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    Summary
    EudraCT Number:2013-000307-17
    Sponsor's Protocol Code Number:DIAN-TU-001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-09-03
    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 ConcernedUK - MHRA
    A.2EudraCT number2013-000307-17
    A.3Full title of the trial
    A Phase II/III randomized, double-blind, placebo-controlled, cognitive endpoint, multicenter study of potential disease modifying therapies in individuals at risk for and with 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 Individuals at Risk for or With a Type of 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 Eli Lilly; The Alzheimer's Association; AVID Radio Pharmaceuticals; National Institutes of Health (NIH)
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportJanssen Research and Development, LLC
    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-mailsusanmills@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.3.1Product nameSolanezumab
    D.3.2Product code LY2062430
    D.3.4Pharmaceutical form Solution for infusion
    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 INNSolanezumab
    D.3.9.1CAS number 955085-14-0
    D.3.9.2Current sponsor codeLY2062430
    D.3.9.3Other descriptive nameSOLANEZUMAB
    D.3.9.4EV Substance CodeSUB37126
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number20
    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 nameGantenerumab
    D.3.2Product code RO4909832
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGantenerumab
    D.3.9.1CAS number 645-35-2
    D.3.9.2Current sponsor codero4909832
    D.3.9.3Other descriptive nameHISTIDINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB14110MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Yes
    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 infusion
    D.8.4Route of administration of the placeboIntravenous use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous 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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assess cognitive efficacy of gantenerumab, solanezumab in individuals who have mutations causing dominantly inherited Alzheimer’s disease as measured by change in the DIAN-TU cognitive composite score between baseline and a minimum of 4 years. Comparisons will be made between each drug and placebo but not between the active drugs.
    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.Biomarker Endpoints used at interim analysis: Assess target engagement of each study drug in individuals who have mutations causing dominantly inherited Alzheimer’s disease as measured by the change from baseline to interim analysis for the biomarker measure for each drug. The biomarker endpoints are specified for each drug based on mechanism of action. Comparisons between the active drug and pooled placebo will be made at each interim for a study drug arm, however there will be no comparisons between active drugs.
    3.Comparisons between each drug and placebo for change in values between baseline and endpoint for additional clinical and cognitive measures
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Addendum 1: Tau Imaging Version 3.0, 29 Mar 2016
    E.3Principal inclusion criteria
    Subjects must meet ALL inclusion criteria:

    1. -15 to +10 EYO (secondary prevention population): within -15 to +10 years of the estimated age at symptom onset, or, if symptomatic, within 10 years of their age at symptom onset; CDR 0 to 1, inclusive; known
    carrier or at 50% risk (affected parent or sibling); or
    2. Younger than -15 EYO (primary prevention population): more than 15 years younger (<-15) than 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, subject will be withdrawn from tudy. Subjects meeting inclusion #2 (primary prevention) are only eligible for the cognitive run-in (CRI) period of this protocol.
    3. Are able and willing to complete all study-related testing, evaluations and procedures.
    E.4Principal exclusion criteria
    Subjects will be excluded if they have a major or unstable illness or are unable to complete all study related testing. Exclusions include implanted metal that cannot be removed for MR scanning, required anticoagulation and pregnancy.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint will be the relative rate of cognitive decline between active drug and pooled placebo using the DIAN-TU Cognitive Composite score after treatment for a minimum of 4 years.
    The DIAN-TU composite score is calculated from four cognitive measures: 1) The Delayed Recall of the International Shopping List Test, 2) The Delayed Recall score of the Logical Memory IIa subtest from the Wechsler Memory Scale-Revised, 3) The Digit Symbol Substitution Test total score from the Wechsler Adult Intelligence Scale-Revised, and 4) The Mini Mental State Examination total score.
    E.5.1.1Timepoint(s) of evaluation of this end point
    A minimum of 4 years (last subject enrolled) with anticipation of a maximum of 7 years (first subject enrolled).
    E.5.2Secondary end point(s)
    Assess safety and tolerability of each study drug in individuals who have mutations causing dominantly inherited Alzheimer’s disease.

    The biomarker endpoints used for the interim biomarker analyses are specific for each drug based on mechanism of action. These are listed in the drug-specific appendices. Biomarker endpoints will assess change between baseline and endpoint for:
    1) Cerebral amyloid imaging using [11C]PiB-PET. Change in the amount of fibrillar amyloid deposition as measured by [11C]PiB-PET scans is the biomarker endpoint for gantenerumab. Most mutation carriers who are in the range of -15 to + 10 years of dementia onset have increased [11C]PiB-PET signal in some brain regions (Bateman et al., 2012). The composite PiB standardized uptake value ratio (C-SUVR, the composite SUVR of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and temporal cortex) is used as the biomarker endpoint.
    2) Change in total amyloid-beta 1-42 (Aβ42) in CSF. The concentrations of CSF total Aβ42 will be the biomarker endpoint for solanezumab, specifically different treatment effects on total CSF Aβ42. An increase in total CSF Aβ42 is consistent with target engagement in the central compartment (Siemers et al., 2010).
    3)Change in CSF amyloid-beta peptide concentration as measured by Aβ40, will be the biomarker endpoint for JNJ-54861911.

    Secondary study endpoints will also measure change between baseline and endpoint and will include:

    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 CDR Sum of Boxes (CDR-SB) and clinician’s diagnostic assessment
    • Geriatric Depression Scale (GDS)
    • Neuropsychiatric Inventory Questionnaire (NPI-Q)
    • Functional Assessment Scale (FAS)
    • Mini Mental State Examination (MMSE)

    Cognitive measures to be obtained at baseline and annual visits will be administered at host DIAN-TU site include:
    • International Shopping List Test (12-Item Word List Learning): 3 learning trials, Immediate Recall, 30-min Delayed Recall (Cogstate)
    • Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-min Delayed/Reversed Recall (Cogstate)
    • Cogstate Detection Task
    • Cogstate Identification Task
    • Cogstate One Card Learning Test
    • Cogstate One-Back Task
    • Behavioral Pattern Separation Object Task
    • Memory Complaint Questionnaire (MAC-Q)
    • Trailsmaking Test Part A & B
    • WMS-R Digit Span
    • WAIS-R Digit-Symbol Substitution Test
    • Raven’s Progressive Matrices (Set A)
    • Category Fluency (Animals & Vegetables)
    • WMS-R Logical Memory (Immediate & Delayed Recall)

    A subset of these measures will be administered by the site or home health nurse at 24 week intervals when not the annual visits. This subset includes:
    • International Shopping List Test (12-ltem Word List Learning): 3 learning trials, Immediate Recall,30-min Delayed Recall (Cogstate)
    • Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30 min Delayed/Reversed Recall (Cogstate)
    • Cogstate Detection Task
    • Cogstate Identification Task
    • Cogstate One Card Learning Test
    • Cogstate One-Back Task
    • Trails making test parts A & B
    • WMS-R Digit Span
    • WAIS-R Digit-Symbol Substitution Test
    • WMS-R Logical Memory (Immediate & Delayed Recall)
    • For the CRI period and drug arms other than gantenerumab and
    solanezumab, additional cognitive battery subset tests include:
    - Category Fluency (Animals & Vegetables)
    - Mini Mental State Examination (MMSE)
    E.5.2.1Timepoint(s) of evaluation of this end point
    • For Solanezumab and Gantenerumab arms: a single biomarker interim analysis will be done when 100% of the active subjects have completed 2 years of randomized treatment (Visit 28)
    • For JNJ-5486199 arm: An interim analysis of the cognitive composite endpoint to assess whether JNJ-54861911 has achieved significant slowing in cognitive decline, will be conducted when all the subjects complete 3-year randomized treatment.Potential biomarker interim analyses that may be performed for this drug arm: futility IA of CSF Aβ40 after 1-year treatment for 50% of randomized subjects
    • Clinical and cognitive measures to be obtained at baseline and annual visits.
    • A subset of cognitive measures will be administered at 24 week intervals when not the annual visits.
    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 trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    China
    Colombia
    France
    Germany
    Ireland
    Italy
    Japan
    Mexico
    Netherlands
    Spain
    United Kingdom
    United States
    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
    Drug arms will close when the last patient enrolled, in concurrently
    enrolling drug arms ,completed 4 years of treatment.
    Subjects can continue in the CRI period until a study drug arm is
    opened for randomization, but no longer than approximately 2 years.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years10
    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 years10
    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: 384
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 121
    F.4.2.2In the whole clinical trial 444
    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)
    If a drug/arm demonstrates clinical/cognitive benefit, the patient will be
    invited to an Open-label extension study.
    After the study ends or after the OLE the patient will receive Standard
    of care
    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 Decision2013-10-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-08
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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