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)

Study Description

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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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Study Design

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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

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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

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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

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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

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Contacts

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

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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

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Expanded registry 

Publications:

Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC; Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012 Aug 30;367(9):795-804. doi: 10.1056/NEJMoa1202753. Epub 2012 Jul 11. Erratum in: N Engl J Med. 2012 Aug 23;367(8):780.

Farlow M, Arnold SE, van Dyck CH, Aisen PS, Snider BJ, Porsteinsson AP, Friedrich S, Dean RA, Gonzales C, Sethuraman G, DeMattos RB, Mohs R, Paul SM, Siemers ER. Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement. 2012 Jul;8(4):261-71. doi: 10.1016/j.jalz.2011.09.224. Epub 2012 Jun 5.

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
Last Update Posted:	January 23, 2018
Last Verified:	January 2018

Keywords provided by Washington University School of Medicine:

Alzheimer's; Alzheimer's Disease; Dominantly Inherited Alzheimer's Disease; Dominantly Inherited Alzheimer's Network; Autosomal Dominant Alzheimer's Disease; Early Onset Alzheimer's Disease	Dementia; Mutation; Genetic Mutation; 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