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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. (DIAN-TU)

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ClinicalTrials.gov Identifier: NCT01760005
Recruitment Status : Recruiting
First Posted : January 3, 2013
Last Update Posted : November 21, 2017
Sponsor:
Collaborators:
Information provided by (Responsible Party):

Study Description
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.

Condition or disease Intervention/treatment Phase
Alzheimers Disease Dementia Alzheimers Disease, Familial Drug: Gantenerumab Drug: Solanezumab Drug: Matching Placebo (Gantenerumab) Drug: Matching Placebo (Solanezumab) Drug: JNJ-54861911 Drug: Matching Placebo (JNJ-54861911) Phase 2 Phase 3

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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 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, solanezumab, JNJ-54861911) 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 disease progression model (CDPM) endpoint design will allow for detection of these subtle cognitive changes.


Study Design

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 438 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : December 2012
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : December 2023


Arms and Interventions

Arm Intervention/treatment
Experimental: Gantenerumab Drug: Gantenerumab
Subcutaneously every 4 weeks at escalating doses
Other Name: RO4909832
Experimental: Solanezumab Drug: Solanezumab
Intravenous infusion every 4 weeks at escalating doses
Other Name: LY2062430
Placebo Comparator: Matching placebo (Gantenerumab) Drug: Matching Placebo (Gantenerumab)
Subcutaneous injection of placebo every 4 weeks
Placebo Comparator: Matching Placebo (Solanezumab) Drug: Matching Placebo (Solanezumab)
Intravenous infusion of placebo every 4 weeks
Experimental: JNJ-54861911 Drug: JNJ-54861911
25 mg daily oral tablet
Placebo Comparator: Matching Placebo (JNJ-54861911) Drug: Matching Placebo (JNJ-54861911)
Daily oral placebo tablet


Outcome Measures

Primary Outcome Measures :
  1. Assess cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by change in the DIAN-TU cognitive composite score. [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]

Secondary Outcome Measures :
  1. Gantenerumab: Cerebral amyloid imaging using [11C]PiB-PET. [ Time Frame: Baseline and Weeks 52, 104, and 208 ]
  2. Solanezumab: Total Abeta 1-42 (Aβ42) in CSF. [ Time Frame: Baseline, Week 104 ]
  3. JNJ-54861911: CSF amyloid-beta peptide concentration as measured by Abeta 1-42 (Aβ42) in CSF. [ Time Frame: Baseline, Week 208 ]
  4. Change from Baseline in Clinical Measures [ Time Frame: Baseline, week 208 ]
    • Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinician's diagnostic assessment
    • Geriatric Depression Scale (GDS)
    • Neuropsychiatric Inventory Questionnaire (NPI-Q)
    • Functional Assessment Questionnaire (FAQ)
    • Mini Mental Status Exam (MMSE)

  5. Change from Baseline in Cognitive Measures [ Time Frame: Baseline, week 208 ]
    • 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)
    • Cogstate Detection Task
    • Cogstate Identification Test
    • Cogstate One Card Learning Test
    • Cogstate One-Back (OBK) Task
    • Behavioral Pattern Separation Object Task
    • Memory Complaint 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 (Animals & Vegetables)
    • Wechsler Memory Scale Logical Memory I Paragraph Memory (Immediate & Delayed Recall)


Other Outcome Measures:
  1. Safety and Tolerability Outcome Measures [ Time Frame: Baseline, week 208 ]
    • Neurological findings
    • Laboratory test results
    • ECG findings
    • Safety MRIs


Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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 a 50% chance of having an autosomal dominant Alzheimer's disease (ADAD) mutation (e.g. parent or sibling with a known AD-causing mutation)
  • 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.
  • JNJ-54861911 study arm only: Hypopigmentation abnormality of the skin such as vitiligo, other than small localized findings, at baseline dermatological test.
  • JNJ-54861911 study arm only: Subjects with the APP Swedish Mutation
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01760005


Contacts
Contact: Ellen Ziegemeier, MA 844-DIANEXR (342-6397) dianexr@neuro.wustl.edu

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Locations
United States, Alabama
University of Alabama in Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Principal Investigator: Erik Roberson         
United States, California
University of California San Diego Medical Center Recruiting
La Jolla, California, United States, 92037
Principal Investigator: Doug Galasko         
United States, Connecticut
Yale University School of Medicine Recruiting
New Haven, Connecticut, United States, 06510
Principal Investigator: Christopher Van Dyck         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30329
Principal Investigator: James Lah         
United States, Indiana
Indiana University School of Medicine Recruiting
Indianapolis, Indiana, United States, 46202
Principal Investigator: Jared Brosch         
United States, Missouri
Washington University in St. Louis Recruiting
Saint Louis, Missouri, United States, 63110
Principal Investigator: Barbara Snider         
United States, New York
Columbia University Active, not recruiting
New York, New York, United States, 10032
United States, Pennsylvania
University of Pittsburgh Active, not recruiting
Pittsburgh, Pennsylvania, United States, 15213
United States, Rhode Island
Butler Hospital Active, not recruiting
Providence, Rhode Island, United States, 02096
United States, Washington
University of Washington Active, not recruiting
Seattle, Washington, United States, 98195
Australia, New South Wales
Neuroscience Research Australia Active, not recruiting
Randwick, New South Wales, Australia, 2031
Australia, Victoria
Mental Health Research Institute Active, not recruiting
Melbourne, Victoria, Australia, 3010
Australia, Western Australia
The McCuster Foundation of Alzheimer's Disease Research Active, not recruiting
Nedlands, Western Australia, Australia, 6009
Canada, British Columbia
UBC Hospital Active, not recruiting
Vancouver, British Columbia, Canada, V6T 2B5
Canada, Ontario
Sunnybrook Health Sciences Centre Active, not recruiting
Toronto, Ontario, Canada, M4N 3M5
Canada, Quebec
McGill Center for Studies in Aging Recruiting
Verdun, Quebec, Canada, H4H 1R3
Principal Investigator: Serge Gauthier         
France
CHU de Toulouse - Hôpital Purpan Active, not recruiting
Toulouse, Haute Garonne, France, 31059
Hopital Roger Salengro - CHU Lille Active, not recruiting
Lille, Nord, France, 59037
Groupe Hospitalier Pitie-Salpetriere Active, not recruiting
Paris cedex 13, Paris, France, 69677
Hopital Neurologique Pierre Wertheimer Active, not recruiting
Bron cedex, Rhone, France, 69677
CHU de Rouen - Hôpital Charles Nicolle Active, not recruiting
Rouen, Seine Maritime, France, 76031
Italy
IRCCS Centro San Giovanni di Dio Fatebenefratelli Not yet recruiting
Brescia, Italy, 25125
Principal Investigator: Giovanni Frisoni         
Azienda Ospedaliera Universitaria Careggi Not yet recruiting
Firenze, Italy, 50134
Principal Investigator: Sandro Sorbi         
Puerto Rico
University of Puerto Rico, School of Medicine Active, not recruiting
San Juan, Puerto Rico, 00936
Spain
Hospital Clínic I Provincial de Barcelona Recruiting
Barcelona, Spain, 8036
Principal Investigator: Raquel Sanchez Valle         
United Kingdom
The National Hospital for Neurology and Neurosurgery Active, not recruiting
London, Greater London, United Kingdom, WC1B 3BG
Sponsors and Collaborators
Washington University School of Medicine
Eli Lilly and Company
Hoffmann-La Roche
Alzheimer's Association
National Institute on Aging (NIA)
Avid Radiopharmaceuticals
Accelerating Medicines Partnership (AMP)
Janssen Research and Development
Investigators
Study Director: Randall J Bateman, MD Washington University School of Medicine
More Information

Additional Information:
Publications:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01760005     History of Changes
Other Study ID Numbers: DIAN-TU-001
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 )
The Alzheimer's Association ( Other Grant/Funding Number: DIAN-TU NG-16-434362 )
R56AG053267 ( U.S. NIH Grant/Contract )
GHR Foundation ( Other Grant/Funding Number: File 4401 )
First Posted: January 3, 2013    Key Record Dates
Last Update Posted: November 21, 2017
Last Verified: November 2017

Keywords provided by Washington University School of Medicine:
Alzheimer's
Alzheimer's Disease
Dementia
Mutation
Genetic Mutation
Dominantly Inherited Alzheimer's Disease
Dominantly Inherited Alzheimer's Network
Autosomal Dominant Alzheimer's Disease
Early Onset Alzheimer's Disease
DIAN
DIAN-TU
DIAN TU

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs