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Benralizumab Airway Remodeling Study in Severe Eosinophilic Asthmatics (CHINOOK)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03953300
Recruitment Status : Recruiting
First Posted : May 16, 2019
Last Update Posted : November 6, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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

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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 : May 27, 2022
Estimated Study Completion Date : May 27, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

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.




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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Able to understand and give written informed consent and has signed a written informed consent form (ICF) approved by the Investigator's Institutional Review Board (IRB)/Ethics Committee (EC), prior to conducting any study related procedures (including withholding of any asthma medications required for procedures).
  2. Male or female aged 18 through 65 years at the time of Visit 1.
  3. 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.
  4. 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 subject 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.
  5. Morning pre-BD FEV1 ≥50 to <80% of predicted normal value (PNV) and ≥1 liter (L) at Visit 2.
  6. A blood eosinophil count of: ≥300 cells/µL during screening at Visit 1 or Visit 2 or ≥150 to <300 cells/µL during screening at Visit 1 or Visit 2 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.
  7. Weight of ≥40 kg.
  8. Negative serum pregnancy test for female subjects of childbearing potential at Visit 1.
  9. Negative urine pregnancy test in female subjects of childbearing potential prior to randomization and administration of IP.
  10. Women of childbearing potential (WOCBP) must use one highly effective form of birth control. A highly effective method of contraception is defined as one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Women of childbearing potential who are sexually active with a non-sterilized male partner must agree to use one highly effective methods of birth control, as defined above, from enrolment throughout the study and to within 16 weeks after last dose of study drug.
  11. Acceptable inhaler technique, as judged by the Investigator.
  12. Asthma control questionnaire (ACQ-6) >1.5.
  13. Compliance with inhaled asthma maintenance medication >70% (calculated in the period from Visit 2 to Visit 3). The screening/run-in period may be extended to accommodate this criterion.
  14. Fewer than 12 exacerbations within the 6 months prior to Visit 3.

Exclusion Criteria:

  1. Clinically important pulmonary disease other than asthma or subjects 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 disorder that in the opinion of the Investigator can affect the safety of the subject during the study, influence the findings of the studies or their interpretations, or impede the subject'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. Subjects who use e-cigarettes or smoke marijuana will also be excluded from the study.
  6. Alcohol or drug abuse (past or present) or any conditions associated with poor compliance.
  7. Subjects who are scheduled to be admitted to hospital or undergo inpatient surgery during the study.
  8. History of anaphylaxis to any biologic therapy.
  9. Known history of allergy or reaction to any component of the investigational product (IP) formulation.
  10. History of cancer:

    • Subjects 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 subject is in complete remission and curative therapy was completed at least 12 months prior to the date informed consent is obtained
    • Subjects who have had other malignancies are eligible provided that the subject is in complete remission and curative therapy was completed at least 5 years prior to the date informed consent is obtained
  11. 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
  12. A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
  13. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to enroll.
  14. Any medical condition that requires chronic treatment with chronic anti-coagulation, chronic aspirin or anti-platelet therapy.
  15. Use of anticoagulants within 4 weeks prior to randomization in to the study.
  16. 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.
  17. Use of immunosuppressive medication within 3 months prior to the date informed consent is obtained.
  18. Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
  19. 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.
  20. Previously received benralizumab (MEDI-563).
  21. 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.
  22. Change to allergen immunotherapy or new allergen immunotherapy within 30 days prior to the date of informed consent and anticipated changes in immunotherapy during the study.
  23. Receipt of bronchial thermoplasty in the last 24 months prior to Visit 1
  24. Participation in an interventional clinical study during the past 3 months or subjects previously randomized into this study. If it is documented that the subject was known to be on placebo treatment of a completed study, then a 3-month period is not required.
  25. Receipt of any investigational non-biologic within 30 days or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
  26. Any clinically significant abnormal findings, which in the opinion of the Investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject's ability to complete the entire duration of the study.
  27. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times the upper limit of normal (ULN), confirmed by repeated testing during the screening period.
  28. Currently pregnant, breastfeeding or lactating women.
  29. Blood draws of 100 mL or more within 45 days prior to enrolment in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03953300


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

  Show 32 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Mario Castro, MD University of Kansas School of Medicine 3901 Rainbow Blvd. Kansas City, KS 66160, United States of America (USA)

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03953300     History of Changes
Other Study ID Numbers: D3250C00059
2018-003391-13 ( EudraCT Number )
First Posted: May 16, 2019    Key Record Dates
Last Update Posted: November 6, 2019
Last Verified: November 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Asthma
Eosinophilic Asthma
Lung Diseases
Inhaled Corticosteroids
ICS
LABA
benralizumab
Fasenra
mechanism of action
remodeling
Additional relevant MeSH terms:
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Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Benralizumab
Anti-Asthmatic Agents
Respiratory System Agents