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出境医 / 临床实验 / Benralizumab Airway Remodeling Study in Severe Eosinophilic Asthmatics (CHINOOK)

Benralizumab Airway Remodeling Study in Severe Eosinophilic Asthmatics (CHINOOK)

Study Description
Brief Summary:

The purpose of the study is to evaluate effect of benralizumab on structural and lung function changes in severe eosinophilic asthmatics.

Changes will be assessed over 48 week treatment period in patients with persistent symptoms despite standard therapy of inhaled corticosteroids (ICS) plus long acting B2-agonist (LABA) with or without additional controller medication.

Patients who complete treatment will enter 4 weeks follow-up period


Condition or disease Intervention/treatment Phase
Asthma Biological: Benralizumab Biological: Placebo Phase 4

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 4, Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Benralizumab on Structural and Lung Function Changes in Severe Eosinophilic Asthmatics
Actual Study Start Date : October 8, 2019
Estimated Primary Completion Date : September 29, 2023
Estimated Study Completion Date : September 29, 2023
Arms and Interventions
Arm Intervention/treatment
Experimental: Benralizumab
Administrated subcutaneously (SC) every 4 weeks for the first 3 doses, then every 8 weeks
 Biological: Benralizumab
Benralizumab: 30 mg/mL solution for injection in accessorized prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks - Weeks 16, 24, 32, 40.
Placebo Comparator: Placebo
Administrated subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks
 Biological: Placebo
Matching placebo will be administered subcutaneously with accessorized prefilled syringe (APFS) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks - Weeks 16, 24, 32, 40.
Outcome Measures
Primary Outcome Measures :
  1. The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies

  2. The change in airway wall area percentage as the overall median for airway generations 3 and 4 combined as measured by quantitative computed tomography (QCT) imaging [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in airway wall area percentage as the overall median for airway generations 3 and 4 combined as measured by quantitative computed tomography (QCT) imaging


Secondary Outcome Measures :
  1. The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies

  2. The change in eosinophil numbers, expressed as number/mm2 in epithelium and submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in eosinophil numbers, expressed as number/mm2 in epithelium and submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies

  3. Absolute change in air trapping of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in air trapping of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans

  4. Absolute change in air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory computed tomography (CT) scans [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory computed tomography (CT) scans

  5. Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT)

  6. Change in endobronchial biopsies on airway epithelial cell integrity [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on airway epithelial cell integrity

  7. Change in endobronchial biopsies on reticular basement membrane (RBM) thickening [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on reticular basement membrane (RBM) thickening

  8. Change in endobronchial biopsies on vascularization of the sub-mucosa [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on vascularization of the sub-mucosa

  9. Change in endobronchial biopsies on airway smooth muscle mass percentage [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on airway smooth muscle mass percentage

  10. Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC)

  11. Absolute change in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) as measured by airwave oscillometry (AO) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) as measured by airwave oscillometry (AO)

  12. Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO)

  13. Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV)

  14. Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC)

  15. Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC)

  16. Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) RV/TLC ratio [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume / total lung capacity (RV/TLC) ratio

  17. Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC)

  18. Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC)

  19. Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV)

  20. Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC)

  21. Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC)

  22. Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) RV/TLC ratio [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume / total lung capacity(RV/TLC) ratio

  23. Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC)

  24. Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC)

  25. Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV)

  26. Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC)

  27. Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC)

  28. Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP RV/TLC ratio [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume / total lung capacity (RV/TLC) ratio

  29. Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC)

  30. Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC)

  31. Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry

  32. Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry

  33. Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry

  34. Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC)


Other Outcome Measures:
  1. Number of Adverse events (AEs)/serious adverse events (SAEs). [ Time Frame: From baseline to Week 52 (Visit 11) ]
    Number of Adverse events (AEs)/serious adverse events (SAEs).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female aged 18 through 70 years.
  2. History of physician-diagnosed asthma requiring continuous treatment with medium- or high-dose ICS (>250μg fluticasone dry powder formulation equivalents total daily dose) plus LABA with or without additional controller medication for at least 12 months prior to Visit 1.
  3. Documented current treatment with high-dose ICS plus LABA for at least 3 months prior to Visit 1 with or without additional asthma maintenance medication. If the prticipant is taking ICS plus LABA, the ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose during the last 3 months prior to Visit 1 must have been >500 µg/day fluticasone propionate dry powder formulation or equivalent daily.
  4. Morning pre-BD FEV1 ≥50 to <80% of predicted normal value (PNV) and ≥1 liter (L).
  5. A blood eosinophil count of: ≥300 cells/µL during screening or ≥150 to <300 cells/µL during screening plus one of the following: presence of nasal polyps or pre-BD FVC <65% predicted at Visit 2 or sputum eosinophil count of ≥2% at Visit 2.
  6. Negative pregnancy test.
  7. Asthma control questionnaire (ACQ-6) >1.5.
  8. Fewer than 12 exacerbations within the 6 months prior to Visit 3.

Exclusion Criteria:

  1. Clinically important pulmonary disease other than asthma or participants who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
  2. Life-threatening asthma, defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1.
  3. A history of allergies or adverse drug reactions to medications used for pre-bronchoscopy procedures.
  4. Any disorders that is not stable in the opinion of the Investigator and could affect the safety of the participant during the study, influence the findings of the studies or their interpretations, or impede the participant's ability to complete the entire duration of the study.
  5. Current smokers. Ex-smokers must not have smoked for a minimum of 12 months and should not have a smoking history >15 pack-years at Visit 1. Participants who use e-cigarettes or smoke marijuana will also be excluded from the study.
  6. History of anaphylaxis to any biologic therapy.
  7. Known history of allergy or reaction to any component of the investigational product (IP) formulation.

  8. History of cancer:

    • Participants who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the participant is in complete remission and curative therapy was completed at least 12 months prior to the date informed consent is obtained
    • Participants who have had other malignancies are eligible provided that the participant is in complete remission and curative therapy was completed at least 5 years prior to the date informed consent is obtained
  9. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy
  10. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
  11. Current active liver disease, except for chronic stable hepatitis B and C, or other stable chronic liver disease are acceptable if participant otherwise meets eligibility criteria.
  12. Any medical condition that requires chronic treatment with chronic anti-coagulation, chronic aspirin or anti-platelet therapy.
  13. Use of anticoagulants within 4 weeks prior to randomization in to the study.
  14. Use of non-steroidal anti-inflammatory drugs (NSAIDs) within 72 hours before or aspirin within 7 days of randomization, or longer or as judged by the Investigator.
  15. Use of chronic (i.e. >4 weeks) immunosuppressive medication within 3 months prior to the date informed consent is obtained.
  16. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
  17. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
  18. Previously received benralizumab (MEDI-563). Participants that participated in other studies with benralizumab but have been confirmed to have received placebo are eligible.
  19. Receipt of live attenuated vaccines 30 days prior to the date of randomization. Receipt of inactive/killed vaccinations (e.g. inactive influenza) is allowed provided they are not administered within 1 week before/after any IP administration.
  20. Receipt of bronchial thermoplasty in the last 24 months prior to Visit 1
  21. Receipt of any investigational non-biologic within 22 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
  22. Currently pregnant, breastfeeding or lactating women.
  23. Radiological findings suggestive of a respiratory disease other than asthma that is contributing to the participant's respiratory symptoms.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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United States, California
Research Site Not yet recruiting
Los Angeles, California, United States, 90033
United States, Connecticut
Research Site Recruiting
New Haven, Connecticut, United States, 06510
United States, Georgia
Research Site Not yet recruiting
Decatur, Georgia, United States, 30033
United States, Iowa
Research Site Recruiting
Iowa City, Iowa, United States, 52242
United States, Kansas
Research Site Recruiting
Kansas City, Kansas, United States, 66160
United States, Maryland
Research Site Not yet recruiting
Baltimore, Maryland, United States, 21224
United States, Massachusetts
Research Site Withdrawn
Boston, Massachusetts, United States, 02114
United States, Michigan
Research Site Recruiting
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
Research Site Not yet recruiting
Rochester, Minnesota, United States, 55905
United States, Missouri
Research Site Not yet recruiting
Saint Louis, Missouri, United States, 63110
United States, New York
Research Site Not yet recruiting
Port Jefferson Station, New York, United States, 11777
United States, North Carolina
Research Site Recruiting
Durham, North Carolina, United States, 27705
Research Site Withdrawn
Greenville, North Carolina, United States, 27834
Research Site Recruiting
New Bern, North Carolina, United States, 28562
Research Site Recruiting
Winston-Salem, North Carolina, United States, 27104
United States, Pennsylvania
Research Site Recruiting
Philadelphia, Pennsylvania, United States, 19107
Research Site Recruiting
Philadelphia, Pennsylvania, United States, 19140
Research Site Recruiting
Pittsburgh, Pennsylvania, United States, 15213
United States, Texas
Research Site Recruiting
Galveston, Texas, United States, 77555
United States, Virginia
Research Site Withdrawn
Williamsburg, Virginia, United States, 23188
Canada, Alberta
Research Site Recruiting
Calgary, Alberta, Canada, T2N 4Z6
Research Site Suspended
Edmonton, Alberta, Canada, T6G 2G3
Canada, Ontario
Research Site Suspended
Hamilton, Ontario, Canada, L8N 4A6
Denmark
Research Site Recruiting
Aarhus N, Denmark, 8200
Research Site Recruiting
Hvidovre, Denmark, 2650
Research Site Recruiting
København NV, Denmark, 2400
Research Site Recruiting
Naestved, Denmark, 4700
Research Site Recruiting
Odense C, Denmark, 5000
Research Site Recruiting
Vejle, Denmark, 7100
Research Site Recruiting
Ålborg, Denmark, 9000
Sweden
Research Site Recruiting
Göteborg, Sweden, 413 45
Research Site Recruiting
Lund, Sweden, 221 85
United Kingdom
Research Site Suspended
Liverpool, United Kingdom, L7 8XP
Research Site Recruiting
London, United Kingdom, W1G 8HU
Research Site Suspended
Oxford, United Kingdom, OX3 7LE
Sponsors and Collaborators
AstraZeneca
Investigators
Layout table for investigator information
Principal Investigator: Mario Castro, MD University of Kansas School of Medicine 3901 Rainbow Blvd. Kansas City, KS 66160, United States of America (USA)
Tracking Information
First Submitted Date  ICMJE April 10, 2019
First Posted Date  ICMJE May 16, 2019
Last Update Posted Date June 10, 2021
Actual Study Start Date  ICMJE October 8, 2019
Estimated Primary Completion Date September 29, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
  • The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in eosinophil numbers expressed as number/mm2 in submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies
  • The change in airway wall area percentage as the overall median for airway generations 3 and 4 combined as measured by quantitative computed tomography (QCT) imaging [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in airway wall area percentage as the overall median for airway generations 3 and 4 combined as measured by quantitative computed tomography (QCT) imaging
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 14, 2019)
  • The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in eosinophil numbers, expressed as number/mm2 in epithelium as measured by major basic protein (MBP) staining in endobronchial biopsies
  • The change in eosinophil numbers, expressed as number/mm2 in epithelium and submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies [ Time Frame: From baseline to Week 48 (Visit 10) ]
    The change in eosinophil numbers, expressed as number/mm2 in epithelium and submucosa as measured by major basic protein (MBP) staining in endobronchial biopsies
  • Absolute change in air trapping of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in air trapping of the lung with expiratory density less than -856 Hounsfield Units (HU), and as expiratory-to-inspiratory ratio of mean lung density on computed tomography (CT) scans
  • Absolute change in air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory computed tomography (CT) scans [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in air trapping/small airway obstruction derived from regional matching of the inspiratory/expiratory computed tomography (CT) scans
  • Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in airway lumen volume and airway resistance as measured by quantitative computed tomography (QCT)
  • Change in endobronchial biopsies on airway epithelial cell integrity [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on airway epithelial cell integrity
  • Change in endobronchial biopsies on reticular basement membrane (RBM) thickening [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on reticular basement membrane (RBM) thickening
  • Change in endobronchial biopsies on vascularization of the sub-mucosa [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on vascularization of the sub-mucosa
  • Change in endobronchial biopsies on airway smooth muscle mass percentage [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on airway smooth muscle mass percentage
  • Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in endobronchial biopsies on mucin 5AC, oligomeric mucus/gel-forming (MUC5AC)
  • Absolute change in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) as measured by airwave oscillometry (AO) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in R5-R20 (peripheral airway resistance defined as the difference in resistance between 5 Hz [R5, total respiratory system resistance] and 20 Hz [R20, central resistance]) as measured by airwave oscillometry (AO)
  • Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in area under the reactance curve (AX) as measured by airwave oscillometry (AO)
  • Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV)
  • Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC)
  • Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC)
  • Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) RV/TLC ratio [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume / total lung capacity (RV/TLC) ratio
  • Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC)
  • Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC)
  • Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume (RV)
  • Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) total lung capacity (TLC)
  • Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) inspiratory capacity (IC)
  • Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) RV/TLC ratio [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) residual volume / total lung capacity(RV/TLC) ratio
  • Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP)functional residual capacity (FRC)
  • Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Absolute change in post-bronchodilator (BD) whole body plethysmogrpahy (WBP) vital capacity (VC)
  • Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume (RV)
  • Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP total lung capacity (TLC)
  • Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP inspiratory capacity (IC)
  • Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP RV/TLC ratio [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP residual volume / total lung capacity (RV/TLC) ratio
  • Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP functional residual capacity (FRC)
  • Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change from pre-bronchodilator (BD) whole body plethysmogrpahy (WBP) to post-BD WBP vital capacity (VC)
  • Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) as measured by spirometry
  • Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in post-bronchodilator (BD) forced vital capacity (FVC) as measured by spirometry
  • Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in post-bronchodilator (BD) FEV1/FVC as measured by spirometry
  • Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC) [ Time Frame: From baseline to Week 48 (Visit 10) ]
    Change in basophil number (number/mm2) in endobronchial biopsies as measured by immunohistochemistry (IHC)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 14, 2019) 		Number of Adverse events (AEs)/serious adverse events (SAEs). [ Time Frame: From baseline to Week 52 (Visit 11) ]
Number of Adverse events (AEs)/serious adverse events (SAEs).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Benralizumab Airway Remodeling Study in Severe Eosinophilic Asthmatics
Official Title  ICMJE A Phase 4, Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Benralizumab on Structural and Lung Function Changes in Severe Eosinophilic Asthmatics
Brief Summary

The purpose of the study is to evaluate effect of benralizumab on structural and lung function changes in severe eosinophilic asthmatics.

Changes will be assessed over 48 week treatment period in patients with persistent symptoms despite standard therapy of inhaled corticosteroids (ICS) plus long acting B2-agonist (LABA) with or without additional controller medication.

Patients who complete treatment will enter 4 weeks follow-up period
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE
  • Biological: Benralizumab
    Benralizumab: 30 mg/mL solution for injection in accessorized prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks - Weeks 16, 24, 32, 40.
  • Biological: Placebo
    Matching placebo will be administered subcutaneously with accessorized prefilled syringe (APFS) every 4 weeks for the first 3 doses - Weeks 0, 4 and 8, and then every 8 weeks - Weeks 16, 24, 32, 40.
Study Arms  ICMJE
  • Experimental: Benralizumab
    Administrated subcutaneously (SC) every 4 weeks for the first 3 doses, then every 8 weeks
    Intervention: Biological: Benralizumab
  • Placebo Comparator: Placebo
    Administrated subcutaneously every 4 weeks for the first 3 doses, then every 8 weeks
    Intervention: Biological: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 14, 2019) 		81
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 29, 2023
Estimated Primary Completion Date September 29, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female aged 18 through 70 years.
  2. History of physician-diagnosed asthma requiring continuous treatment with medium- or high-dose ICS (>250μg fluticasone dry powder formulation equivalents total daily dose) plus LABA with or without additional controller medication for at least 12 months prior to Visit 1.
  3. Documented current treatment with high-dose ICS plus LABA for at least 3 months prior to Visit 1 with or without additional asthma maintenance medication. If the prticipant is taking ICS plus LABA, the ICS and LABA can be parts of a combination product or given by separate inhalers. The ICS dose during the last 3 months prior to Visit 1 must have been >500 µg/day fluticasone propionate dry powder formulation or equivalent daily.
  4. Morning pre-BD FEV1 ≥50 to <80% of predicted normal value (PNV) and ≥1 liter (L).
  5. A blood eosinophil count of: ≥300 cells/µL during screening or ≥150 to <300 cells/µL during screening plus one of the following: presence of nasal polyps or pre-BD FVC <65% predicted at Visit 2 or sputum eosinophil count of ≥2% at Visit 2.
  6. Negative pregnancy test.
  7. Asthma control questionnaire (ACQ-6) >1.5.
  8. Fewer than 12 exacerbations within the 6 months prior to Visit 3.

Exclusion Criteria:

  1. Clinically important pulmonary disease other than asthma or participants who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
  2. Life-threatening asthma, defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1.
  3. A history of allergies or adverse drug reactions to medications used for pre-bronchoscopy procedures.
  4. Any disorders that is not stable in the opinion of the Investigator and could affect the safety of the participant during the study, influence the findings of the studies or their interpretations, or impede the participant's ability to complete the entire duration of the study.
  5. Current smokers. Ex-smokers must not have smoked for a minimum of 12 months and should not have a smoking history >15 pack-years at Visit 1. Participants who use e-cigarettes or smoke marijuana will also be excluded from the study.
  6. History of anaphylaxis to any biologic therapy.
  7. Known history of allergy or reaction to any component of the investigational product (IP) formulation.

  8. History of cancer:

    • Participants who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the participant is in complete remission and curative therapy was completed at least 12 months prior to the date informed consent is obtained
    • Participants who have had other malignancies are eligible provided that the participant is in complete remission and curative therapy was completed at least 5 years prior to the date informed consent is obtained
  9. A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy
  10. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
  11. Current active liver disease, except for chronic stable hepatitis B and C, or other stable chronic liver disease are acceptable if participant otherwise meets eligibility criteria.
  12. Any medical condition that requires chronic treatment with chronic anti-coagulation, chronic aspirin or anti-platelet therapy.
  13. Use of anticoagulants within 4 weeks prior to randomization in to the study.
  14. Use of non-steroidal anti-inflammatory drugs (NSAIDs) within 72 hours before or aspirin within 7 days of randomization, or longer or as judged by the Investigator.
  15. Use of chronic (i.e. >4 weeks) immunosuppressive medication within 3 months prior to the date informed consent is obtained.
  16. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
  17. Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
  18. Previously received benralizumab (MEDI-563). Participants that participated in other studies with benralizumab but have been confirmed to have received placebo are eligible.
  19. Receipt of live attenuated vaccines 30 days prior to the date of randomization. Receipt of inactive/killed vaccinations (e.g. inactive influenza) is allowed provided they are not administered within 1 week before/after any IP administration.
  20. Receipt of bronchial thermoplasty in the last 24 months prior to Visit 1
  21. Receipt of any investigational non-biologic within 22 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
  22. Currently pregnant, breastfeeding or lactating women.
  23. Radiological findings suggestive of a respiratory disease other than asthma that is contributing to the participant's respiratory symptoms.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Canada,   Denmark,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03953300
Other Study ID Numbers  ICMJE D3250C00059
2018-003391-13 ( EudraCT Number )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mario Castro, MD University of Kansas School of Medicine 3901 Rainbow Blvd. Kansas City, KS 66160, United States of America (USA)
PRS Account AstraZeneca
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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