Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Early Onset Alzheimer's Disease Caused by a Genetic Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Washington University School Of Medicine

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

20 Dec 2022 → ongoing

Decision date (initial)

2024-07-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

The Alzheimer's Association · National Institutes of Health (NIH) · Eisai Co. Ltd.

External identifiers

EU CT number

2024-515198-91-00

EudraCT number

2013-000307-17

ClinicalTrials.gov

NCT01760005

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Safety, Pharmacodynamic, Others

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.

Secondary objectives 2

1. Assess safety and tolerability of each study drug in individuals who have mutations causing dominantly inherited Alzheimer's disease.
2. The data collected in the CRI period will be used for analysis in the respective drug arm under which participants are randomized and treated.

Conditions and MedDRA coding

Dominantly Inherited Alzheimer Disease (DIAD)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. -10 to +10 EYO (secondary prevention population): within -10 to +10 years (inclusive) of the estimated age at symptom onset, CDR 0 to 1, inclusive; known eligible mutation carrier or at 50% risk (affected parent or sibling);
2. -25 to -11 EYO (primary prevention population): within 11 to 25 years younger than their estimated age at symptom onset, CDR 0, known carrier or mutation in their family pedigree; if the at-risk parent is deemed a non-carrier at any point, participants will be withdrawn from study.
3. Willing to complete the main study-related testing, evaluations, and procedures.

Exclusion criteria 1

1. Participants will be excluded if they have a major or unstable illness that would prevent trial participation or are unable to complete main study related testing. Exclusions include MRI contraindications, required anticoagulation and pregnancy. Participants who know they are mutation non-carriers are not eligible.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The Primary Outcome is defined in the appendix, and may include biomarker, cognitive, or clinical outcomes. Comparisons will be made between active drug, mutation positive placebos, and control groups, e.g. eligible DIAN-OBS participants.

Secondary endpoints 9

1. Assess safety and tolerability of each study drug in individuals who have mutations causing dominantly inherited Alzheimer's disease.
2. Biomarker Endpoints used at interim analysis: Assess target engagement with biomarker endpoints specified for each drug based on mechanism of action. Assess AD biomarkers, including soluble biochemical measures (e.g. amyloid-beta and tau), imaging measures of pathology (e.g. amyloid and tau PET), and AD biomarker changes (e.g. atrophy measured by MRI, hypometabolism by FDG PET, and neurodegeneration measured by Neurofilament light).
3. Comparison between each drug and placebo in change from baseline for the following measures:a.Clinical measures obtained at baseline and annual visits will be administered at theDIAN-TU site include:-Clinical Dementia Rating™(CDR)including Clinical Dementia Rating Sum of Boxes™(CDRSB)-Clinician's diagnostic assessment-Geriatric Depression Scale(GDS)-Neuropsychiatric Inventory Questionnaire(NPI-Q)-FAS-MMSE also measured at the26week timepoint between annual visits with the below cognitive battery
4. b.Cognitive measures to obtained at Baseline and every 26 weeks will be administered at the DIAN-TU site or via homehealth nurse trial-certified cognitive rater include:-DIAN Memory Complaint Questionnaire (MAC-Q)-Buschke and Grober Free and Cued Selective Reminding Test Immediate Recall(FCSRT-IR)-Wechsler Memory Scale-Revised(WMS-R) Logical Memory/Paragraph Memory/Alternate Paragraphs for Logical Memory I&II-VersionsA and Alternate Paragraph for Logical Memory I&II-VersionB-Category Fluency -
5. b. Cognitive measures to be obtained at Baseline and every 26 weeks (~6 months) in will be administered at the DIAN-TU site or via home health nurse trial-certified cognitive rater include: Weschler Adult Intelligence Scale-Revised (WAIS-R) Digit-Symbol Substitution Test - Trailmaking Test parts A & B - Weschler Memory Scale-Revised (WMS-R) Digit Spatial Span Forward and Backward - Ambulatory Research in Cognition (ARC) smartphone-based cognitive assessments (Grids, Prices, Symbols)
6. Imaging measures obtained in randomized drug arms include the following:a.Glucose metabolism PET imaging with FDG-PET b.Amyloid PET imaging with [11C]PiB-PET c.TauPET imaging with[18F]MK-6240 d.Structural brain measures with volumetric MRI e.Functional connectivity MRI(fc-MRI) f.Diffusion Tensor Imaging MRI,including diffusion basis spectrum imaging g.Blood flow measures by Arterial Spin Labeling (ASL)MRI h.Assessment of MRI features such as MCH, WMH, cerebral infarctions and ARIA on MRIsequence
7. Fluid biomarker measures that may be included as secondary or exploratory endpoints as specified in the drug-specific appendix and/or SAP, include the following: a. CSF and plasma amyloid species analyses b. CSF and plasma tau species analyses c. CSF and plasma neurofilament light chain analyses d. Additional CSF and blood biomarkers of AD, neurodegeneration, neuroinflammation, or other biomarkers
8. Assess longitudinal change in biomarker, cognitive and clinical measures in individuals who do not have mutations causing DIAD (mutation-negative placebo group). Additional drug-specific endpoints may be listed in each drug-specific appendix.
9. For E2814 arm:Symptomatic Population(Cohort 1):To determine whetherE2814 is superior to placebo when is concurrently administered with lecanemab in change from Week24 to Week208 in Clinical Dementia Rating Scale Sum of Boxes(CDR-SB)Asymptomatic Population(Cohort 2):To determine whether E2814 is superior to placebo when is administered alone and then concurrently with lecanemab in change from Week0 to Week104(interim analysis)and Week208(final analysis) in CSF phosphorylated tau(ptau217/tot tau)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Washington University School Of Medicine

Sponsor organisation

Washington University School Of Medicine

Address

660 South Euclid Avenue 8056

City

Saint Louis

Postcode

63110-1010

Country

United States

Scientific contact point

Organisation

Washington University School Of Medicine

Contact name

Susan Mills, Senior Director, Clin Operations

Public contact point

Organisation

Washington University School Of Medicine

Contact name

Susan Mills, Senior Director, Clin Operations

Third parties 11

Locations

5 EU/EEA countries · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 112 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications