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    Summary
    EudraCT Number:2016-004128-42
    Sponsor's Protocol Code Number:E2609-G000-302
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-04-27
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2016-004128-42
    A.3Full title of the trial
    A Placebo-Controlled, Double-Blind, Parallel-Group, 24-Month Study to Evaluate the Efficacy and Safety of E2609 in Subjects with Early Alzheimer’s Disease
    Um estudo de 24 meses controlado por placebo, em dupla ocultação, de grupos paralelos para avaliar a eficácia e segurança de E2609 em participantes com doença de Alzheimer em fase inicial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Placebo-Controlled, Double-Blind, Parallel-Group, 24-Month Study to Evaluate the Efficacy and Safety of E2609 in Subjects with Early Alzheimer’s Disease
    Um estudo de 24 meses controlado por placebo, em dupla ocultação, de grupos paralelos para avaliar a eficácia e segurança de E2609 em participantes com doença de Alzheimer em fase inicial
    A.4.1Sponsor's protocol code numberE2609-G000-302
    A.5.4Other Identifiers
    Name:IND NumberNumber:109308
    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 SponsorEisai Ltd.
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEisai Ltd
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportEisai Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEisai Ltd.
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressMosquito Way
    B.5.3.2Town/ cityHatfield, Hertfordshire
    B.5.3.3Post codeAL10 9SN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0044845676 1400
    B.5.5Fax number0044845676 1486
    B.5.6E-mailLMedInfo@eisai.net
    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 nameElenbecestat
    D.3.2Product code E2609
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNElenbecestat
    D.3.9.2Current sponsor codeE2609
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Early Alzheimer Disease including mild cognitive impairment (MCI) due to AD/Prodromal AD and the early stages of mild AD
    E.1.1.1Medical condition in easily understood language
    Clinical Dementia
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10012271
    E.1.2Term Dementia Alzheimer's type
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10074616
    E.1.2Term Prodromal Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine whether elenbecestat (E2609) is superior to placebo on the change from baseline in the Clinical Dementia Rating - Sum Of Boxes (CDR-SB) at 24 months in subjects with Early Alzheimer’s Disease (EAD)
    E.2.2Secondary objectives of the trial
    Secondary Objectives
    •To evaluate the safety and tolerability of elenbecestat (E2609) in subjects with EAD
    •To determine whether elenbecestat (E2609) is superior to placebo on the time to worsening of Clinical Dementia Rating (CDR) scores in subjects with EAD
    •To determine whether elenbecestat (E2609) is superior to placebo on the time to conversion to dementia for subjects who were not clinically staged as having dementia at Baseline based on a clinical diagnosis evaluated every 3 months
    •To determine whether elenbecestat (E2609) is superior to placebo on the rate of change over time (mean slope) based on CDR-SB score over 24 months in subjects with EAD
    •To determine whether elenbecestat (E2609) is superior to placebo on the Alzheimer’s Disease Assessment Scale-Cognition14 (ADAS-cog14), Mini Mental State Examination (MMSE), and Functional Assessment Questionnaire (FAQ) at 24 months in subjects with EAD

    Please refers to the Study Protocol for further objectives
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Two longitudinal biomarker substudies will evaluate the effects of study treatment on the underlying pathophysiology of AD using Amyloid PET and/or CSF biomarkers. Participation in the substudies is optional and will require specific consent that will not affect enrollment or treatment in the main study.
    E.3Principal inclusion criteria
    1. MCI due to Alzheimer’s disease or Mild Alzheimer’s disease according to the National Institute of Aging – Alzheimer’s Association (NIA-AA) core clinical criteria and must have all of the following at screening:
    a. MMSE score equal to or greater than 24
    b. CDR global score of 0.5
    c. CDR Memory Box score of 0.5 or greater
    2. A history of subjective memory decline with gradual onset and slow progression over the last 1 year before Screening; this MUST be corroborated by a study partner
    3. Cognitive impairment of at least 1 SD from age-adjusted norms in total recall or delayed recall on the ISLT.
    4. Positive biomarker for brain amyloid pathology as indicated by at least 1 of the following:
    a. PET assessment of amyloid imaging agent uptake into brain. Note: Amyloid PET screens will be performed according to local regulatory guidelines and thus may be restricted for those subjects who are not suitable for lumbar puncture (LP) to obtain CSF for testing of eligibility.
    b. CSF AD assessment (eg Aβ(1-42), tau:Aβ(1-42) ratio) NOTE: Subjects may undergo both the Amyloid PET and CSF assessments, but need a positive amyloid result in only 1 of the 2 procedures to confirm eligibility. Subjects who consent to Amyloid PET or CSF for eligibility purposes are not required to participate in the Amyloid PET or CSF longitudinal substudies. Use of a historical Amyloid positive PET (conducted within 12 months before the planned date of randomization) is acceptable for determination of eligibility but will not suffice for the baseline assessment if the subject wishes to consent to the Amyloid PET longitudinal substudy. The historical imaging data must be made available to the sponsor.
    5. Male or female subjects between 50 and 85 years of age, inclusive at the time of consent
    6. If receiving an AChEI or memantine or both for AD, must be on a stable dose for at least 12 weeks prior to Randomization. Treatment-naïve subjects with AD can be entered into the study.
    7. Subjects must have been on stable doses of all other (ie, non-AD related) permitted concomitant medications for at least 4 weeks prior to Randomization, except for medications which are administered as short courses (eg, up to 3 weeks unless discussed and agreed with Medical Monitor) of treatment (eg, anti-infectives) or which are to be used on a Pro re nata (PRN) basis. Subjects who require a short course of treatment, such as an anti-infective, may be randomized once the acute illness has completely resolved, even if the concomitant medication continues.
    8. Must have an identified study partner (defined as a person able to support the subject for the duration of the study and who spends at least 8 hours per week with the subject). The study partner must be literate and able to provide written informed consent. In addition, this person must be willing and able to provide follow-up information on the subject throughout the course of the study. This person must, in the opinion of the investigator, spend sufficient time with the subject on a regular basis such that they can reliably fulfill the requirements of being a study partner. A study partner need not be living in the same residence with the subject. For such a study partner not residing with the subject, the investigator has to be satisfied that the subject can contact the study partner readily during the times when the study partner is not with the subject. Study partners need to provide input to the following assessments: CDR, FAQ, EQ-5D, QOL-AD, Zarit’s Burden Interview, and the clinical assessment of suicidality. Consideration can occur for the investigator to decide whether the study partner can provide information over the telephone or whether the study partner must attend the study visits in person with the subject.
    9. Provide written informed consent. Subjects must, in the investigator's judgment, have the capacity to consent(capacity to consent should be determined in accordance with applicable professional standards and local laws/regulations).
    E.4Principal exclusion criteria
    1. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive
    beta-human chorionic gonadotropin test). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
    Females of child-bearing potential who:
    •Within 28 days before study entry, did not use a highly effective method of contraception, which includes any of the following:
    o total abstinence (if it is their preferred and usual lifestyle)
    o an intrauterine device or intrauterine hormone-releasing system
    o an oral contraceptive (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation.)
    o have a vasectomized partner with confirmed azoospermia.
    •Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation.
    For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide.
    NOTE: All females will be considered to be of child-bearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
    2. Any condition that may be contributing to cognitive impairment above and beyond that caused by
    the subject’s AD
    3. Subjects with a history of seizures within 5 years of Screening or subjects with disturbance likely
    to be due to seizures within 5 years of Screening
    4. History of transient ischemic attacks (TIA) or stroke within 12 months of Screening
    5. Modified Hachinski Ischemia Score greater than 4 at Screening
    6. Any of the following psychiatric symptoms:
    • Psychiatric diagnosis or symptoms, (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures
    • Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, at Screening, or at the Randomization Visit, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening
    7. Have any contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (eg, in skull and cardiac devices other than those approved as safe for use in MRI scanners) or
    • Have any evidence of other clinically significant lesions that could indicate a dementia diagnosis other than AD on brain MRI at Screening.
    • Exhibit other significant pathological findings on central read of the brain MRI at Screening, including but not limited to: an area of superficial siderosis; evidence of cerebral vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts; evidence of stroke involving a major vascular territory, severe small vessel or diffuse white matter disease as defined by a score of 3 on the age-related white matter changes scare; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be exclusionary).
    8. Subjects who have a history of moderate to severe hepatic impairment (eg, Child-Pugh Class B or C). Any 2 of the following criteria at Screening would exclude the subject: INR ≥ 1.7; bilirubin ≥ 1.5 × ULN; albumin < LLN; ascites or hepatic encephalopathy. Please note that a single significant abnormality could meet criteria for moderate impairment. (revised per Amendment 01)
    9. Results of laboratory tests conducted during screening that are outside the following limits:
    • Absolute lymphocyte count (ALC) below Lower Limit of Normal (LLN) or below 800 per mm3 (whichever is higher); ALC will be derived from the complete blood count (CBC) with differential representing the normal lymphocytes (with atypical lymphocytes removed and presented as a separate count if they are present) and calculated by the white blood cell count × percentage of lymphocytes. (revised per Amendment 01)
    • Thyroid stimulating hormone (TSH) above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator (this applies to all subjects whether or not they are taking thyroid supplements)
    See study protocol for further exclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in the CDR-SB at 24 months
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 24 months
    E.5.2Secondary end point(s)
    •Time to worsening of CDR scores by 24 months (eg, the worsening of global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits at which global CDR is undertaken)
    •Time to conversion to dementia by 24 months for subjects who were not clinically staged as dementia at Baseline based on clinical diagnosis
    •The rate of change over time (mean slope) based on CDR-SB score over 24 months
    •Change from baseline in CDR-SB at 27 months (ie, 24 months of treatment plus 3 months posttreatment follow-up)
    •Change from baseline in ADAS-cog14, MMSE, and FAQ at 24 months
    •Change from baseline in ADAS-cog14 Word List (immediate recall and delayed recall) at 24 months

    Biomarker Endpoints
    •Change from baseline in amyloid PET SUVR composite at 24 months for brain amyloid levels
    •Change from baseline in CSF biomarkers t-tau and p-tau at 24 months
    •Change from baseline in CSF amyloid biomarkers Aβ(1-42), and Aβ(1-x) at 24 months
    •Change from baseline in total hippocampal volume at 24 months using vMRI
    •Change from baseline in the preservation of connectivity on fMRI at 24 months

    Exploratory Endpoints
    •Time to change of concomitant AD treatment (ie, dose increase and/or initiation of treatment with AChEI or memantine after randomization) by 24 months
    •The proportion of subjects at 24 months who received dose increases and/or initiation of treatment with AChEI or memantine after randomization
    •The rate of change over time (mean slope) based on NPI-10 item score over 24 months
    •Change from baseline in NPI-10 item at 24 months
    •Change from baseline in EQ-5D (subject self-reported, study partner self-reported, and subject measured by proxy) and QOL-AD (subject and study partner) at 24 months
    •Change from baseline in Zarit’s Burden Interview at 24 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to the relevant endpoint for the specific timepoint
    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 Yes
    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 Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    quality of life
    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) No
    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 trial2
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA130
    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
    Canada
    China
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Hong Kong
    Hungary
    Italy
    Japan
    Korea, Republic of
    Poland
    Portugal
    Singapore
    Slovakia
    South Africa
    Spain
    Taiwan
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1130
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 1330
    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)
    All subjects, regardless of whether they complete all 24 months of treatment or discontinue study drug prematurely, will complete 2 post-treatment Follow-Up Visits (Visit 14 and Visit 15 respectively).
    An open-label Extension Phase will be available for subjects who complete the full 24 months of treatment in the Core study following HA approval. The OLE Phase will continue until commercial availability of E2609,or until a positive risk-benefit assessment in this indication is not demonstrated.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-18
    P. End of Trial
    P.End of Trial StatusOngoing
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