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Completed

NCT Number: 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

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.

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Key information

Conditions

Asthma Bronchial Diseases Hypersensitivity Hypersensitivity, Immediate Immune System Diseases Lung Diseases Lung Diseases, Obstructive Respiratory Hypersensitivity Respiratory Tract Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Research Site, Buenos Aires, Argentina

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Provision of informed consent prior to any study specific procedures.
  • Female and male aged from 18 to 75 years, inclusively.
  • History of physician-diagnosed asthma requiring treatment with medium dose ICS and LABA.
  • Elevated level of peripheral blood eosinophil
  • Documented treatment with high-dose ICS and LABA for at least 6 months prior to Visit 1
  • 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.
  • 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.
  • Morning pre-bronchodilator (Pre-BD) FEV1 of <80% predicted
  • 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.

  • At least 1 documented asthma exacerbation in the previous 12 months prior to the date informed consent is obtained
  • Optimized OCS dose reached at least 2 weeks prior to randomization
  • 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)
  • At least 70% compliance with OCS use
  • At least 70% compliance with usual asthma controller ICS-LABA
  • Minimum 70% (i.e. 10 of 14 days) compliance with asthma daily diary (morning and evening diary)

Exclusion criteria

  • 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.
  • 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
  • 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
  • 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
  • History of life-threatening asthma
  • Asthma control reached at an OCS dose of ≤5mg during run-in/OCS optimization phase
  • Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS dose reduction criteria at Visit 5
  • 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.
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the upper limit of normal (ULN) confirmed during screening period

Treatment and study plan

Benralizumab

Biological

Benralizumab administered subcutaneously every 4 weeks

Placebo

Biological

Placebo subcutaneously on study week 0 until study week 24 inclusive.

Primary outcomes

  1. Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control

    Time frame: Week 28

    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

Secondary outcomes

  1. Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control

    Time frame: Week 28

    Number and percentage of patients in different categories of percent reduction from baseline in final OCS dose.

  2. Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL

    Time frame: Week 28

    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

  3. 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

    Time frame: Week 28

    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

  4. 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

    Time frame: Week 28

    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose-final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

  5. 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.

    Time frame: Week 28

    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

  6. The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control

    Time frame: Week 28

    Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.

  7. Number and Percentage of Patients With ≥1 Asthma Exacerbation

    Time frame: Immediately following the randomisation through Study Week 28

    Number and percentage of patients with at least one post randomisation asthma exacerbation.

  8. Time to the First Asthma Exacerbation

    Time frame: The time from randomisation to the date of first asthma exacerbation over 28 weeks

    Time to the first occurrence of asthma exacerbation post randomisation

  9. Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit

    Time frame: The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks.

    Time to the first exacerbation requiring hospitalization or ER visit post randomisation

  10. The Annualized Rate of Asthma Exacerbation

    Time frame: 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

    The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator adjusted by the time of follow-up.

  11. The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization

    Time frame: 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

    The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator that are associated with an emergency room visit or a hospitalization adjusted by the time of follow-up.

  12. Number of Days in Hospital Due to Asthma

    Time frame: 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

    Number of days in hospital due to asthma, if none, 0 day is considered

  13. Change From Baseline to Week 28 in Pre-bronchodilator FEV1

    Time frame: Change from baseline at week 28

    Baseline is defined as the last non-missing value prior to the first dose of study treatment. Change from baseline to Week 28 in two treatment groups is compared to placebo group.

  14. Change From Baseline to Week 28 in Asthma Symptom Scores (Total)

    Time frame: Change from baseline at week 28

    Asthma symptoms during night time and daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma), and total asthma symptom score is the sum of the daytime and night time score (0 to 6). Lower score (0) is indicating better asthma symptom, while higher score (6) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.

  15. Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime)

    Time frame: Change from baseline at week 28

    Asthma symptoms during daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.

  16. Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime)

    Time frame: Change from baseline at week 28

    Asthma symptoms during night time are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.

  17. Change From Baseline to Week 28 in Rescue Medication Use

    Time frame: Change from baseline at week 28

    Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this will be considered as missing. The number of inhalations (puffs) per day will be calculated as follows: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of day inhaler puffs + 2 x [number of day nebulizer times].

  18. Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow)

    Time frame: Change from baseline at week 28

    Morning peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data.

  19. Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow)

    Time frame: Change from baseline at week 28

    Evening peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data

  20. Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication

    Time frame: Change from baseline at week 28

    Baseline is defined as the proportion of nights from the evening of study day -14 to the morning of study day 1.Each timepoint is calculated as bi-weekly proportions based on daily diary data. If more than 50% of data are missing in a 14 day period then this will be considered as missing.Proportion of nights with noctural awakenings is defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data.

  21. Change From Baseline to Week 28 in ACQ-6

    Time frame: Change from baseline at week 28

    ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.

  22. ACQ-6 Responders (Improvement) at Week 28

    Time frame: Week 28

    Improvement is defined as ACQ-6 (End of treatment - baseline) <= -0.5. No change is defined as ACQ-6 (End of treatment - baseline) >-0.5 and <0.5. Deterioration is defined as ACQ-6 (End of treatment - baseline) >= 0.5. ACQ-6 score is defined as the average of the first 6 items of the ACQ questionnaire on symptoms, activity limitations and rescue medication.Scores range from 0 (totally controlled) to 6 (severely uncontrolled). Baseline is defined as the last non-missing value prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable ACQ-6 at week 28 are considered non-responder.

  23. Change From Baseline at Week 28 in AQLQ(S)+12 (Overall)

    Time frame: Change from baseline at week 28

    AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of >=0.5 are considered clinically meaningful.

  24. AQLQ(s)+12 Responders (Improvement) at Week 28

    Time frame: Week 28

    AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. Improvement is defined as AQLQ(S)+12 (End of treatment - baseline)>=0.5. No change is defined as AQLQ(S)+12 (End of treatment - baseline) >-0.5 and <0.5. Deterioration is defined as AQLQ(S)+12 (End of treatment - baseline) <= -0.5. Baseline is defined as the last AQLQ(S)+12 score prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable score at week 28 are considered as non-responder.

  25. Extent of Exposure

    Time frame: From first dose to Week 24

    Duration of exposure from first dose date to last dose date.

  26. Serum Concentration of Benralizumab

    Time frame: Pre-first dose to Week 36

    Pre-dose serum concentrations at each visit

  27. Anti-drug Antibody Response

    Time frame: From baseline to follow-up Week 36

    Number and percentage of patients in different ADA response categories

  28. Percent Change From Baseline in Blood Eosinophil Counts

    Time frame: Change from baseline at Week 28

    Percent change from baseline in blood eosinophil counts at week 28

  29. Total Lung Capacity

    Time frame: From baseline to Week 28

    Change from baseline in total lung capacity

  30. Residual Volume

    Time frame: From baseline to Week 28

    Change from baseline in residual volume

  31. Vital Capacity

    Time frame: From baseline to Week 28

    Change from baseline in vital capacity

  32. Functional Residual Capacity

    Time frame: From baseline to Week 28

    Change from baseline in functional residual capacity

  33. Inspiratory Capacity

    Time frame: From baseline to Week 28

    Change from baseline in inspiratory capacity

Sponsors and collaborators

Lead sponsor

AstraZeneca

Industry

Registry information

Official study 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)

Important dates

Study start
2014
Primary completion
2016
Study completion
2016
First posted
Mar 3, 2014
Registry last updated
Jun 8, 2018

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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