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

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ClinicalTrials.gov Identifier: NCT03170271
Recruitment Status : Active, not recruiting
First Posted : May 31, 2017
Last Update Posted : June 24, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Brief 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.

Condition or disease Intervention/treatment Phase
Asthma Drug: Benralizumab (Medi-563) Drug: Placebo Phase 3

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 659 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3b Study to Evaluate the Safety and Efficacy of Benralizumab 30 mg sc in Patients With Severe Asthma Uncontrolled on Standard of Care Treatment
Actual Study Start Date : July 7, 2017
Estimated Primary Completion Date : September 12, 2019
Estimated Study Completion Date : September 24, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

Arm Intervention/treatment
Experimental: Benralizumab (Medi-563)
Benralizumab (Medi563) Administered subcutaneously 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).
Drug: Benralizumab (Medi-563)
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 Comparator: Placebo
Administered subcutaneously at Visit 4 (day 0), Visit 6 (day 28 +/- 3 days), Visit 7 (day 56 +/- 3 days) and Visit 9 (day 112 +/- 3 days)
Drug: Placebo
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)




Primary Outcome Measures :
  1. Effect of benralizumab on the rate of asthma exacerbations and the annualized rate of asthma exacerbations between benralizumab and placebo. [ Time Frame: 24 weeks after start of dosing. ]
    The annualized rate of asthma exacerbations between benralizumab and placebo.


Secondary Outcome Measures :
  1. Effect of benralizumab on patient-reported disease specific quality of life - Saint George Respiratory Questionnaire (SGRQ) [ Time Frame: Baseline (Visit 4) to the end of treatment (EOT; Day 168/Week 24) ]
    The change from baseline in Saint George Respiratory Questionnaire (SGRQ) to the end of treatment. The absolute range for the total and each sub-scale is 0-100 expressed as a %. A higher score indicates worse outcomes.


Other Outcome Measures:
  1. Number of adapted GINA step category changes. [ Time Frame: Reported from the first background medication taper visit 15 of the open label extension through to the end of study visit 27. Time Frame = 48 weeks (Visit 15 (Week 32) to the End of Study Visit 27 (Week 80)). ]
    To assess the potential for benralizumab treated patients to reduce their standard of care asthma controller regimen while maintaining asthma control. Number of adapted GINA step category changes.

  2. Change in continuous asthma efficacy measures [ Time Frame: 48 weeks (visit 15 (Week 32) to the End of Study Visit 27 (Week 80)). ]
    Change in St Georges Respiratory Questionnaire (SGRQ) score. The absolute range for the total and each sub-scale is 0-100 expressed as a %. A higher score indicates worse outcomes.

  3. Change in continuous asthma efficacy measures [ Time Frame: 48 weeks (Visit 15 (Week 32) to the End of Study Visit 27 (Week 80)). ]
    Change in Asthma Control Questionnaire-6 (ACQ6). The absolute range for the ACQ6 score is 0-6 with higher scores indicating a worse outcome.

  4. Number of Clinically significant asthma exacerbations [ Time Frame: Reported from the first background medication taper visit 15 of the open label extension through to the end of study visit 27 (Visit 15 (week 32) to the End of Study Visit (week 80)). ]
    Clinically significant asthma exacerbations



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 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03170271


  Show 197 Study Locations
Sponsors and Collaborators
AstraZeneca
Investigators
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Principal Investigator: Brad Goodman, MD Aero Allergy Research Lab of Savannah
Principal Investigator: Vinay Sikand, MD Sikand Institute of Pulmonary Research
Principal Investigator: Willaim Cherry, MD Riverside Medical Center

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03170271     History of Changes
Other Study ID Numbers: D3250C00045
2017-001040-35 ( EudraCT Number )
First Posted: May 31, 2017    Key Record Dates
Last Update Posted: June 24, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by AstraZeneca:
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
Additional relevant MeSH terms:
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Benralizumab
Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Anti-Asthmatic Agents
Respiratory System Agents