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

Dementia Clinical Trial

— DIAN-TU  

Official title:

A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled Platform Trial of Potential Disease Modifying Therapies Utilizing Biomarker, Cognitive, and Clinical Endpoints in Dominantly Inherited Alzheimer's Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT06424236
• Other study ID #: DIAN-TU-001 (Gant OLE)
• Secondary ID: The Alzheimer's
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: June 30, 2020
• Est. completion date: November 13, 2023

Study information

• Verified date: May 2024
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers.

Description:

Alzheimer's disease (AD) is defined by the presence of abnormal accumulations of amyloid protein (plaques) and tau protein (tangles) in the brain. The double-blind arm of DIAN-TU-001 Master protocol (NCT01760005) tested whether gantenerumab provided a clinical benefit by slowing the onset or the worsening of the disease. A clinical benefit was not observed in the double-blind part of the DIAN-TU-001 study. However, gantenerumab was associated with improvements in measures of amyloid and tau and an improvement in an overall measure of neurodegeneration (when nerve cells in the brain lose function over time). It is not known whether these changes may provide future clinical benefits. Based on this information, an exploratory Open Label Extension (OLE) will further study the effect of gantenerumab on these Alzheimer-related proteins and their relationship to disease progression. After this final evaluation of study treatment with gantenerumab used in the gantenerumab / solanezumab double-blind arm of the Master protocol (NCT01760005), participants from the double-blind arm known to carry the genetic mutation for AD have been invited to participate in an OLE period to receive active gantenerumab study treatment as part of the DIAN-TU-001 Master protocol. The OLE period of the study planned to provide study treatment with gantenerumab for up to 3 years (36 months). This study will continue to collect brain scans, blood, and spinal fluid tests (also called biomarkers), as well as cognitive testing. The idea is to determine if gantenerumab has favorable effects on these tests as it may prevent or delay the symptoms of AD. Update: Based on the completed studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer's disease (DIAD) participants in the DIAN-TU-001 OLE study were benefiting from gantenerumab high-dose treatment. After evaluation, it was decided to discontinue the DIAN-TU-001 gantenerumab OLE.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 73
• Est. completion date: November 13, 2023
• Est. primary completion date: August 12, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Between 18-80 years of age
• Individuals who know they have an Alzheimer's disease-causing mutation
• Individuals who have participated in the double-blind period
• In the opinion of the investigator and sponsor, treatment is not contraindicated for safety
• Capable of receiving drug and appropriate clinical safety assessment
• 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.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimers Disease
• Alzheimers Disease, Familial
• Dementia

Intervention

Drug:
• Gantenerumab
Open-label administered Subcutaneously every 4 weeks at escalating doses

Locations

Country	Name	City	State
Australia	Mental Health Research Institute	Melbourne	Victoria
Australia	The McCuster Foundation of Alzheimer's Disease Research	Nedlands	Western Australia
Australia	Neuroscience Research Australia	Randwick	New South Wales
Canada	UBC Hospital	Vancouver	British Columbia
France	Hopital Neurologique Pierre Wertheimer	Bron cedex	Rhone
France	Hopital Roger Salengro - CHU Lille	Lille	Nord
France	Groupe Hospitalier Pitie-Salpetriere	Paris cedex 13	Paris
France	CHU de Rouen - Hôpital Charles Nicolle	Rouen	Seine Maritime
France	CHU de Toulouse - Hôpital Purpan	Toulouse	Haute Garonne
Ireland	St Vincent's University Hospital	Dublin
Puerto Rico	University of Puerto Rico, School of Medicine	San Juan
Spain	Hospital Clínic I Provincial de Barcelona	Barcelona
United Kingdom	The National Hospital for Neurology and Neurosurgery	London	Greater London
United States	Emory University	Atlanta	Georgia
United States	University of Alabama in Birmingham	Birmingham	Alabama
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	University of California San Diego Medical Center	La Jolla	California
United States	Yale University School of Medicine	New Haven	Connecticut
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Butler Hospital	Providence	Rhode Island
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	University of Washington	Seattle	Washington

Sponsors (4)

Lead Sponsor	Collaborator
Washington University School of Medicine	Alzheimer's Association, Hoffmann-La Roche, National Institute on Aging (NIA)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Ireland,  Puerto Rico,  Spain,  United Kingdom, 

References & Publications (11)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in amyloid load as measured by [11C]PiB-PET composite standardized uptake value ration (C-SUVR)	The composite PiB partial volume corrected standardized uptake value ratio is used as the biomarker endpoint for amyloid deposition. Corresponding analyses based on conversion of SUVR to centiloid will be performed by Washington University.	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Clinical Dementia Rating (CDR) Sum of Boxes	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the CDR Sum of Boxes. Minimum score 0; maximum score 18. Higher score indicates worse performance.	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Clinical Dementia Rating (CDR) Global	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the CDR Global. Minimum score 0; maximum score 3. Higher score indicates worse performance.	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Functional Assessment Scale (FAS)	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Functional Assessment Scale (FAS). Higher score indicates worse performance.	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Mini-Mental State Examination (MMSE)	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Mini-Mental State Examination (MMSE). Minimum score 0; maximum score 30. Lower score indicates worse performance.	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Tau PET Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR)	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Tau PET Binding Partial Volume Corrected Standardized Uptake Value Ratio (Tau PET SUVR)	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Cerebrospinal Fluid (CSF) phosphorylated Tau (pTau)-181	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Cerebrospinal Fluid (CSF) phosphorylated Tau (pTau)-181	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Neurofilament Light chain (NfL) in CSF (CSF NfL)	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the Neurofilament Light chain (NfL) in CSF (CSF NfL)	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in Cerebrospinal Fluid (CSF) Amyloid Beta1-42/40	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in CSF Amyloid Beta1-42/40	Week 0 and Weeks 48, 104, and 156
Secondary	Annual Rate of change in DIAN-TU Open Label Extension Cognitive Composite	Evaluate the efficacy of gantenerumab in reducing disease progression as assessed in the DIAN-TU OLE Cognitive Composite. The Cognitive Composite is calculated using the WMS-R Digit Span Backward Recall (Minimum score 0; Maximum score 7. Lower indicates worse performance.), the Category Fluency (Animals) value (Minimum score 0; Maximum score Unlimited. Lower score indicates worse performance.), the Wechsler Adult Intelligence Scale Digit Symbol Substitution test (Minimum score 0; Maximum score 93. Lower score indicates worse performance.) , and the Mini Mental State Examination (Minimum score 0; Maximum score 30. Lower score indicates worse performance).	Week 0 and Weeks 48, 104, and 156

External Links

•   Expanded registry