE Argentina,   Australia,   Brazil,   Canada,   China,   Colombia,   France,   Germany,   Ireland,   Italy,   Japan,   Mexico,   Netherlands,   Puerto Rico,   Spain,   United Kingdom,   United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01760005
Other Study ID Numbers  ICMJE DIAN-TU-001 (Master)
The Alzheimer's Association ( Other Grant/Funding Number: DIAN TTU-12-243040 )
U01AG042791 ( U.S. NIH Grant/Contract )
2013-000307-17 ( EudraCT Number )
R01AG046179 ( U.S. NIH Grant/Contract )
REec-2014-0817 ( Registry Identifier: Spanish Clinical Studies Registry )
The Alzheimer's Association ( Other Grant/Funding Number: DIAN-TU Tau-15-347219 )
GHR Foundation ( Other Grant/Funding Number: File 4401 )
Alzheimer's Association ( Other Identifier: HDE 18S84914 )
The Alzheimer's Association ( Other Grant/Funding Number: DIAN-TU NG-16-434362 )
R56AG053267 ( U.S. NIH Grant/Contract )
U01AG059798 ( U.S. NIH Grant/Contract )
R01AG053267 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Access to DIAN-TU trial data will follow the DIAN-TU data access policy, which complies with the guidelines established by the Collaboration for Alzheimer's Prevention [CAP REF].
Responsible Party Washington University School of Medicine
Study Sponsor  ICMJE Washington University School of Medicine
Collaborators  ICMJE
  • Eli Lilly and Company
  • Hoffmann-La Roche
  • Alzheimer's Association
  • National Institute on Aging (NIA)
  • Avid Radiopharmaceuticals
  • Accelerating Medicines Partnership (AMP)
Investigators  ICMJE
Study Director: Randall J Bateman, MD Washington University School of Medicine
PRS Account Washington University School of Medicine
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP