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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)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01760005
Recruitment Status : Completed
First Posted : January 3, 2013
Last Update Posted : August 5, 2020
Sponsor:
Collaborators:
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

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) Phase 2 Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 194 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Interventional
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
Actual Study Start Date : December 2012
Actual Primary Completion Date : November 22, 2019
Actual Study Completion Date : March 6, 2020


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




Primary Outcome Measures :
  1. Assess change in cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) in the MDPM. Wechsler Memory Scale-Revised Logical Memory Delayed Recall Test [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  2. Assess change in cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) in the MDPM. Wechsler Adult Intelligence Sale Digit Symbol Substitution Test (WAIS) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  3. Assess change in cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) in the MDPM. International Shopping List Task (ISLT) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  4. Assess change in cognitive efficacy in individuals with mutations causing dominantly inherited AD as measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE) in the MDPM. Mini-Mental State Examination (MMSE) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]

Secondary Outcome Measures :
  1. Gantenerumab: Rate of change over time- Clinical Dementia Rating Sum of Boxes (CDR-SB) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  2. Gantenerumab: Rate of change over time- Functional Assessment Scale (FAS) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  3. Solanezumab: Clinical Measures- Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) and clinicians diagnostic assessment [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  4. Solanezumab: Clinical Measures- Geriatric Depression Scale (GDS) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  5. Solanezumab: Clinical Measures- Neuropsychiatric Inventory Questionnaire (NPI-Q) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  6. Solanezumab: Clinical Measures- Functional Assessment Scale (FAS) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  7. Solanezumab: Clinical Measures- Mini-Mental Status State Examination (MMSE) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  8. Solanezumab: Cognitive Measures- International Shopping List Test (12-Item Word List Learning): 3 learning trials, Immediate Recall, 30-min Delayed/Reversed Recall (Cogstate) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  9. Solanezumab: Cognitive Measures- Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-min Delayed/Reversed Recall (Cogstate) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  10. Solanezumab: Cognitive Measures- Trailmaking Test parts A & B [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  11. Solanezumab: Cognitive Measures- WMS-R Digit Span [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  12. Solanezumab: Cognitive Measures- WAIS-R Digit-Symbol Substitution Test [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  13. Solanezumab: Cognitive Measures- Raven's Progressive Matrices (Set A) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  14. Solanezumab: Cognitive Measures- Category Fluency (Animals & Vegetables) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  15. Solanezumab: Cognitive Measures- WMS-R Logical Memory (Immediate & Delayed Recall) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  16. Solanezumab: Cognitive Measures- Alternative multivariate composite: (1) Digit Span backwards; (2) Logical Memory (Immediate); (3) Trailmaking B; (4) Category Fluency (Animals) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  17. Solanezumab: Imaging Measures- Brain amyloid load as measured by [11C]PiB-PET [ Time Frame: Baseline and Weeks 52, 104 and 208 ]
  18. Solanezumab: Imaging Measures- Brain amyloid load as measured by florbetapir PET [ Time Frame: Baseline and Weeks 52, 104 and 208 ]
  19. Solanezumab: Imaging Measures- Brain glucose metabolism as measured by fluorodeoxyglucose (FDG)-PET [ Time Frame: Baseline and Weeks 52, 104 and 208 ]
  20. Solanezumab: Imaging Measures- Brain atrophy as measured by cortical thickness of regions of interest, whole brain volume and ventricular volume (volumetric MRI) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  21. Solanezumab: Imaging Measures- Brain tau load as measured by flortaucipir PET [ Time Frame: Baseline and Weeks 52, 104 and 208 ]
  22. Solanezumab: Fluid Biomarker Measures- CSF Aβ 40 and 42, free and total [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  23. Solanezumab: Fluid Biomarker Measures- CSF Tau and pTau [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  24. Solanezumab: Fluid Biomarker Measures- CSF Neurofilament light chain (NfL) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  25. Solanezumab: Fluid Biomarker Measures- Plasma Neurofilament light chain (NfL) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  26. Solanezumab: Fluid Biomarker Measures- Plasma Aβ 40 and 42, total [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]
  27. Solanezumab: Fluid Biomarker Measures- Plasma Anti-drug antibodies (ADA) [ Time Frame: Baseline and Weeks 52, 104, 156, and 208 ]

Other Outcome Measures:
  1. Additional Outcome Measures: Change from Baseline in Cognitive Measures- A Cogstate multivariate endpoint: Cogstate Detection Task, Cogstate Identification Task, Cogstate One Card Learning Test, and Cogstate One Back Task [ Time Frame: Baseline, week 208 ]
  2. Additional Outcome Measures: Change from Baseline in Cognitive Measures- An alternative multivariate endpoint: Logical Memory Immediate Recall, Digit Span Backward Recall, Category Fluency (Animals), Trailmaking Test Part B [ Time Frame: Baseline, week 208 ]
  3. Additional Outcome Measures: Change from Baseline in Cognitive Measures- International Shopping List Test (12-Item Word List Learning) (Cogstate) [ Time Frame: Baseline, week 208 ]
  4. Additional Outcome Measures: Change from Baseline in Cognitive Measures- WMS-R Logical Memory (Delayed and Immediate Recall) [ Time Frame: Baseline, week 208 ]
  5. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Wechsler Adult Intelligence Scale - Revised (WAIS-R) Digit-Symbol Substitution Test [ Time Frame: Baseline, week 208 ]
  6. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Cogstate Identification Task [ Time Frame: Baseline, week 208 ]
  7. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Cogstate One Card Learning Test [ Time Frame: Baseline, week 208 ]
  8. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Cogstate One-Back Task [ Time Frame: Baseline, week 208 ]
  9. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Wechsler Memory Scale - Revised (WMS-R) Digit Span Backward and Forward Recall [ Time Frame: Baseline, week 208 ]
  10. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Category Fluency (Animals & Vegetables) [ Time Frame: Baseline, week 208 ]
  11. Additional Outcome Measures: Change from Baseline in Cognitive Measures- Trailmaking Tests parts A & B [ Time Frame: Baseline, week 208 ]
  12. Additional Outcome Measures: Clinical Efficacy Measures- Clinical Dementia Rating (CDR), including CDR sum of boxes (CDR-SB) [ Time Frame: Baseline, week 208 ]
  13. Additional Outcome Measures: Clinical Efficacy Measures- Functional Assessment Scale (FAS) [ Time Frame: Baseline, week 208 ]
  14. Additional Outcome Measures: Clinical Efficacy Measures- Global Clinical Dementia Rating (CDR) [ Time Frame: Baseline, week 208 ]
  15. Additional Outcome Measures: Clinical Efficacy Measures- Mini-Mental State Examination (MMSE) [ Time Frame: Baseline, week 208 ]
  16. Additional Outcome Measures: Clinical Efficacy Measures- Neuropsychiatric Inventory Questionnaire (NPI-Q) [ Time Frame: Baseline, week 208 ]
  17. Additional Outcome Measures: Imaging Efficacy Endpoints- Change from baseline in amyloid load based on imaging with [11C]PIB-PET [ Time Frame: Baseline, week 208 ]
  18. Additional Outcome Measures: Imaging Efficacy Endpoints- [18F]AV-1451 Tau PET measures of neurofibrillary tangle (NFT) burden [ Time Frame: Baseline, week 208 ]
  19. Additional Outcome Measures: Fluid Biomarker Efficacy Endpoints- Change in CSF Total Abeta1-40 and Abeta1-42 (free+bound) [ Time Frame: Baseline, week 208 ]
  20. Additional Outcome Measures: Fluid Biomarker Efficacy Endpoints- Change in CSF free Abeta1-40 and free Abeta1-42 [ Time Frame: Baseline, week 208 ]
  21. Additional Outcome Measures: Fluid Biomarker Efficacy Endpoints- Change in CSF Abeta1-40 and CSF Abeta1-42 [ Time Frame: Baseline, week 208 ]
  22. Additional Outcome Measures: Fluid Biomarker Efficacy Endpoints- Change in CSF Tau and CSF pTau181 [ Time Frame: Baseline, week 208 ]
  23. Additional Outcome Measures: Fluid Biomarker Efficacy Endpoints- Change in CSF and plasma NfL [ Time Frame: Baseline, week 208 ]
  24. Additional Outcome Measures: Fluid Biomarker Efficacy Endpoints- Change in plasma Abeta1-40 and Abeta1-42 [ Time Frame: Baseline, week 208 ]
  25. Other Additional Analysis Endpoints: Imaging Biomarkers- Functional Connectivity MRI measures (fc-MRI) [ Time Frame: Baseline, week 208 ]
  26. Other Additional Analysis Endpoints: Imaging Biomarkers- Diffusion Tensor Imaging (DTI) MRI including diffusion basis spectrum imaging (DBSI) [ Time Frame: Baseline, week 208 ]
  27. Other Additional Analysis Endpoints: Imaging Biomarkers- Blood flow measures by Arterial Spin Labeling (ASL) MRI [ Time Frame: Baseline, week 208 ]
  28. Other Additional Analysis Endpoints: Cognitive Tests- Raven's Progressive Matrices (Set A) [ Time Frame: Baseline, week 208 ]
  29. Other Additional Analysis Endpoints: Cognitive Tests- Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-min Delayed Recall (Cogstate) [ Time Frame: Baseline, week 208 ]
  30. Other Additional Analysis Endpoints: Cognitive Tests- Behavioral Pattern Separation Object Task [ Time Frame: Baseline, week 208 ]
  31. Other Additional Analysis Endpoints: Clinical Assessments- Geriatric Depression Scale (GDS) [ Time Frame: Baseline, week 208 ]
  32. Other Additional Analysis Endpoints: Clinical Assessments- Memory Complaint Questionnaire (MAC-Q) [ Time Frame: Baseline, week 208 ]
  33. Other Additional Analysis Endpoints: Safety and Tolerability Outcome Measures- Incidence and severity of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and treatment discontinuations [ Time Frame: Baseline, week 208 ]
  34. Other Additional Analysis Endpoints: Safety and Tolerability Outcome Measures- Neurological findings [ Time Frame: Baseline, week 208 ]
  35. Other Additional Analysis Endpoints: Safety and Tolerability Outcome Measures- Clinical laboratory evaluations [ Time Frame: Baseline, week 208 ]
  36. Other Additional Analysis Endpoints: Safety and Tolerability Outcome Measures- ECG findings [ Time Frame: Baseline, week 208 ]
  37. Other Additional Analysis Endpoints: Safety and Tolerability Outcome Measures- Columbia Suicide severity rating scale (CSSRS) [ Time Frame: Baseline, week 208 ]
  38. Other Additional Analysis Endpoints: Safety and Tolerability Outcome Measures- Safety MRIs including amyloid-related imaging abnormalities (ARIAs) [ Time Frame: Baseline, week 208 ]


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.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
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 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.

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


Locations
Show Show 25 study locations
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)
Investigators
Layout table for investigator information
Study Director: Randall J Bateman, MD Washington University School of Medicine
Additional Information:
Publications:

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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01760005    
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 )
GHR Foundation ( Other Grant/Funding Number: File 4401 )
Alzheimer's Association ( Other Identifier: HDE 18S84914 )
First Posted: January 3, 2013    Key Record Dates
Last Update Posted: August 5, 2020
Last Verified: July 2020
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 Network
Autosomal Dominant Alzheimer's Disease
Early Onset Alzheimer's Disease
DIAN
DIAN-TU
DIAN TU
DIAD
Additional relevant MeSH terms:
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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