A Study of the Safety and Effectiveness of Benralizumab to Treat Patients With Severe Uncontrolled Asthma.
Condition: Asthma
MeSH terms: Asthma
Intervention: Benralizumab (Medi-563); Placebo
Intervention description: 30mg Benralizumab administered as a subcutaneous injection at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days) In the open label ANDHI IP sub study, all patients will receive benralizumab subcutaneously at Day 168 (Week 24), Day 196 (Week 28), Day 224 (Week 32), Day 280 (Week 40), Day 336 (Week 48), Day 392 (Week 56), Day 448 (Week 64), and Day 504 (Week 72).; Placebo administered as a subcutaneous injection at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)
Intervention MeSH terms: Benralizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 660.0
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; Additional relevant MeSH terms:; Asthma; Inflammation; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Pathologic Processes

Summary:

      The purpose of this study is to investigate the effect of benralizumab on the rate of asthma
      exacerbations, patient reported quality of life and lung function during the 24-week
      treatment in patients with uncontrolled, severe asthma with an eosinophilic phenotype. A
      subset of patients will be assessed for their ongoing chronic rhinosinusitis with nasal
      polyps. The study design has been updated to include a 56-week open label ANDHI in Practice
      (ANDHI IP) sub study upon the completion of the 24-week double-blind period of the ANDHI
      study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female and male patients aged 18 to 75 years inclusively at the time of Visit 1 with a
             history of physician-diagnosed asthma requiring treatment with medium-to-high dose
             Inhaled Corticosteroids (ICS) plus asthma controller, for at least 12 months prior to
             Visit 1.

          2. Documented current treatment with high daily doses of ICS plus at least one other
             asthma controller for at least 3 months prior to Visit 1.

          3. History of at least 2 asthma exacerbations while on ICS plus another asthma controller
             that required treatment with systemic corticosteroids (IM, IV, or oral) in the 12
             months prior to Visit 1.

          4. ACQ6 score ≥1.5 at Visit 1.

          5. Screening pre-bronchodilator (pre-BD) FEV1 of <80% predicted at Visit 2.

          6. Excessive variability in lung function by satisfying ≥ 1 of the following criteria:

               1. Airway reversibility (FEV1 ≥12%) using a short-acting bronchodilator demonstrated
                  at Visit 2 or Visit 3.

               2. Airway reversibility to short-acting bronchodilator (FEV1 ≥12%) documented during
                  the 12 months prior to enrolment Visit 1.

               3. Daily diurnal peak flow variability of >10% when averaged over 7 continuous days
                  during the study run-in period

               4. An increase in FEV1 of ≥12% and 200 mL after a therapeutic trial of systemic
                  corticosteroid (eg, OCS), given outside of an asthma exacerbation, documented in
                  the 12 months prior enrolment Visit 1.

               5. Airway hyper-responsiveness (methacholine: PC20 of <8 mg/mL, histamine: PD20 of
                  <7.8 μmol, mannitol: decrease in FEV1 as per the labelled product instructions)
                  documented in the 24 months prior to randomization Visit 4.

          7. Peripheral blood eosinophil count either:

               -  300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2

        OR

        ≥150 to <300 cells/μL assessed by central laboratory at either Visit 1 or Visit 2, IF ≥1 of
        the following 5 clinical criteria (a to e) is met:

          1. Using maintenance OCS (daily or every other day OCS requirement in order to maintain
             asthma control; maximum total daily dose 20 mg prednisone or equivalent) at screening

          2. History of nasal polyposis

          3. Age of asthma onset ≥18 years

          4. Three or more documented exacerbations requiring systemic corticosteroid treatment
             during the 12 months prior to screening

          5. Pre-bronchodilator forced vital capacity <65% of predicted, as assessed at Visit 2
             (note that screening pre-BD FEV1 Inclusion Criterion #6 must still be satisfied)

        For inclusion in the open label ANDHI IP sub study patients should meet the following
        criteria:

          1. Patients study must have completed ANDHI EOT Visit 11.

          2. Written informed consent must also be obtained prior to any study related procedures
             being performed in the open label ANDHI IP sub study.

          3. Patients who have received any approved or investigational targeted biologic for the
             treatment of asthma (e.g. commercial mepolizumab, reslizumab, benralizumab) may be
             included if the last dose is ≥ 2 months of Visit 13.

        Exclusion Criteria:

          1. Clinically important pulmonary disease other than asthma

          2. Acute upper or lower respiratory infections within 30 days prior to the date informed
             consent.

          3. 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.

          4. History of alcohol or drug abuse within 12 months prior to the date informed consent
             is obtained.

          5. A history of known immunodeficiency disorder.

          6. Current smokers or former smokers with a smoking history of ≥10 pack years.

          7. Previously received benralizumab (MEDI-563).

          8. Receipt of any investigational medication as part of a research study within
             approximately 5 half-lives prior to randomization.

          9. Receipt of immunoglobulin or blood products within 30 days prior to the date informed
             consent is obtained.

         10. Receipt of live attenuated vaccines 30 days prior to the date of randomization; other
             types of vaccines are allowed.

         11. Concurrent enrolment in another interventional or post-authorization safety study

        Exclusion criteria for the open label ANDHI IP sub study:

        Patients should not enter the open label ANDHI IP sub study if any of the following
        exclusion criteria are fulfilled. Each exclusion criterion should be reviewed in all
        potential participants, including those who transition directly from the double-blind
        period and those with a delay between completing the EOT Visit 11 and the first open label
        visit (Visit 13).

          1. Patients who participated in the double-blind period but failed to complete the ANDHI
             EOT Visit 11. Patients who completed the ANDHI FU Visit 12 are not excluded from
             participation in the ANDHI IP sub study.

          2. Unable to commit to the monthly visits as required by the protocol, or unable to
             commit to undergoing protocol guided reductions in asthma therapy, as directed by the
             Investigator.

          3. Patients who experienced a severe or serious treatment-related AE during the
             double-blind period and, and those whom Investigator judges it is not in the patient's
             best interest to extend possible treatment with benralizumab.

          4. Approved or off-label use of systemic immunosuppressive medications within 3 months
             prior to the first open label visit (Visit 13). These include but are not limited to
             small molecules such as methotrexate, cyclosporine, azathioprine, and
             immunosuppressive/immunomodulating biologics such as tumour necrosis factor (TNF)
             blockers. Regular use of systemic OCS is also excluded except for the indication of
             asthma.

          5. Receipt of live attenuated vaccines 30 days prior to the first visit in the open label
             ANDHI IP sub study (Visit 13); other types of vaccines are allowed.

          6. Planned surgical procedures during the conduct of the study.

          7. Positive urine pregnancy test at Visit 13, or currently breastfeeding or lactating
             women.