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    Summary
    EudraCT Number:2009-013705-34
    Sponsor's Protocol Code Number:D0540C00004
    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:2009-07-23
    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 number2009-013705-34
    A.3Full title of the trial
    A double-blind, placebo controlled, randomised, parallel group, single centre, phase IIa study to investigate the efficacy, tolerability and safety of 8 doses of
    AZD8848 administered intranasally once weekly in mild to
    moderate allergic asthma patients challenged with an inhaled allergen.
    A.4.1Sponsor's protocol code numberD0540C00004
    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 nameAZD8848
    D.3.2Product code AZD8848
    D.3.4Pharmaceutical form Nasal spray, solution
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPNasal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 866269-28-5
    D.3.9.2Current sponsor codeAZD8848
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.6
    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 placeboNasal spray, solution
    D.8.4Route of administration of the placeboNasal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Allergic Asthma
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.0
    E.1.2Level LLT
    E.1.2Classification code 10001705
    E.1.2Term Allergic asthma
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of AZD8848 on the Late Asthmatic Response (LAR)
    compared with placebo after 8 doses of once weekly intranasal administration in
    mild to moderate asthma patients challenged with inhaled allergen (Main Part only).
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of AZD8848 compared with placebo after 8 doses of once
    weekly intranasal administration in mild to moderate asthma patients challenged
    with inhaled allergen as measured by the Early Asthmatic Response (EAR),
    Bronchial Hyperreactivity (BHR) and Sputum Biomarkers (Main Part only).
    • To investigate tolerability and safety of AZD8848 after 8 doses of once weekly
    intranasal administration in asthma patients (Pilot and Main Parts).
    • To investigate plasma concentrations of the acid metabolite around Cmax after the
    first and last dose of AZD8848 administered intranasally (concentrations represent
    the sum of AZD8848 and acid metabolite) (Main Part only).
    • To investigate the influence of butyrylcholinesterase genotype on pharmacokinetic
    and pharmacodynamic responses (Main Part only).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The sub study taking the form of samples for DNA analysis of pharmacogenetic (PGt) analysis.

    The participation in the genetic research activity is an optional part of the study. Patients must give separate informed consent before a blood sample is taken. Pharmacogenetic data will be reported separately from the CSR.
    E.3Principal inclusion criteria
    1. Provision of informed consent prior to any study specific procedures

    2. Male or female patients aged 18 to 55 years (inclusive). Females must be of non-childbearing potential or must have been stable on a highly effective contraceptive method for at least 3 months prior to Visit 1 and be willing to continue on the chosen contraceptive method, with additional use of a condom, until Visit 19. Women must be non-lactating and must have a date of menstruation consistent with non-pregnancy (see section 4.1.2 for more details)

    3. A minimum of 6 months documented history of asthma defined according to the
    GINA guidelines (Global Initiative for Asthma 2008) prior to Visit 1

    4. The presence of allergic sensitivity (grass, house dust mite, cat) verified by a
    positive skin prick test documented within the previous 24 months or at Visit 1

    5. FEV1 (forced expiratory volume in 1 second) >70% of predicted normal value,
    prebronchodilator

    6. The presence of an Early Asthmatic Response corresponding to ≥ 20% FEV1
    decrease within 2 hours post-allergen challenge as verified and documented within
    the previous 12 months or at screening. The inhaled allergen will be one of those giving a positive response in the skin prick test (see section 6.2.1).

    7. Methacholine PC20 (the provocative concentration of methacholine causing a 20%
    fall in FEV1) <16 mg/mL as verified and documented within the previous 12
    months or at screening (Visit 1)

    8. Body mass index between 19 and 33 kg/m2

    9. Non- or ex-smokers who are expected to not smoke for the duration of the trial up
    to Visit 12 (an ex-smoker being defined as someone who <10 pack-year history and
    who has completely stopped smoking for at least 6 months before Visit 1)

    10. Ability to metabolise AZD8848 (an in vitro screening assay will determine esterase metabolic activity in a blood sample taken at Visit 1 using a pre-defined limit)


    For inclusion in the main part, note the additional criteria for LAR:

    6. Early Asthmatic Response corresponding to ≥20% FEV1 decrease within 2 hours
    and Late Asthmatic Response corresponding to ≥15 % FEV1 decrease between 4-10
    hours post-allergen challenge on two consecutive occasions. The inhaled allergen
    will be the one of those giving a positive response in the skin prick test (see section 6.2.1).
    E.4Principal exclusion criteria
    1. Any clinically relevant disease and/or abnormality (past or present), which, in the
    opinion of the Investigator, may either put the patient at risk because of
    participation in the study, or influence the results of the study, or the patient’s
    ability to participate in the study. Includes pregnant or lactating females.

    2. Symptomatic allergic rhinitis (those with a history of allergic rhinitis may
    participate if asymptomatic at screening and if, in the opinion of the Investigator, it
    is unlikely that disease exacerbation will occur during the course of the study)

    3. Any clinical relevant abnormal findings in physical examination, clinical chemistry,
    haematology, urinalysis, vital signs, or ECG at baseline which, in the opinion of the
    investigator, may put the patient at risk because of participation in the study

    4. QTcF >450ms, confirmed with repeated measurements at Visit 1

    5. Rhythm, conduction (eg intermittent or constant Bundle branch block;
    Intraventricular conduction disturbance with repolarisation changes: intermittent or
    constant AV block (including 1st degree AV block with PR interval >220msec, 2nd
    or 3rd degree AV block)); or morphologic changes affecting repolirization (eg, flat,
    biphasic or inverted T waves in primary lead V2), that may limit ability to measure
    QTc and assess changes in QTc intervals or QTc morphology

    6. History of additional risk factors for Torsade de pointes (eg heart failure,
    hypokaelamia, family history of Long QT syndrome, or sudden death)

    7. Medical history suggesting or confirming abnormal immune function, except for
    asthma

    8. Family history (parent or sibling) of autoimmune disease including but not limited
    to Wegener’s granulomatosis, system lupus erythematosus, rheumatoid arthritis,
    Sjögren’s syndrome, multiple sclerosis, autoimmune thrombocytopenia, primary
    biliary cirrhosis or any other autoimmune disease considered clinically relevant by
    the investigator

    9. Any detection of anti-PR3 autoantibodies in the blood

    10. History of or ongoing immunotherapy

    11. Topical or inhaled glucocorticosteroid +/- Long-Acting β-Agonists (LABAs)
    treatment within 4 weeks prior to Visit 1

    12. Systemic glucocorticosteroid therapy for any reason within 6 weeks prior to Visit 1

    13. Antihistamine treatment within 1 week prior to Visit 1. This period should be extended for antihistamines with a long half-life (see exclusion criteria 14)

    14. Use of any medication (including vaccinations, over the counter drugs and herbal medicines such as St John's Wort) or therapy within 2 weeks prior to Visit 1 which may potentially expose the patient to any significant systemic exposure
    that may interfere with the objectives of the study or the safety of the patients as
    judged by the investigator, except for inhaled short-acting β2 agonists for treatment
    of asthma symptoms and occasional intake of paracetamol

    15. An exacerbation of asthma (use of oral or parenteral antibiotics and/or
    glucocorticosteriods and/or hospitalisation related to asthma) within 4 weeks prior
    to Visit 1, or during the screening period

    16. Positive results on screening tests for pregnancy, hepatitis B, C and/or HIV

    17. Any respiratory tract infection (bacterial, viral or fungal infections of the airways)
    or any other clinically significant illness within 2 weeks prior to Visit 1 being
    symptomatic enough to affect study conduct or the well-being of the patient as
    judged by the investigator

    18. Structural abnormalities of the nose or nasal disorder symptomatic enough to cause significant nasal obstruction as judged by the Investigator

    19. Known or suspected hypersensitivity to Investigational drug or any excipients

    20. Definite or suspected personal history of significant adverse drug
    reactions/anaphylactic reaction

    21. History of or current alcohol and/or drug abuse, as judged by the Investigator, or
    positive drugs of abuse test

    22. Planned surgery, dental procedure, or hospitalisation during the study, and/or major surgery or significant trauma within 3 months of Visit 1

    23. Participation in another clinical study with an Investigational Product within 3
    months before the start of the present study

    24. Have significant blood loss (>500 mL) or donated blood in the 30 days before Visit 1 or donation of > 1350 mL within 12 months prior to Visit 1

    25. Patients who, in the opinion of the Investigator, should not participate in the study

    26. Involvement in the planning and/or conduct of the study (applies to both
    AstraZeneca staff and/or staff at the study site)

    27. Previous randomisation of treatment in the present study
    E.5 End points
    E.5.1Primary end point(s)
    • Efficacy
    − FEV1 (Late Asthmatic Response) - Primary Variable
    − FEV1 (Early Asthmatic Response)
    − PC20 (Methacholine challenge)
    − Sputum Cellularity and Cytokines

    • Safety and Tolerability
    − Vital signs, ECG, clinical chemistry, haematology, urinalysis, physical
    examination, clinical inspection of the nose, spirometry (FEV1), autoantibodies,
    adverse events

    • Pharmacokinetics and Pharmacogenetics
    − Concentration of acid metabolite in plasma (representing the sum of the
    concentration of AZD8848 and acid metabolite)
    − Butyrylcholinesterase gene
    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 Yes
    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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    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 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 is defined as LSLV, the last telephone contact performed for the Main Part of the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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) No
    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 state59
    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)
    The long-term safety follow-up after ended dosing is included in the trial.
    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 Decision2009-08-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2009-10-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2011-12-05
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