A Study of the Safety and Effectiveness of Benralizumab to Treat Patients With Severe Uncontrolled Asthma.

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.

This is a Phase IIIb, randomized, double-blind, placebo controlled, parallel group study designed to evaluate the efficacy and the safety of repeat dosing of benralizumab 30 mg subcutaneous (sc) versus placebo on top of standard of care asthma therapy in patients with severe uncontrolled asthma. Approximately 630 patients with peripheral blood eosinophil counts ≥150 cells/μL will be randomized 2:1 to receive benralizumab 30 mg sc or matched placebo for 24 weeks.

After enrolment, eligible patients will enter an up to 42-day screening/run-in period. Patients who meet eligibility criteria will be randomized 2:1 on Day 0 to receive either benralizumab or placebo every 56 days (every 8 weeks) through Week 16, with end of treatment (EOT) at Day 168 (Week 24). At the completion of the 24-week doubleblind period of the ANDHI study, eligible patients in benralizumab and placebo arm may enter a 56-week open label period (ANDHI in Practice \[ANDHI IP\] substudy), in which concomitant asthma therapies will be tapered as directed by the protocol in those patients who achieve and maintain asthma control (defined as ACQ6 score \<1.5 and no clinically significant asthma exacerbations that required a burst of systemic corticosteroid or a hospitalization due to asthma between reduction visits) with add-on benralizumab.

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.