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.

NCT04623242 | Completed Phase 2 Results DMC

• 8 other identifiers: DIAN-TU-001 (gant-sola)The Alzheimer's AssociationU01AG0427912013-000307-17R01AG046179REec-2014-0817GHR FoundationAlzheimer's Association
• Study Type: interventional
• Target: 194
• Locations: 8 countries
• Sites: 25

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

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

Outcome Measures

Primary Outcomes (1)

• Assess Cognitive Efficacy in Individuals With Mutations Causing Dominantly Inherited AD as Measured by the DIAN-Multivariate Cognitive Endpoint (DIAN-MCE);

  Multivariate Disease Progression Model adjusted for Estimated Years to Onset (EYO)and includes all timepoints up to treatment discontinuation. The treatment effect is reported relative to the mutation positive placebo arm. Multivariate Cognitive Endpoint comprising: (i) Wechsler Memory Scale-Revised Logical Memory Delayed Recall Test (MEMUNITS), (ii) Wechsler Adult Intelligence Scale Digit Symbol Substitution Test (WAIS), (iii) Mini-Mental State Examination (MMSE), and (iv) International Shopping List Task (ISLT). Measurements for each test were normalized using the mean (SD) at DIAN-TU-001 baseline for mutation negative subjects. Higher scores indicate more favourable cognitive performance.

  Baseline through Week 260

Secondary Outcomes (42)

• Gantenerumab: Rate of Change Over Time- Clinical Dementia Rating Sum of Boxes (CDR-SB)

  Baseline and Weeks 52, 104, 156, 208 and 260

• Gantenerumab: Rate of Change Over Time- Functional Assessment Scale (FAS)

  Baseline and Weeks 52, 104, 156, 208 and 260

• Gantenerumab: Imaging Measures Composite [11C] PiB Partial Volume Corrected Regional Spread Function Standardized Uptake Value Ratio - Composite

  Baseline, Weeks 52, 104 and 208

• Solanezumab: Clinical Measures- Clinical Dementia Rating (CDR)

  Baseline and Weeks 52, 104, 156, and 208

• Solanezumab: Clinical Measures- CDR Sum of Boxes (CDR-SB)

  Baseline and Weeks 52, 104, 156, and 208

Study Arms (4)

Gantenerumab

EXPERIMENTAL

Drug: Gantenerumab

Solanezumab

EXPERIMENTAL

Drug: Solanezumab

Matching placebo (Gantenerumab)

PLACEBO COMPARATOR

Drug: Matching Placebo (Gantenerumab)

Matching Placebo (Solanezumab)

PLACEBO COMPARATOR

Drug: Matching Placebo (Solanezumab)

Interventions

Gantenerumab DRUG

Subcutaneously every 4 weeks at escalating doses

Also known as: RO4909832

Gantenerumab

Solanezumab DRUG

Intravenous infusion every 4 weeks at escalating doses

Also known as: LY2062430

Solanezumab

Matching Placebo (Gantenerumab) DRUG

Subcutaneous injection of placebo every 4 weeks

Matching placebo (Gantenerumab)

Matching Placebo (Solanezumab) DRUG

Intravenous infusion of placebo every 4 weeks

Matching Placebo (Solanezumab)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Eli Lilly and Company: collaborator
• Hoffmann-La Roche: collaborator
• Alzheimer's Association: collaborator
• National Institute on Aging (NIA): collaborator
• Avid Radiopharmaceuticals: collaborator
• Accelerating Medicines Partnership (AMP): collaborator

Study Sites (25)

University of Alabama in Birmingham

Birmingham, Alabama, 35294, United States

Location

University of California San Diego Medical Center

La Jolla, California, 92037, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

Indiana University School of Medicine

Indianapolis, Indiana, 46202, United States

Location

Washington University in St. Louis

St Louis, Missouri, 63110, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Butler Hospital

Providence, Rhode Island, 02096, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Neuroscience Research Australia

Randwick, New South Wales, 2031, Australia

Location

Mental Health Research Institute

Melbourne, Victoria, 3010, Australia

Location

The McCuster Foundation of Alzheimer's Disease Research

Nedlands, Western Australia, 6009, Australia

Location

UBC Hospital

Vancouver, British Columbia, V6T 2B5, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

McGill Center for Studies in Aging

Verdun, Quebec, H4H 1R3, Canada

Location

CHU de Toulouse - Hôpital Purpan

Toulouse, Haute Garonne, 31059, France

Location

Hopital Roger Salengro - CHU Lille

Lille, Nord, 59037, France

Location

Groupe Hospitalier Pitie-Salpetriere

Paris, Paris, 69677, France

Location

Hopital Neurologique Pierre Wertheimer

Bron, Rhone, 69677, France

Location

CHU de Rouen - Hôpital Charles Nicolle

Rouen, Seine Maritime, 76031, France

Location

St Vincent's University Hospital

Dublin, DUBLIN 4, Ireland

Location

University of Puerto Rico, School of Medicine

San Juan, 00936, Puerto Rico

Location

Hospital Clínic I Provincial de Barcelona

Barcelona, 8036, Spain

Location

The National Hospital for Neurology and Neurosurgery

London, Greater London, WC1B 3BG, United Kingdom

Location

Related Publications (13)

• 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.

  PMID: 22784036 BACKGROUND

• 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.

  PMID: 22672770 BACKGROUND

• Bateman RJ, Benzinger TL, Berry S, Clifford DB, Duggan C, Fagan AM, Fanning K, Farlow MR, Hassenstab J, McDade EM, Mills S, Paumier K, Quintana M, Salloway SP, Santacruz A, Schneider LS, Wang G, Xiong C; DIAN-TU Pharma Consortium for the Dominantly Inherited Alzheimer Network. The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model. Alzheimers Dement. 2017 Jan;13(1):8-19. doi: 10.1016/j.jalz.2016.07.005. Epub 2016 Aug 29.

  PMID: 27583651 BACKGROUND

• Mills SM, Mallmann J, Santacruz AM, Fuqua A, Carril M, Aisen PS, Althage MC, Belyew S, Benzinger TL, Brooks WS, Buckles VD, Cairns NJ, Clifford D, Danek A, Fagan AM, Farlow M, Fox N, Ghetti B, Goate AM, Heinrichs D, Hornbeck R, Jack C, Jucker M, Klunk WE, Marcus DS, Martins RN, Masters CM, Mayeux R, McDade E, Morris JC, Oliver A, Ringman JM, Rossor MN, Salloway S, Schofield PR, Snider J, Snyder P, Sperling RA, Stewart C, Thomas RG, Xiong C, Bateman RJ. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris). 2013 Oct;169(10):737-43. doi: 10.1016/j.neurol.2013.07.017. Epub 2013 Sep 6.

  PMID: 24016464 BACKGROUND

• Wang G, Berry S, Xiong C, Hassenstab J, Quintana M, McDade EM, Delmar P, Vestrucci M, Sethuraman G, Bateman RJ; Dominantly Inherited Alzheimer Network Trials Unit. A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer's disease. Stat Med. 2018 Sep 20;37(21):3047-3055. doi: 10.1002/sim.7811. Epub 2018 May 14.

  PMID: 29761523 BACKGROUND

• Weninger S, Carrillo MC, Dunn B, Aisen PS, Bateman RJ, Kotz JD, Langbaum JB, Mills SL, Reiman EM, Sperling R, Santacruz AM, Tariot PN, Welsh-Bohmer KA. Collaboration for Alzheimer's Prevention: Principles to guide data and sample sharing in preclinical Alzheimer's disease trials. Alzheimers Dement. 2016 May;12(5):631-2. doi: 10.1016/j.jalz.2016.04.001. No abstract available.

  PMID: 27157073 BACKGROUND

• 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.

  PMID: 26203303 BACKGROUND

• McDade E, Bateman RJ. Stop Alzheimer's before it starts. Nature. 2017 Jul 12;547(7662):153-155. doi: 10.1038/547153a. No abstract available.

  PMID: 28703214 BACKGROUND

• McDade E, Wang G, Gordon BA, Hassenstab J, Benzinger TLS, Buckles V, Fagan AM, Holtzman DM, Cairns NJ, Goate AM, Marcus DS, Morris JC, Paumier K, Xiong C, Allegri R, Berman SB, Klunk W, Noble J, Ringman J, Ghetti B, Farlow M, Sperling RA, Chhatwal J, Salloway S, Graff-Radford NR, Schofield PR, Masters C, Rossor MN, Fox NC, Levin J, Jucker M, Bateman RJ; Dominantly Inherited Alzheimer Network. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology. 2018 Oct 2;91(14):e1295-e1306. doi: 10.1212/WNL.0000000000006277. Epub 2018 Sep 14.

  PMID: 30217935 BACKGROUND

• Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ; Dominantly Inherited Alzheimer Network. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. doi: 10.1212/WNL.0000000000000596. Epub 2014 Jun 13.

  PMID: 24928124 BACKGROUND

• Weng H, Bateman R, Morris JC, Xiong C. Validity and power of minimization algorithm in longitudinal analysis of clinical trials. Biostat Epidemiol. 2017;1(1):59-77. doi: 10.1080/24709360.2017.1331822. Epub 2017 Jun 13.

  PMID: 29250611 BACKGROUND

• Wagemann O, Liu H, Wang G, Shi X, Bittner T, Scelsi MA, Farlow MR, Clifford DB, Supnet-Bell C, Santacruz AM, Aschenbrenner AJ, Hassenstab JJ, Benzinger TLS, Gordon BA, Coalier KA, Cruchaga C, Ibanez L, Perrin RJ, Xiong C, Li Y, Morris JC, Lah JJ, Berman SB, Roberson ED, van Dyck CH, Galasko D, Gauthier S, Hsiung GR, Brooks WS, Pariente J, Mummery CJ, Day GS, Ringman JM, Mendez PC, St George-Hyslop P, Fox NC, Suzuki K, Okhravi HR, Chhatwal J, Levin J, Jucker M, Sims JR, Holdridge KC, Proctor NK, Yaari R, Andersen SW, Mancini M, Llibre-Guerra J, Bateman RJ, McDade E; Dominantly Inherited Alzheimer Network-Trials Unit. Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease: The DIAN-TU-001 Randomized Clinical Trial. JAMA Neurol. 2024 Jun 1;81(6):582-593. doi: 10.1001/jamaneurol.2024.0991.

  PMID: 38683602 DERIVED

• Atkins KJ, Evered L, Scott DA, Fowler C, Masters CL, Silbert B. Cerebrospinal fluid sampling for research of Alzheimer's disease and other neurodegenerative diseases when lumbar punctures are performed by anaesthetists. BMJ Neurol Open. 2022 Sep 5;4(2):e000335. doi: 10.1136/bmjno-2022-000335. eCollection 2022.

  PMID: 36110925 DERIVED

Related Links

• Expanded registry

MeSH Terms

Conditions

Alzheimer Disease; Dementia

Interventions

gantenerumab; solanezumab

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Results Point of Contact

• Title: Administrative Director
• Organization: Washington University

DIAN-TUDataRequest@wustl.edu

(314) 221-8344

Study Officials

• Randall J Bateman, MD

  Washington University School of Medicine

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Interventional

Study Record Dates

• First Submitted: October 14, 2020
• First Posted: November 10, 2020
• Study Start: December 1, 2012
• Primary Completion: November 22, 2019
• Study Completion: March 6, 2020
• Last Updated: September 22, 2022
• Results First Posted: September 22, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

AU (3); US (10); IE (1); PR (1); CA (3); FR (5); GB (1); ES (1)