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    Summary
    EudraCT Number:2009-015525-37
    Sponsor's Protocol Code Number:D1950C00006
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2009-10-27
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2009-015525-37
    A.3Full title of the trial
    Safety, Tolerability and Pharmacokinetics of 3 Dose regimens of AZD1446
    vs. Placebo as an Add-on Treatment to Donepezil:
    A Multi-centre, Double-blind, Randomised, Placebo controlled, Parallel
    group Phase IIa Study in Patients with Mild to Moderate Alzheimer’s
    Disease during 4 weeks of Treatment
    A.4.1Sponsor's protocol code numberD1950C00006
    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 SponsorAstraZeneca AB
    B.1.3.4CountrySweden
    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 nameAZD1446 30 mg capsules
    D.3.2Product code AZD1446
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    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 placeboCapsule, hard
    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
    Patients with mild to moderate Alzheimer's Desease
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    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 evaluate the safety and tolerability of 3 dose regimens of AZD1446 compared to placebo as an add-on treatment to donepezil for 4 weeks in patients with mild to moderate Alzheimer’s disease (AD)
    E.2.2Secondary objectives of the trial
    · To evaluate any effect of AZD1446 as an add-on treatment to donepezil on the pharmacokinetics (PK) of donepezil
    · To characterize the PK of AZD1446 as an add-on treatment to donepezil in AD patients, using population analysis
    · To evaluate the effects of 2 different doses of AZD1446 as an add-on treatment to donepezil compared to placebo on changes from baseline in global functioning using Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC, Shneider et al, 1997)
    · To analyse Apolipoprotein E genotype in relation to drug response and other clinical endpoints
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Provision of written informed consent before initiation of any study related procedures. Patients who are deemed incapable of providing informed consent may be enrolled if written informed consent has been obtained from patient’s Legally Authorised Representative in accordance with the local regulation.
    Provision of written informed consent from the caregiver
    2. Female and male patients aged 60 to 85 years, inclusive at the day of enrolment (Visit 1)
    3. Male patients should be willing to use barrier contraception, ie condoms, even if their partners are post-menopausal, be surgically sterile or are using accepted contraceptive methods, from the first day of dosing until 3 months after the last dose of the investigational product
    4. Clinical diagnosis of probable Alzheimer’s disease according to the NINCDS-ADRDA criteria
    5. History of progressive worsening of memory and other cognitive functions for at least 12 months prior to Visit 1
    6. Hachinski ischaemic score ≤ 4
    7. CT/MRI results consistent with the diagnosis of AD and not older than 12 months prior to Visit 1. The CT/MRI should have been performed in order to support the diagnosis of AD, or after the patient has been diagnosed with AD
    8. Treatment with stable dose of donepezil (10 mg) for at least 3 months (12 weeks) prior to inclusion in the study (Visit 1). The patient must continue to take the same dose of donepezil during the whole study (V1 till follow-up)
    9. MMSE score 12-24
    10. Body mass index (BMI=weight/height2) of 18-30 kg/m2 as calculated by the investigator at enrolment
    11. Clcrea ≥50 ml/min estimated according to the formula by Cockroft and Gault with S Cr determined by Jaffe’s method (or if the enzymatic method is used, the S-Cr value used for calculating Clcrea should reflect the expected value as if the Jaffe method was used) (see section 11.4)
    12. The patient should be willing to donate a blood sample for determination of APOE genotype
    13. The patient should have an appropriate caregiver at home, or in a community dwelling (caregiver who sees the patient at least 2-3 times a week and is capable of giving appropriate information regarding patient’s health, functioning and behaviour). The same caregiver is required for all visits
    14. The patient and the caregiver should be able to understand, speak and read local language. In case of language dysfunction due to Alzheimer’s Disease, the patient should at least formerly have been able to understand, speak and read local language. The caregiver should be able to understand, speak and read local language.
    15. The patient and the caregiver should be able to understand and comply with the requirements of the study, as judged by the investigator
    16. For inclusion in the optional exploratory genetic research, patients must provide informed consent for optional exploratory genetic research. If a patient declines to participate in the optional exploratory genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this CSP, as long as they consent.
    E.4Principal exclusion criteria
    1. Significant neurological disease or dementia other than Alzheimer’s Disease, eg,
    mixed dementia, frontotemporal dementia, Lewy body dementia and Parkinson’s
    disease, that may affect cognition or ability to complete the study
    2. Possible, probable or definite vascular dementia in accordance with NINDS-AIREN
    criteria
    3. Current episode or symptoms of major depressive disorder or other major
    psychiatric disorders according to the DSM-IV Axis I criteria
    4. Current significant or unstable disease eg, epilepsy that, in the judgment of the
    investigator, is likely to deteriorate or affect the patient’s safety, influence cognitive
    assessments or affect ability to complete the study
    5. History of any malignant disease within the past 5 years with the exception of minor superficial skin diseases (ie, basal cell carcinoma and squamous cell carcinoma)
    6. Myocardial infarction or acute coronary syndrome within the last year
    7. Abnormal vital signs, after 10 minutes supine rest, defined as any of the following
    or clinically significant as judged by investigator:
    − Systolic BP >160 mm Hg
    − Diastolic BP >90 mm Hg
    − Heart rate <40 or >85 beats per minute
    − Significant orthostatic reaction as judged by the investigator
    8. Poorly controlled diabetes mellitus, as judged by the investigator, or diabetes
    mellitus patient requiring any dose of insulin during the last 6 months
    9. Known or suspected systemic infection (eg, HBV, HCV, HIV, tuberculosis) as
    judged by the investigator
    10. Clinically significant abnormal findings in physical examination or vital signs that
    may affect the ability of the patient to complete study procedures, patient safety or
    data interpretation, as judged by the investigator
    11. History of allergy/hypersensitivity reactions:
    − History or present symptoms or signs of severe allergy/hypersensitivity
    reactions including severe food allergy, as judged by the investigator
    − History or present symptoms or signs of Quincke oedema, angiooedema or
    urticaria pigmentosa, or history of repeated episodes of urticaria, regardless
    causative agent
    − History or present symptoms or signs of asthma of any severity, as judged by
    the investigator
    − History of hypersensitivity to drugs of a similar class to AZD1446, as judged
    by the investigator
    12. Clinically significant ECG abnormalities as judged by the investigator based on
    assessment by a centrally located experienced cardiologist interpreting the ECG
    13. Prolonged QTcF >450 msec or shortened QTcF <350 msec or family history of
    long QT syndrome
    14. Impaired vision and hearing making cognitive testing difficult as judged by the
    investigator
    15. Any clinically significant abnormalities in clinical chemistry, haematology, B12 or
    urinalysis results as judged by the investigator
    16. Use of smoking cessation therapy within 4 weeks prior to enrolment visit and
    during the study. Smoking cessation therapy including but not limited to
    buproprion, varenicline; any dosage form of nicotine replacement therapy
    17. Use of memantine or any AchEIs (Acetylcholine-esterase inhibitors) other than
    donepezil within 3 months prior to the first administration of study drug and during
    the study
    18. Use of certain drugs with narrow therapeutic range (such as, but mot limited to:
    aminoglycoside antibiotics, lithium, digoxin, methotrexate, metformin) within 4
    weeks prior to the first administration of study drug
    19. Use of other anti AD drugs, psychostimulants, mood stabilizers, antipsychotics,
    anticonvulsants, anticholinergics, urinary spasmolytics, anti-parkinson drugs,
    antihistamines, anti-asthmatics or beta blockers within 4 weeks prior to enrolment
    20. Use of anxiolytics, antidepressants and hypnotics 4 weeks prior to enrolment
    (Visit 1), unless on regular dosing for more than 4 weeks
    21. Use of any strong inhibitors of CYP3A4 enzymes during the last 4 weeks prior to
    the first administration of study drug and during the study
    22. Current clinically significant or unstable respiratory, gastrointestinal, heart,
    cerebrovascular, haematological, hepatic, renal disease or other major disease as
    judged by the investigator
    23. Known or suspected drug or alcohol abuse or addiction as defined by the DSM-IV
    and not in full remission
    24. Positive toxicology test for illegal or non-prescribed substances of abuse at
    screening
    25. Male patients planning to father a child or donate sperm during and for 3 months
    after the last intake of study drug
    E.5 End points
    E.5.1Primary end point(s)
    Primary outcome variables (safety):
    • Adverse events (AEs)
    • Laboratory variables (blood, urine)
    • Vital signs
    • Physical examination
    • Electrocardiogram (ECG)
    • Columbia Suicide Rating Scale (C-SSRS, Posner et al 2007)
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    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.8.3 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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    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 years0
    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
    Alzheimer's Desease patients who are deemed incapable of providing informed consent may be enrolled if written informed consent has been obtained from patient’s Legally Authorised Representative in accordance with the local regulation.
    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 60
    F.4.2.2In the whole clinical trial 60
    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)
    Not applicable
    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 Decision2009-12-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2010-07-29
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