A Study to Evaluate the Onset of Effect and Time Course of Change in Lung Function With Benralizumab in Severe, Uncontrolled Asthma Patients With Eosinophilic Inflammation
Condition: Asthma
MeSH terms: Asthma; Inflammation
Intervention: Benralizumab; Placebo
Intervention description: Benralizumab administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days); Placebo administered subcutaneously at Visit 1 (Day 0), Visit 8 (Day28 +/- 3 days) and Visit 9 (Day 56 +/- 3 days)
Intervention MeSH terms: Benralizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 233.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases

Summary:

      The purpose of this study is to investigate the onset and maintenance of effect of
      benralizumab on lung function, blood eosinophils, asthma control metrics and quality of life
      during 12-week treatment in patients with uncontrolled, severe asthma with eosinophilic
      inflammation. A subset of patients will take part in body plethysmography substudy to further
      investigate the effect on lung function.
    

Eligibility criteria:

        Inclusion criteria

          1. Written informed consent for study participation must be obtained prior to any study
             related procedures being performed and according to international guidelines and/or
             applicable European Union (EU) guidelines.

          2. Female and male aged 18 to 75 years inclusively at the time of Visit 1

          3. Documented current treatment with ICS and LABA for at least 30 days prior to Visit 1.
             The ICS and LABA can be parts of a combination product or given by separate inhalers.
             The ICS dose must be greater than or equal to 500 μg/day fluticasone propionate dry
             powder formulation or equivalent daily. Additional asthma controller medications, eg,
             oral corticosteroids, long-acting antimuscarinics (LAMAs), LTRAs, theophylline etc.
             are allowed if they have been used for at least 30 days prior to Visit 1

          4. History of at least 2 asthma exacerbations that required treatment with systemic
             corticosteroids (intramuscular (IM), intravenous (IV), or oral) in the 12 months prior
             to Visit 1. For patients receiving corticosteroids as a maintenance therapy, the
             corticosteroid treatment for the exacerbation is defined as a temporary increase of
             their maintenance dose.

          5. Pre-bronchodilator (pre-BD) FEV1 of < 80% predicted at Visit 2 or Visit 3

          6. ACQ-6 score ≥1.5 at Visit 1

          7. Evidence of asthma as documented by airway reversibility (FEV1 ≥12% and 200 ml)
             demonstrated at Visit 1, Visit 2 or Visit 3. For patients entering the body
             plethysmography sub-study, reversibility must be demonstrated at Visit 1 or at Visit 2
             only

          8. Peripheral blood eosinophil count of ≥300 cells/μL assessed by central lab at Visit 1

          9. Women of childbearing potential (WOCBP) must use an effective form of birth control
             confirmed by the Investigator. WOCBP must also have negative serum pregnancy test
             result on Visit 1.

             Women not of childbearing potential are defined as women who are either permanently
             sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who
             are postmenopausal. Women will be considered postmenopausal if they have been
             amenorrheic for 12 months prior to the planned date of randomization without an
             alternative medical cause. The following agespecific requirements apply:

               -  Women <50 years old are considered postmenopausal if they have been amenorrheic
                  for 12 months or more following cessation of exogenous hormonal treatment and
                  follicle stimulating hormone (FSH) levels in the postmenopausal range.

               -  Women ≥50 years old are considered postmenopausal if they have been amenorrheic
                  for 12 months or more following cessation of all exogenous hormonal treatment.

         10. All male patients who are sexually active must agree to use a double barrier method of
             contraception (condom with spermicide) from the first dose of IP until 16 weeks after
             their last dose

         11. Weight of ≥40 kg

        Additional inclusion criteria applicable for the Body Plethysmography substudy 1.Residual
        volume ≥125% of predicted at Visit 3.

        Inclusion criteria at randomization visit

          1. At least 1 of the following within 7 days prior to randomization:

               -  Daytime or nighttime asthma symptoms for 2 or more days;

               -  Rescue SABA use for 2 or more days;

               -  Nighttime awakenings due to asthma at least 1 night during the 7-day period

          2. ACQ >0.75 at Visit 4 prior to randomization.

          3. A negative urine pregnancy test in WOCBP prior to administration of IP

        Exclusion criteria

          1. Clinically important pulmonary disease other than asthma (eg, active lung infection,
             COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome
             associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary
             ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other
             than asthma, that are associated with elevated peripheral eosinophil counts (eg,
             allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome,
             hypereosinophilic syndrome)

          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. Acute upper or lower respiratory infections requiring antibiotics or antiviral
             medication within 30 days prior to the date informed consent is obtained or during the
             screening/run-in period

          4. An upper respiratory tract infection or an asthma exacerbation that required treatment
             with systemic corticosteroids or an increase in regular maintenance dose of OCS during
             the screening/run-in period prior to randomization Visit 4

          5. Any disorder, including, but not limited to, cardiovascular, gastrointestinal,
             hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic,
             haematological, psychiatric, or major physical impairment that is not stable in the
             opinion of the Investigator and could:

               -  Affect the safety of the patient throughout the study

               -  Influence the findings of the studies or their interpretations

               -  Impede the patient's ability to complete the entire duration of study

          6. Known history of allergy or reaction to any component of the investigational product
             formulation

          7. History of anaphylaxis to any biologic therapy

          8. History of Guillain-Barré syndrome

          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. Any clinically significant abnormal findings in physical examination, vital signs,
             hematology, clinical chemistry, or urinalysis during screening period, which in the
             opinion of the Investigator, may put the patient at risk because of his/her
             participation in the study, or may influence the results of the study, or the
             patient's ability to complete entire duration of the study

         11. Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality
             obtained during the screening/run-in period, which in the opinion of the Investigator
             may put the patient at risk or interfere with study assessments

         12. History of alcohol or drug abuse within 12 months prior to the date informed consent
             is obtained

         13. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a
             positive medical history for hepatitis B or C. Patients with a history of hepatitis B
             vaccination without history of hepatitis B are allowed to enroll

         14. A history of known immunodeficiency disorder including a positive human
             immunodeficiency virus (HIV) test

         15. Current smokers or former smokers with a smoking history of ≥10 pack years. A former
             smoker is defined as a patient who quit smoking at least 6 months prior to Visit 1

         16. Current malignancy, or history of malignancy, except for:

               -  Patients 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
                  patient is in remission and curative therapy was completed at least 12 months
                  prior to the date informed consent was obtained.

               -  Patients who have had other malignancies are eligible provided that the patient
                  is in remission and curative therapy was completed at least 5 years prior to the
                  date informed consent was obtained.

         17. Use of immunosuppressive medication (including but not limited to: oral
             corticosteroids [for reasons other than asthma], methotrexate, troleandomycin,
             cyclosporine, azathioprine, intramuscular long-acting depot corticosteroids or any
             experimental anti-inflammatory therapy) within 3 months prior to the date informed
             consent

         18. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥1.5 times
             the upper limit of normal (ULN) confirmed during screening period

         19. Receipt of immunoglobulin or blood products within 30 days prior to the date informed
             consent is obtained

         20. Receipt of any marketed (eg, omalizumab, mepolizumab etc.) or investigational biologic
             within 4 months or 5 half-lives prior to the date informed consent is obtained,
             whichever is longer

         21. Receipt of live attenuated vaccines 30 days prior to the date of randomization

         22. Receipt of any investigational medication within 30 days or 5 half-lives prior to
             randomization, whichever is longer

         23. Previously received benralizumab (MEDI-563)

         24. Planned surgical procedures during the conduct of the study

         25. Currently breastfeeding or lactating women

         26. Previous randomization in the present study

         27. Concurrent enrolment in another interventional or post-authorization safety study
             (PASS).

         28. AstraZeneca staff involved in the planning and/or conduct of the study

         29. Employees of the study center or any other individuals involved with the conduct of
             the study or immediate family members of such individuals

        Exclusion criteria at randomization Visit 4

        1. Greater than/equal to 20% change in mean Pre BD FEV1 value at randomization Visit 4 from
        the mean pre BD FEV1 calculated from the pre BD FEV1 recorded at Visit 2 and Visit 3