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    Summary
    EudraCT Number:2019-001800-39
    Sponsor's Protocol Code Number:D3251C00014
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-08-03
    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 ConcernedGreece - EOF
    A.2EudraCT number2019-001800-39
    A.3Full title of the trial
    A Multicenter, Randomized, Double-blind, Chronic-dosing, Parallel-group,
    Placebo-controlled Phase 3 Study to Evaluate the Efficacy and Safety of
    Benralizumab 100 mg in Patients with Moderate to Very Severe Chronic
    Obstructive Pulmonary Disease (COPD) with a History of Frequent COPD
    Exacerbations and Elevated Peripheral Blood Eosinophils (RESOLUTE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and Safety of Benralizumab in Moderate to Very Severe Chronic
    Obstructive Pulmonary Disease (COPD) with a History of Frequent Exacerbations
    A.3.2Name or abbreviated title of the trial where available
    RESOLUTE
    A.4.1Sponsor's protocol code numberD3251C00014
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04053634
    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 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 supportAstraZeneca AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstraZeneca
    B.5.2Functional name of contact pointInformation Center
    B.5.3 Address:
    B.5.3.1Street AddressN/A
    B.5.3.2Town/ cityN/A
    B.5.3.3Post codeN/A
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 302 885 1180
    B.5.6E-mailinformation.center@astrazeneca.com
    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 nameBenralizumab
    D.3.2Product code Medi-563
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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 INNBenralizumab
    D.3.9.1CAS number 1044511-01-4
    D.3.9.2Current sponsor codeMEDI-563
    D.3.9.3Other descriptive nameBenralizumab
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Yes
    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 injection in pre-filled syringe
    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
    Chronic Obstructive Pulmonary Disease
    E.1.1.1Medical condition in easily understood language
    COPD
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10009033
    E.1.2Term Chronic obstructive pulmonary disease
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal 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 evaluate the effect of benralizumab on
    COPD exacerbations in patients with moderate to very
    severe COPD
    E.2.2Secondary objectives of the trial
    - To evaluate the effect of benralizumab on
    severe COPD exacerbations (leading to hospitalization
    or death)
    - To evaluate the effect of benralizumab on
    COPD exacerbations involving emergency room visits
    and hospitalizations
    - To evaluate the effect of benralizumab on
    other parameters associated with COPD exacerbations
    - To evaluate the effect of benralizumab on
    health status/health-related quality of life
    - To evaluate the effect of benralizumab on
    respiratory symptoms
    - To evaluate the effect of benralizumab on
    pulmonary function
    - To evaluate the effect of benralizumab on all
    cause and respiratory-related mortality
    - To evaluate the effect of benralizumab on
    health care resource utilization due to COPD
    - To evaluate the pharmacokinetics and immunogenicity
    of benralizumab in this patient population
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Title: A Multicenter, Randomized, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab 100 mg in Patients with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) with a History of Frequent COPD Exacerbations and Elevated Peripheral Blood Eosinophils (RESOLUTE) - Mechanistic Sub-Study

    Sub-study included within Protocol Amendment 2.0, 02 December 2019

    Objectives:
    - To evaluate the effect of benralizumab 100 mg on COPD exacerbations of different phenotypes (e.g. eosinophilic, neutrophilic, viral, and bacterial), classified based on sputum cell counts as well as sputum and blood biomarkers
    - To evaluate the effect of benralizumab 100 mg on airway eosinophilia (sputum) during stable disease and at exacerbation
    - To evaluate the effect of benralizumab 100 mg on the kinetics of airway inflammatory biomarkers throughout stable disease and exacerbation
    - To evaluate the effect of benralizumab 100 mg on the kinetics of systemic inflammation (blood and urine) throughout stable disease and at exacerbation
    - To evaluate the effects of benralizumab 100 mg on the whole blood transcriptome (in a subset of COPD patients) for pharmacodynamic markers a of exposure or predictive markers a of clinical response to benralizumab treatment
    - To evaluate the effect of benralizumab 100 mg on the phenotype of airway and peripheral blood leukocytes, including eosinophils, assessed by flow cytometry
    - To evaluate the effect of benralizumab 100 mg on the airway (sputum) microbiome at stable disease and at exacerbation
    - To evaluate the effect of benralizumab 100 mg on airway structure and function
    - To evaluate the effect of benralizumab 100 mg on large and small airway function
    - To evaluate the effect of benralizumab 100 mg on mucus plugging
    - To evaluate the effect of benralizumab 100 mg on emphysema progression
    E.3Principal inclusion criteria
    1 Provision of informed consent

    2 Age 40 to 85 years

    3 Male and/or female.

    4 Current or former smoker with a tobacco history of ≥10 pack-years.

    5 History of moderate to very severe COPD with a post-bronchodilator FEV1/FVC<0.70 and FEV1 ≤65% of predicted normal value.

    6 Documented history of 2 or more COPD exacerbations that required treatment with systemic corticosteroids and/or hospitalization within 52 weeks prior to enrollment.
    (a) Exacerbations treated with antibiotics alone are excluded unless accompanied by treatment with systemic corticosteroids and/or hospitalization.
    (b) Hospitalization is defined as an inpatient admission ≥24 hours
    (c) Previous exacerbations should be confirmed to have occurred while on stable triple therapy for COPD.

    7 Documented use of triple (ICS/LABA/LAMA) background therapy for COPD throughout the year (52 weeks) prior to enrollment.
    (a) ICS in a dose approved for COPD or equivalent to ≥250 mcg of fluticasone propionate daily
    (b) Total cumulative duration of not being on triple background therapy must not exceed 2 months.
    (c) Stable therapy/doses for the last 3 months prior to randomization.

    8 Blood eosinophil count ≥300/μL at screening and documented historical eosinophil count of ≥150/μL within 52 weeks of enrollment (or repeated testing during run-in).

    9 CAT total score ≥15 at Visit 1.

    10 Negative pregnancy test for females of childbearing potential (WOCBP) at Visit 1.

    11 Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control from enrollment throughout the study and within 12 weeks after last dose of IP.

    Women not of childbearing potential are defined as women who are either permanently sterilized or postmenopausal (confirmed by FSH test for women <50 years).
    E.4Principal exclusion criteria
    1 Clinically important pulmonary disease other than COPD
    2 Current diagnosis of asthma, prior history of asthma or asthma-COPD overlap according to GINA/GOLD. Childhood history of asthma is allowed and defined as asthma diagnosed and resolved before theage of 18.
    3 Radiological findings of a respiratory disease other than COPD contributing to respiratory symptoms. Solitary pulmonary nodules without appropriate follow up or findings of acute infection.
    4 Another pulmonary or systemic disease associated with elevated peripheral eosinophil counts.
    5 Any unstable disorder that could affect patient safety, study findings or the patient’s ability to complete the study.
    6 Any clinically significant abnormal findings in physical examination, vital signs, ECG, laboratory tests could affect patient safety, study findings or the patient’s ability to complete the study.
    7 Cor pulmonale and/or right ventricular failure.
    8 Long-term treatment with oxygen >4.0 L/min and/or oxyhemoglobin saturation <89% while breathing supplemental oxygen.
    9 Use of any non-invasive positive pressure ventilation device (NIPPV). Note: use of CPAP for Sleep Apnea Syndrome is allowed.
    10 Known immunodeficiency disorder, including positive HIV-1/2 testing.
    11 Active liver disease. Chronic stable hepatitis B and C (including positive HBsAg or hepatitis C antibody testing), or other stable chronic liver disease are acceptable.
    12 ALT or AST ≥3 times the upper limit of normal, confirmed by repeated testing during the run-in period.
    13 Helminth parasitic infection within 24 weeks prior to enrollment, not treated or failed to respond to standard of care therapy.
    14 Alcohol or drug abuse within the past year, which may compromise the study data.
    15 Malignancy, current or within the past 5 years, except for adequately treated non invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1. Suspected malignancy or undefined neoplasms.
    16 Evidence of active tuberculosis, as judged by investigator. Patients with a recent (within 2 years) first-time or newly positive PPD or Quantiferon test need to complete an appropriate course of treatment before enrollment. Evaluation will be according to the local standard of care.
    17 Participation, or planned participation, in intensive COPD rehabilitation program (maintenance phase of a rehabilitation is allowed).
    18 History of surgical or endoscopic lung volume reduction within the 6 months prior to enrollment. History of partial or total lung resection (single lobe or segmentectomy is acceptable).
    19 Scheduled major surgical procedure during the study. Minor elective procedures are allowed.
    20 History of anaphylaxis to benralizumab or any other biologic therapy.
    21 Receipt of blood products or immunoglobulins within 30 days prior to randomization.
    22 Receipt of any marketed or investigational biologic product within 4 months or 5 half-lives prior to randomization, whichever is longer.
    23 Receipt of live attenuated vaccines 30 days prior to randomization.
    24 Chronic use of immunosuppressive medication or expected need for chronic use during the study.
    25 Chronic use of antibiotics if duration of treatment is <9 months prior to randomization. Chronic macrolide or other antibiotic therapy is allowed provided the patient has been on stable dose/regimen for ≥9 months prior to randomization and has had ≥2 COPD exacerbations while on stable therapy.
    26 Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to enrollment.
    27 Receipt of benralizumab within 12 months prior to enrollment.
    28 Known history of allergy or reaction to any component of the IP formulation.
    E.5 End points
    E.5.1Primary end point(s)
    Annualized rate of moderate or severe COPD exacerbations, where a COPD exacerbation is defined by symptomatic worsening of COPD requiring:

    • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of
    corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or

    • Use of antibiotics; and/or

    • An inpatient hospitalization or death due to COPD
    E.5.1.1Timepoint(s) of evaluation of this end point
    over first 56 weeks
    E.5.2Secondary end point(s)
    1. Annualized rate of severe COPD exacerbations, where a severe COPD exacerbation is defined by symptomatic worsening of COPD requiring an inpatient hospitalization or results in death due to COPD

    2. Annualized rate of COPD exacerbations that are associated with an emergency room/emergency department visit or a hospitalization due to COPD


    3. Time to first COPD exacerbation

    4. • SGRQ total and domain scores
    • CAT total score

    5. E-RS:COPD total and domain scores

    6. Change from baseline in pre-dose/pre-bronchodilator FEV1 at the study site

    7. Mortality rate

    8. Annual rate of hospitalizations due to COPD; Length of hospital stay; ICU days; annual rate of hospitalizations and emergency department visits combined due to COPD; annual rate of unscheduled outpatient visits including unscheduled visits to study sites due to COPD; and annual rate of unscheduled healthcare encounters due to COPD

    9. • Serum benralizumab concentration
    • Anti-benralizumab antibodies
    E.5.2.1Timepoint(s) of evaluation of this end point
    Over 56 weeks or through End of Treatment
    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 Yes
    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 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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA86
    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
    Austria
    Belgium
    Brazil
    Canada
    Chile
    Colombia
    Czech Republic
    Denmark
    Germany
    Greece
    Hungary
    Italy
    Japan
    Korea, Republic of
    Mexico
    Netherlands
    New Zealand
    Philippines
    Poland
    Spain
    Sweden
    Turkey
    United Kingdom
    United States
    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
    The end of study is defined as the last expected visit/contact of the last patient undergoing the study.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days28
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days28
    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: 434
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 434
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 266
    F.4.2.2In the whole clinical trial 868
    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)
    None
    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 Decision2020-09-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-09-10
    P. End of Trial
    P.End of Trial StatusOngoing
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