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

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03170271
Recruitment Status : Active, not recruiting
First Posted : May 31, 2017
Last Update Posted : September 22, 2020
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
Actual Primary Completion Date : September 25, 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. The annualized rate of asthma exacerbations between benralizumab and placebo (treatment period 24 weeks) [ Time Frame: 24 weeks after start of dosing. ]
    Exacerbation rate ratio (benralizumab vs. placebo) over the 24 week treatment period.


Secondary Outcome Measures :
  1. The change from baseline (Visit 4) in SGRQ to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24) ]

    The difference in change from baseline in Saint George Respiratory Questionnaire (SGRQ) between benralizumab and placebo to the end of treatment.

    The SGRQ comprises 50-items assessing the health status of patients with airway obstruction diseases. The total score is expressed as a % of overall impairment, in which 100 represent the worst possible health status and 0 indicates the best possible health status.


  2. The change from baseline (Visit 4) in forced expiratory volume in first second (FEV1) over the treatment period (up to and including Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24) ]

    Difference in change from baseline in forced expiratory volume in 1 second (FEV1) between benralizumab and placebo to the end of treatment.

    FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration.


  3. The change from baseline (Visit 4) in Asthma Control Questionnaire 6 (ACQ6) to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24) ]

    Difference in change from baseline in Asthma Control Questionnaire 6 (ACQ-6) between benralizumab and placebo to the end of treatment.

    The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses.


  4. Time to first asthma exacerbation (treatment period 24 weeks) [ Time Frame: Treatment period, 24 weeks ]
    Time to the first occurrence of asthma exacerbation post randomisation.

  5. The change from run-in baseline morning PEF to the EOT (Day 168/Week 24) [ Time Frame: From run-in baseline to EOT (Day 168/Week 24) ]

    Difference in change from baseline in morning PEF between Benralizumab and placebo to the end of treatment.

    Home PEF testing will be performed by the subject in the morning upon awakening using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means.


  6. The change from baseline (Visit 4) Social Functioning (SF) 36v2 to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24) ]

    Difference in change from baseline in SF-36v2 between benralizumab and placebo to the end of treatment.

    SF-36v2 is a 36-item, self report survey of functional health and well-being, with 1-week recall period. Responses to 35 of the 36 items are used to compute an 8-domain profile of functional health and well-being scores. The remaining item compares the patient's current state of health to 1 year ago but is not used to calculate domain scores.


  7. The change from baseline (Visit 4) in PGI-S to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24) ]

    Difference in change from baseline in PGI-S between benralizumab and placebo to the end of treatment.

    The PGI-S is a single question asking the patient to rate the overall severity of their symptoms using a 6-point categorical response scale from 0 to 5 where 0=no symptoms and 5=very severe symptoms. Higher scores indicate a worse outcome. Improvement was defined as a PGI-S at EOT (Week 24) better than PGI-S at baseline. Important improvement was defined as PGI-S at baseline = moderate, severe or very severe symptoms shifting to PGI-S at EOT = no symptoms, very mild or mild symptoms.

    Comparisons of odds of Improvement and odds of Important Improvement via odds ratios (benralizumab vs. placebo) over the 24 week treatment period were also conducted.


  8. The degree of change reported by the patient (PGI-C) and Investigator (CGI-C) expressed as a proportion of each of the 7 possible responses to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24) ]

    Comparison of odds of response via odds ratio (benralizumab vs. placebo) over the 24 week treatment period.

    The CGI-C and the PGI-C are used to evaluate the overall response to treatment, and the assessments use a 7-point rating scale ranging from 1 (Very Much Improved) to 7 (Very Much Worse).


  9. The degree of change reported by the patient in their predominant symptom (Predominant Symptom and Impairment Assessment; PSIA) to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 4) to the EOT (Day 168/Week 24 ) ]

    Difference in change from baseline in PSIA score between benralizumab and placebo to the end of treatment.

    PSIA assesses the degree to which patient-stated bothersome symptoms and impairments change over time. This is achieved by generating an individualized profile of symptoms and impairments ranked in order of importance by the patient (to be performed at Week 0). The symptoms assessed are shortness of breath, wheeze, cough, chest tightness, difficulty sleeping due to asthma, limited typical daily activities, limited physical intense activities, and sensitivity to environmental condition. Post-baseline, patients report the severity of symptom/impairment over the previous 7 days on the individualised PSIA using an 11-point numeric rating scale from 0 (did not experience) to 10 (worst I can imagine).


  10. The change from baseline (Visit 3) in the sino-nasal outcome test (SNOT-22) score to the EOT (Day 168/Week 24) [ Time Frame: From baseline (Visit 3) to the EOT (Day 168/Week 24) ]

    Difference in change from baseline in SNOT-22 score between benralizumab and placebo to the end of treatment.

    SNOT-22 assesses the health status and quality of life of patients with chronic rhinosinusitis with nasal polyposis The 22-questions are scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes)



Other Outcome Measures:
  1. Number of reductions in asthma controller medications from Visit 15 to the end of study (EOS) Visit 27 (Day 560/Week 80) [ Time Frame: From baseline at Visit 15 to the End of Study Visit 27 (Day 560/Week 80) ]
    Reductions of asthma controller medication consider the following categories: LAMA, LTRA, LABA, xanthine, ICS dose [HD-ICS, MD-ICS, LD-ICS or anti-inflammatory reliever].

  2. Number of adapted GINA step category reductions from baseline at Visit 15 to the EOS Visit 27 [ Time Frame: From baseline at Visit 15 to the End of Study Visit 27 (Day 560/Week 80) ]
    For the purpose of this study, GINA steps have been adapted to ignore the fact that all patients will be treated with an add-on benralizumab, which is step 5 by convention (GINA 2020)



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


Locations
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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    
Other Study ID Numbers: D3250C00045
2017-001040-35 ( EudraCT Number )
First Posted: May 31, 2017    Key Record Dates
Last Update Posted: September 22, 2020
Last Verified: September 2020
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
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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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