Clinical trial NCT02075255: Efficacy and Safety Study of Benralizumab to Reduce OCS Use in Patients With Uncontrolled Asthma on High Dose Inhaled Corticosteroid Plus LABA and Chronic OCS Therapy
Official title: A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) to Reduce Oral Corticosteroid Use in Patients With Uncontrolled Asthma on High Dose Inhaled Corticosteroid Plus Long-acting β2 Agonist and Chronic Oral Corticosteroid Therapy (ZONDA)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive Lung Diseases, OCS, Oral Corticosteroids
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2014-03-03
Enrollment: 220
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to confirm if benralizumab can reduce the use of maintenance OCS in systemic corticosteroid dependent patients with severe refractory asthma with elevated eosinophils.


Eligibility criteria: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures.
2. Female and male aged from 18 to 75 years, inclusively.
3. History of physician-diagnosed asthma requiring treatment with medium dose ICS and LABA.
4. Elevated level of peripheral blood eosinophil
5. Documented treatment with high-dose ICS and LABA for at least 6 months prior to Visit 1
6. Chronic oral corticosteroid therapy for at least 6 continuous months directly preceding Visit 1. Subjects must be on doses equivalent to 7.5 - 40 mg/day of prednisolone/prednisone at Visit 1 and be on a stable dose for at least 2 weeks prior to randomization. Patients must agree to switch to study required prednisone/prednisolone as their oral corticosteroid for the duration of the study.
7. Patients with documented failures of OCS reduction within 6 months prior to Visit 1 will not be required to proceed through the dose optimization phase during run-in.
8. Morning pre-bronchodilator (Pre-BD) FEV1 of \<80% predicted
9. Evidence of asthma as documented by either:

   Airway reversibility (FEV1 ≥12% and 200 mL) demonstrated at Visit 1, Visit 2, or Visit 3 using the Maximum Post-bronchodilator Procedure OR Documented reversibility in the previous 24 months prior to Visit 1 OR Airway hyperresponsiveness (PC20 FEV1 methacholine concentration ≤8mg/mL) documented in the previous 12 months prior to planned date of randomization OR Airflow variability in clinic FEV1 ≥20% between 2 consecutive clinic visits documented in the 12 months prior to the planned date of randomization (FEV1 recorded during an exacerbation should not be considered for this criterion).

   All patients must have reversibility testing performed before randomization to establish a baseline characteristic.

   If patients do not demonstrate airway reversibility at either Visit 1 or Visit 2 and this is needed to qualify the patient for randomization, the site should reiterate the need to withhold short- and long-acting bronchodilators prior to Visit 3 in an effort to meet this inclusion criterion.
10. At least 1 documented asthma exacerbation in the previous 12 months prior to the date informed consent is obtained
11. Optimized OCS dose reached at least 2 weeks prior to randomization
12. Additional asthma controller medication must not have been initiated during run in/optimization period (not applicable for management of exacerbations during screening/ run in optimization phase)
13. At least 70% compliance with OCS use
14. At least 70% compliance with usual asthma controller ICS-LABA
15. Minimum 70% (i.e. 10 of 14 days) compliance with asthma daily diary (morning and evening diary)

Exclusion criteria:

1. Clinically important pulmonary disease other than asthma or ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
2. Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 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
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. Any clinically significant abnormal findings in physical examination, vital signs, hematology, clinical chemistry, or urinalysis during run-in/optimization 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
5. History of life-threatening asthma
6. Asthma control reached at an OCS dose of ≤5mg during run-in/OCS optimization phase
7. Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS dose reduction criteria at Visit 5
8. Receipt of oral corticosteroids, other than prednisone or prednisolone, as the maintenance oral steroid controller for asthma symptoms from Visit 1 and throughout the study.
9. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the upper limit of normal (ULN) confirmed during screening period

Primary outcomes:
measure: Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control
timeFrame: Week 28
Secondary outcomes:
measure: Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control
timeFrame: Week 28
measure: Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL
timeFrame: Week 28
measure: The Percentage of Patients With ≥50% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control
timeFrame: Week 28
measure: The Proportion of Eligible Patients With ≥100% Reduction in Average Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control
timeFrame: Week 28
measure: The Proportion of Patients With ≤5.0 mg Reduction on Daily OCS Dose at Visit 14 Compared With Baseline Dose at Visit 6, While Maintaining Asthma Control.
timeFrame: Week 28
measure: The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control
timeFrame: Week 28
measure: Number and Percentage of Patients With ≥1 Asthma Exacerbation
timeFrame: Immediately following the randomisation through Study Week 28
measure: Time to the First Asthma Exacerbation
timeFrame: The time from randomisation to the date of first asthma exacerbation over 28 weeks
measure: Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit
timeFrame: The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks.
measure: The Annualized Rate of Asthma Exacerbation
timeFrame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
measure: The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization
timeFrame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
measure: Number of Days in Hospital Due to Asthma
timeFrame: The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
measure: Change From Baseline to Week 28 in Pre-bronchodilator FEV1
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in Asthma Symptom Scores (Total)
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime)
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime)
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in Rescue Medication Use
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow)
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow)
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication
timeFrame: Change from baseline at week 28
measure: Change From Baseline to Week 28 in ACQ-6
timeFrame: Change from baseline at week 28
measure: ACQ-6 Responders (Improvement) at Week 28
timeFrame: Week 28
measure: Change From Baseline at Week 28 in AQLQ(S)+12 (Overall)
timeFrame: Change from baseline at week 28
measure: AQLQ(s)+12 Responders (Improvement) at Week 28
timeFrame: Week 28
measure: Extent of Exposure
timeFrame: From first dose to Week 24
measure: Serum Concentration of Benralizumab
timeFrame: Pre-first dose to Week 36
measure: Anti-drug Antibody Response
timeFrame: From baseline to follow-up Week 36
measure: Percent Change From Baseline in Blood Eosinophil Counts
timeFrame: Change from baseline at Week 28
measure: Total Lung Capacity
timeFrame: From baseline to Week 28
measure: Residual Volume
timeFrame: From baseline to Week 28
measure: Vital Capacity
timeFrame: From baseline to Week 28
measure: Functional Residual Capacity
timeFrame: From baseline to Week 28
measure: Inspiratory Capacity
timeFrame: From baseline to Week 28
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Centennial
country: United States
facility: Research Site
state: Colorado
city: Denver
country: United States
facility: Research Site
state: Colorado
city: Hialeah
country: United States
facility: Research Site
state: Florida
city: Hialeah
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
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state: Florida
city: Orlando
country: United States
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state: Florida
city: Iowa City
country: United States
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state: Iowa
city: Fort Mitchell
country: United States
facility: Research Site
state: Kentucky
city: Rochester
country: United States
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state: Minnesota
city: Bronx
country: United States
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state: New York
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Middleburg Heights
country: United States
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state: Ohio
city: Oklahoma City
country: United States
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state: Oklahoma
city: Philadelphia
country: United States
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state: Pennsylvania
city: Pittsburgh
country: United States
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state: Pennsylvania
city: Mount Pleasant
country: United States
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state: South Carolina
city: Madison
country: United States
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state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Research Site
city: Caba
country: Argentina
facility: Research Site
city: Florida
country: Argentina
facility: Research Site
city: Mendoza
country: Argentina
facility: Research Site
city: Kozloduy
country: Bulgaria
facility: Research Site
city: Pazardzhik
country: Bulgaria
facility: Research Site
city: Petrich
country: Bulgaria
facility: Research Site
city: Ruse
country: Bulgaria
facility: Research Site
city: Samokov
country: Bulgaria
facility: Research Site
city: Vratsa
country: Bulgaria
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Hamilton
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Quillota
country: Chile
facility: Research Site
city: Rancagua
country: Chile
facility: Research Site
city: Santiago
country: Chile
facility: Research Site
city: Talcahuano
country: Chile
facility: Research Site
city: Talca
country: Chile
facility: Research Site
city: Valparaiso
country: Chile
facility: Research Site
city: Brest Cedex 2
country: France
facility: Research Site
city: Lyon Cedex 04
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Strasbourg Cedex
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Bamberg
country: Germany
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Freiburg
country: Germany
facility: Research Site
city: Grosshansdorf
country: Germany
facility: Research Site
city: Hannover
country: Germany
facility: Research Site
city: Leipzig
country: Germany
facility: Research Site
city: Mainz
country: Germany
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Suwon-si
country: Korea, Republic of
facility: Research Site
city: Bydgoszcz
country: Poland
facility: Research Site
city: Karczew
country: Poland
facility: Research Site
city: Koszalin
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Lubin
country: Poland
facility: Research Site
city: Szczecin
country: Poland
facility: Research Site
city: Tarnów
country: Poland
facility: Research Site
city: Trzebnica
country: Poland
facility: Research Site
city: Wroclaw
country: Poland
facility: Research Site
city: Wrocław
country: Poland
facility: Research Site
city: Łódź
country: Poland
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Adana
country: Turkey
facility: Research Site
city: Ankara
country: Turkey
facility: Research Site
city: Bursa
country: Turkey
facility: Research Site
city: Istanbul
country: Turkey
facility: Research Site
city: İstanbul
country: Turkey
facility: Research Site
city: Dnipropetrovsk
country: Ukraine
facility: Research Site
city: Ivano-Frankivsk
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kharkiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Kyiv
country: Ukraine
facility: Research Site
city: Vinnytsia
country: Ukraine
facility: Research Site
Study officials:
affiliation: St Joseph's Healthcare Hamilton Firestone Institute for Respiratory Health 50 Charlton Avenue East Hamilton
name: Parameswaran Nair, MD,PhD,FRCP,FRCPC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, Barker P, Sproule S, Ponnarambil S, Goldman M; ZONDA Trial Investigators. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N Engl J Med. 2017 Jun 22;376(25):2448-2458. doi: 10.1056/NEJMoa1703501. Epub 2017 May 22.
citation: Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, Jison M, Brooks CL, Papeleu P, Katial R. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. Adv Ther. 2022 May;39(5):2065-2084. doi: 10.1007/s12325-022-02098-1. Epub 2022 Mar 14.
citation: Menzies-Gow A, Corren J, Bel EH, Maspero J, Heaney LG, Gurnell M, Wessman P, Martin UJ, Siddiqui S, Garcia Gil E. Corticosteroid tapering with benralizumab treatment for eosinophilic asthma: PONENTE Trial. ERJ Open Res. 2019 Sep 25;5(3):00009-2019. doi: 10.1183/23120541.00009-2019. eCollection 2019 Jul.
citation: Chupp G, Lugogo NL, Kline JN, Ferguson GT, Hirsch I, Goldman M, Zangrilli JG, Trudo F. Rapid onset of effect of benralizumab on morning peak expiratory flow in severe, uncontrolled asthma. Ann Allergy Asthma Immunol. 2019 May;122(5):478-485. doi: 10.1016/j.anai.2019.02.016. Epub 2019 Feb 23.