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    Summary
    EudraCT Number:2006-004888-54
    Sponsor's Protocol Code Number:E2020-G000-326
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-06-14
    Trial results View 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 number2006-004888-54
    A.3Full title of the trial
    Double-Blind, Parallel-Group Comparison of 23 mg Donepezil Sustained
    Release to 10 mg Donepezil Immediate Release in Patients with Moderate to
    Severe Alzheimer’s Disease
    A.3.2Name or abbreviated title of the trial where available
    E2020-G000-326
    A.4.1Sponsor's protocol code numberE2020-G000-326
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameDonepezil Sustained Release
    D.3.2Product code BNAG SR
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNDonepezil hydrochloride
    D.3.9.2Current sponsor codeE2020
    D.3.9.3Other descriptive name(RS)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine, hydrochloride (IUPAC)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number23
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 RoleComparator
    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 Yes
    D.2.1.1.1Trade name Aricept 10mg IR
    D.2.1.1.2Name of the Marketing Authorisation holderEisai
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameDonepezil 10mg IR
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    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 INNDonepezil hydrochloride
    D.3.9.1CAS number 120011-70-3
    D.3.9.2Current sponsor codeE2020
    D.3.9.3Other descriptive name2,3-dihydro-5,6-dimethoxy-2[[1-(phenylmethyl)-4-piperidinyl]methyl]1-H-inden-1-one hydrochloride
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    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
    Alzheimer's Disease
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to compare 23 mg donepezil SR with 10 mg donepezil IR in the treatment of patients with moderate to severe Alzheimer’s disease.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    • To assess secondary efficacy parameters in support of the co-primary efficacy parameters

    • To perform exploratory quality-of-life assessments in patients administered 23 mg donepezil SR and in their caregivers for comparison with 10 mg donepezil IR

    • To assess the safety and tolerability of 23 mg donepezil SR during administration to Alzheimer’s disease patients

    • To determine whether treatment response is related to rate of drug metabolism as modified by CYP2D6 alleles and whether treatment response is related to the presence of AD risk factor APOE4; exploratory analyses only (Revised per Amendment
    03).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    9.2 INCLUSION CRITERIA

    9.2.1 Inclusion Criteria for Patients


    6) Stable Aricept® dose of 10 mg IR (or 10 mg dose of generic donepezil bioequivalent to Aricept®), taken as a single, daily dose for ≥ 3 months prior to the Screening visit. Tablets must not be broken or crushed. Any patient who splits daily doses (for example, Aricept® taken as two daily 5 mg doses instead of a single 10 mg dose) will not beenrolled in the study.

    7) Cranial image: no evidence of focal disease to account for dementia on any cranial image (MRI or CT) obtained within 12 months prior to Baseline. If no cranial image (MRI or CT) obtained within 12 months prior to Baseline is available, an attempt should be made to obtain the cranial image with contrast (CT and MRI), unless the use of contrast is clinically contra-indicated.

    8) Degree of dementia: MMSE score 1 to 20 at Screening and Baseline



    10) SIB ≤ 90 at both Screening and Baseline. Patients will be allowed to re-screen at a later time if their SIB scores are borderline (after 3 months if these scores are 91 or 92, or after 6 months if these scores are 93 or 94) (revised per amendment 04). At re-screening a new patient ID number will be assigned to these patients, and all screening assessments will be repeated.


    13) Specified doses of SSRIs are allowed in the study. Patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) at doses that are less than or equal to the approved dose range of therapeutic efficacy as specified in the Physician’s Desk Reference or regional equivalent may enter the study provided that the SSRI dose has been stable for at least 3 months prior to Screening. (Added per Amendment 03).

    14) Co-morbid medical conditions must be well-controlled and the patient maintained on stable doses of medications for 3 months. Patients with risk factors of hypertension and cardiac disease may be enrolled in the study, provided that hypertension is controlled by medication in the clinical judgement of the investigator(supine diastolic BP < 95 mm Hg) and cardiac disease (e.g. angina pectoris, congestive heart failure or right bundle branch block is stable on appropriate medication for 3 months prior to Screening. Peripheral vascular disease must have been stable for 3 months prior to Screening.


    16) Patients whose serum B12 levels at Screening are below the normal range may nonetheless be admitted to the study if they subsequently show normal levels prior to Baseline. Patients who are receiving Vitamin B12 supplements should maintain a stable dose/regimen throughout the study.


    18) Concomitant Medications: Patients undergoing treatment with the following medications may be enrolled in the study provided these conditions are met:
    a) Chronic daily benzodiazepine use may be allowed if doses are stable within
    approved dose range consistent with currently accepted standards of practice for at
    least 1 year prior to screening, to be confirmed by Medical Monitor. Chronic
    intermittent use of benzodiazepines may be allowed pending consultation and
    approval by the Medical Monitor but not within 48 hours of scheduled assessment.
    b). Bronchodilator medications for treatment of COPD may be allowed as long as
    drug is administered via metered dose inhaler within approved dose range.
    c). Memantine is allowed if taken at prescribed doses that are less than or equal to
    20mg/day, provided that the dose has been stable for at least 3months prior to Screening.
    d) Additional prescription treatments for AD, such as other cholinesterase
    inhibitors, must have been discontinued for at least 3 months prior to screening.
    Concomitant use of memantine is allowed as noted above.

    19) The patient must have a relative/caregiver who supervises the regular taking of the drug at the correct dose and is alert for possible side effects, unless the patient’s legal guardian takes on this task (Added per Amendment A - Germany).

    20) No history of life-threatening arrhythmias. These include (but are not limited to): unstable atrial flutter, unstable atrial fibrillation, ventricular tachycardia, ventricular fibrillation or tosades de pointes. In any case of doubt, a specialist should be consulted. (Added per Amendment 03).
    E.4Principal exclusion criteria
    9.3 EXCLUSION CRITERIA
    9.3.1 Exclusion Criteria for Patients

    1) Patients taking (a) no medication for Alzheimer’s disease, (b) Aricept® or bioequivalent generic donepezil at doses other than 10 mg daily, or 10 mg for < 3 months before Screening; (c) other medications for Alzheimer’s disease, with the following exceptions (Revised per Amendment 02):

    a. Memantine is allowed if taken at prescribed doses up to 20 mg/day provided the dose has been stable for at least 3 months prior to Screening.

    b. Vitamin E and/or fish oil and/or gingko bilboa are allowed if the doses have been stable for at least 3 months prior to the Screening visit, provided that doses are not changed during the study. Patients undergoing any alternative medical techniques such as acupuncture or acupressure, specifically for the treatment of AD are not eligible to participate in this study.


    3) Patients who have no measurable concentrations of donepezil in blood samples collected at Screening (Corrected per Amendment 02).


    5) Patients with psychiatric disorders affecting the ability to assess cognition such as
    schizophrenia, bipolar or unipolar depression. Patients with clinically significant
    sleep disorders will also be excluded unless these are controlled by treatment and
    clinically stable for > 3 months prior to screening.

    6) Patients with dementia complicated by other organic disease or Alzheimer’s disease with delirium (DSM IV 290.30 or 290.11; Appendix 5).

    7) Patients with drug or alcohol abuse or dependence within the past 5 years according to DSM IV criteria (Appendix 5).

    8) Patients with any active or clinically significant conditions affecting absorption,
    distribution, or metabolism of the study medication (eg, inflammatory bowel disease,
    gastric or duodenal ulcers, hepatic disease, or severe lactose intolerance).

    9) Patients with evidence of clinically significant, active gastrointestinal, renal, hepatic, respiratory, endocrine, or cardiovascular system disease (Revised per Amendment 02)

    10) Patients with a history of malignant neoplasms (does not include basal or squamous cell carcinoma of the skin) treated within 5 years prior to study entry, current evidence of malignant neoplasm, recurrent, metastatic disease. Males with localized prostate cancer requiring no treatment would not be excluded.


    12) Donation of blood or blood products during 30 days prior to Screening or plans to
    donate blood while participating in the study or within 30 days after completion of the study.

    13) Patients who are unwilling or unable to fulfill the requirements of the study.

    14) Known hypersensitivity to acetylcholinesterase inhibitors or memantine (Revised per Amendment 01).

    15) Use of any prohibited prior or concomitant medications as described in Section 10.7 and listed in Appendix 4

    16) Any condition that would make the patient, in the opinion of the investigator,
    unsuitable for the study.

    17) Involvement in any other investigational drug clinical trial during the preceding
    3 months, or likely involvement in any other such trial during the course of this study

    18) Patients taking concomitant antidepressant medication known to have significant
    anticholinergic effects, such as tricyclic antidepressants prescribed at doses recommended.for the treatment of major depression. Prohibited antidepressants are listed in Appendix 4 (Added per Amendment 02).

    19) Patients who cannot swallow or who have difficult swallowing whole tablets. (Added per Amendment 02).

    20) Patients with fecal and/or urinary incontinence who are unable to cooperate with
    routine specimen collection (Added per Amendment 03).

    9.3.2 Exclusion Criteria for Caregivers

    1) Caregivers who are unwilling or unable to give informed consent or otherwise to
    fulfill the requirements of the study.

    2) Caregivers who score above 15 on the CES-D or below 27 on the MMSE (below 25 if the caregiver is illiterate) (Revised per Amendment 02).

    3) Any condition that would make the caregiver, in the opinion of the Investigator,
    unsuitable for the study.
    E.5 End points
    E.5.1Primary end point(s)
    The co-primary parameters for this study are the Severe Impairment Battery (SIB) change from Baseline and the CIBIC+ change from Baseline in the Intent to Treat population using Last Observation Carried Forward (ITT-LOCF) imputation for missing data. For registration applications in Europe, the ADCS-ADL will replace the CIBIC+ as the second co-primary parameter.

    Severe Impairment Battery (SIB)
    The SIB will be administered to patients during the Screening and Baseline Visits and at the 6-, 12-, 18- and 24-week visits. It is essential that the SIB be completed in its entirety at Baseline. If for any reason this assessment is not completed at this visit, the patient will be discontinued.


    Modified Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL).
    The ADCS-ADL (severe scale) consists of a comprehensive battery of ADL questions used to measure a patient’s functional capabilities.40, 48 The modified ADCS-ADL-severe scale is a 19-item scale that has been validated for the assessment of patients with moderate to severe dementia. It measures the most appropriate basic and instrumental abilities (such as walking, grooming, bathing, and eating) in this patient population. Each ADL item is rated from the highest level of independent performance to complete dependence. The scale has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment.

    This inventory will be administered at Baseline and at the 6-, 12-, 18-, and 24-week (or early termination) visits as a rater-administered interview with the caregiver, and will cover the patient’s most typical and consistent performance of each ADL during the previous 4 weeks.

    It is essential that the ADCS-ADL be completed in its entirety at Baseline. If for any reason this assessment is not completed at this visit, the patient will be discontinued.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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 Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA97
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    The end of the study are defined as the last visit of the last subject undergoing the trial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    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.1.3Elderly (>=65 years) Yes
    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 No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    As these patients have moderate to severe alzheimer's disease they may be unable to provide written informed consent. Thus, the patient must assent verbally to participating in the study and the record will note this assent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 710
    F.4.2.2In the whole clinical trial 1200
    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)
    Subjects who complete this study may be eligible to enrol in a one year open-label extension study with 23mg SR. If subjects are not eligible or do not wish to enrol in that study their care will return to standard treatment.
    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 Decision2007-07-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-12-07
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-03-27
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