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    Summary
    EudraCT Number:2013-000307-17
    Sponsor's Protocol Code Number:DIAN-TU-001
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-06-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2013-000307-17
    A.3Full title of the trial
    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 (DIAD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.4.1Sponsor's protocol code numberDIAN-TU-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01760005
    A.5.4Other Identifiers
    Name:The Alzheimer's Association Grant Number:DIAN TTU-12-243040
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorWashington University in St. Louis
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportHoffmann LaRoche
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportThe Alzheimer's Association
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportEisai Co. Ltd.
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportNational Institutes of Health (NIH)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWashington University in St. Louis
    B.5.2Functional name of contact pointSusan Mills, Assoc Director, Clin O
    B.5.3 Address:
    B.5.3.1Street Address4488 Forest Park Ave., Suite 301,
    B.5.3.2Town/ citySt Louis
    B.5.3.3Post codeMO 63108
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1-949-293-5290
    B.5.5Fax number1-314-747-7060
    B.5.6E-mailNEURO_diantuclinops@email.wustl.edu
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code E2814
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNE2814
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLecanemab
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLecanemab
    D.3.9.4EV Substance CodeSUB216130
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection in vial
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Dominantly Inherited Alzheimer Disease (DIAD)
    E.1.1.1Medical condition in easily understood language
    Alzheimer's disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.1
    E.1.2Level LLT
    E.1.2Classification code 10086382
    E.1.2Term Late onset Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.1
    E.1.2Level LLT
    E.1.2Classification code 10086384
    E.1.2Term Early onset Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.

    For OLE arm: See drug specific protocol appendix

    For E2814 arm: See drug specific protocol appendix
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants must meet ALL inclusion criteria, including EYO:

    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); or
    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. Are able and willing to complete the main study-related testing, evaluations, and procedures.
    E.4Principal exclusion criteria
    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.
    E.5 End points
    E.5.1Primary end point(s)
    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.
    Primary endpoints for the OLE period include cerebral amyloid imaging using [11C]PiB-PET as well as the safety and tolerability of treatment with gantenerumab at higher doses.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The timepoints are outlines in in the appendix
    E.5.2Secondary end point(s)
    Additional outcome for the platform, which may be further categorized as secondary or exploratory in the drug-specific appendices in this or prior amendments, and/or statistical analysis plans (SAPs), include the following:
    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. Comparisons between each drug and the placebo arm in change from baseline for the following clinical and cognitive measures listed below:

    a.Clinical measures to be obtained at baseline, and annual visits will be administered at the host DIAN-TU site include:
    - Clinical Dementia Rating™ (CDR), including Clinical Dementia Rating Sum of Boxes™ (CDR SB)
    - Clinician’s diagnostic assessment
    - Geriatric Depression Scale (GDS)
    - Neuropsychiatric Inventory Questionnaire (NPI-Q)
    - Functional Assessment Scale (FAS)
    - Mini Mental State Examination (MMSE) – also measured at the 26 week (6 month) time point between annual visits with the below cognitive battery.
    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:
    - 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 (Immediate & Delayed Recall), /Alternate Paragraphs for Logical Memory I & II - Versions A (Immediate and Delayed) and Alternate Paragraph for Logical Memory I & II - Version B (Immediate and Delayed)
    - Category Fluency (Animals)
    - 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)

    4. Imaging measures obtained in randomized drug arms include the following (see drug-specific appendices and SAPs for outcome classification):
    a. Glucose metabolism positron emission tomography (PET) imaging with FDG-PET
    b. Amyloid PET imaging with [11C]PiB-PET
    c. Tau PET imaging with [18F]MK-6240
    d. Structural brain measures with volumetric MRI
    e. Functional connectivity MRI (fc-MRI)
    f. Diffusion Tensor Imaging (DTI) MRI, including diffusion basis spectrum imaging (DBSI)
    g. Blood flow measures by Arterial Spin Labeling (ASL) MRI
    h. Assessment of MRI features, such as microhemorrhages (MCH), white matter hyperintensities (WMH), cerebral infarctions, and Amyloid Related Imaging Abnormalities (ARIA) on conventional MRI sequences.

    5. 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.

    6.Assess longitudinal change in biomarker, cognitive and clinical measures in individuals who do not have mutations causing dominantly inherited Alzheimer’s disease (mutation-negative placebo group).
    Additional drug-specific endpoints may be listed in each drug-specific appendix. Refer to the final SAP for drug-specific differentiation of endpoint classification based on the respective drug’s target and mechanism of action.

    For E2814 arm:
    Symptomatic Population (Cohort 1): To determine whether E2814 is superior to placebo, when each is concurrently administered with lecanemab, in change from Week 24 to Week 208 in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
    Asymptomatic Population (Cohort 2): To determine whether E2814 is superior to placebo, when each is administered alone and then concurrently with lecanemab, in change from Week 0 to Week 104 (interim analysis) and Week 208 (final analysis) in cerebrospinal fluid (CSF) phosphorylated tau (ptau217)/total tau
    E.5.2.1Timepoint(s) of evaluation of this end point
    For CRI period:
    a. Clinical and tau PET at baseline and annual visits
    b. Cognitive Battery at CRI Entry and every 26 weeks (~6 months)

    This study will assess safety and tolerability of treatment with gantenerumab in individuals at risk for and with DIAD. The primary safety endpoints for the double-blind period and OLE are identical for all study compounds and are listed in the main study protocol.

    For E2814 arm:
    Symptomatic Population (Cohort 1): from Week 24 to Week 208 in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB)
    Asymptomatic Population (Cohort 2): from Week 0 to Week 104 (interim analysis) and Week 208 (final analysis) in cerebrospinal fluid (CSF) phosphorylated tau (ptau217)/total tau
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA13
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Colombia
    Japan
    Mexico
    United States
    France
    Netherlands
    Spain
    Germany
    Italy
    Ireland
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    CRI Period: Subjects can continue in the CRI period until a study drug arm is opened for randomization, but no longer than approximately 2 years.

    OLE Period: Subjects can participate for 3 years (36 months) or until the treatment becomes commercially available in a subject’s country, whichever occurs first.

    Eisai Arm: Subjects can participate for minimum of 4 years until that last participant completes 4 years (total participation may last to approx 7 years depending on time of enrollment)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years15
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years15
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 725
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 205
    F.4.2.2In the whole clinical trial 740
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients will return to the care of their treating physician at the completion of study participation.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Washington University in St. Louis School of Medicine
    G.4.3.4Network Country United States
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-04-05
    P. End of Trial
    P.End of Trial StatusOngoing
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