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

Asthma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02075255
• Other study ID #: D3250C00020
• Status: Completed
• Phase: Phase 3
• Start date: April 28, 2014
• Est. completion date: August 8, 2016

Study information

• Verified date: May 2018
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: August 8, 2016
• Est. primary completion date: August 8, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Asthma

Intervention

Biological:
• Benralizumab
Benralizumab administered subcutaneously every 4 weeks
• Placebo
Placebo subcutaneously on study week 0 until study week 24 inclusive.
• Benralizumab
Benralizumab administered subcutaneously every 4 weeks for the first 3 dose and then every 8 weeks; matching placebo subcutaneously at the 4 week interim to maintain the blind.

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Caba
Argentina	Research Site	Florida
Argentina	Research Site	Mendoza
Bulgaria	Research Site	Kozloduy
Bulgaria	Research Site	Pazardzhik
Bulgaria	Research Site	Petrich
Bulgaria	Research Site	Ruse
Bulgaria	Research Site	Samokov
Bulgaria	Research Site	Vratsa
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Ottawa	Ontario
Canada	Research Site	Quebec
Canada	Research Site	Vancouver	British Columbia
Chile	Research Site	Quillota
Chile	Research Site	Rancagua
Chile	Research Site	Santiago
Chile	Research Site	Talca
Chile	Research Site	Talcahuano
Chile	Research Site	Valparaiso
France	Research Site	Brest Cedex 2
France	Research Site	Lyon Cedex 04
France	Research Site	Marseille
France	Research Site	Montpellier
France	Research Site	Strasbourg Cedex
France	Research Site	Toulouse
Germany	Research Site	Bamberg
Germany	Research Site	Berlin
Germany	Research Site	Freiburg
Germany	Research Site	Grosshansdorf
Germany	Research Site	Hannover
Germany	Research Site	Leipzig
Germany	Research Site	Mainz
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Suwon-si
Poland	Research Site	Bydgoszcz
Poland	Research Site	Karczew
Poland	Research Site	Koszalin
Poland	Research Site	Kraków
Poland	Research Site	Kraków
Poland	Research Site	Lódz
Poland	Research Site	Lubin
Poland	Research Site	Szczecin
Poland	Research Site	Tarnów
Poland	Research Site	Trzebnica
Poland	Research Site	Wroclaw
Poland	Research Site	Wroclaw
Spain	Research Site	Málaga
Spain	Research Site	Valencia
Turkey	Research Site	Adana
Turkey	Research Site	Ankara
Turkey	Research Site	Bursa
Turkey	Research Site	Istanbul
Turkey	Research Site	Istanbul
Ukraine	Research Site	Dnipropetrovsk
Ukraine	Research Site	Ivano-Frankivsk
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Vinnytsia
United States	Research Site	Bronx	New York
United States	Research Site	Centennial	Colorado
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Denver	Colorado
United States	Research Site	Durham	North Carolina
United States	Research Site	Fort Mitchell	Kentucky
United States	Research Site	Hialeah	Florida
United States	Research Site	Hialeah	Florida
United States	Research Site	Iowa City	Iowa
United States	Research Site	Los Angeles	California
United States	Research Site	Madison	Wisconsin
United States	Research Site	Miami	Florida
United States	Research Site	Middleburg Heights	Ohio
United States	Research Site	Mount Pleasant	South Carolina
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Orlando	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Rochester	Minnesota
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Argentina,  Bulgaria,  Canada,  Chile,  France,  Germany,  Korea, Republic of,  Poland,  Spain,  Turkey,  Ukraine, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control	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.	Week 28
Secondary	Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control	Number and percentage of patients in different categories of percent reduction from baseline in final OCS dose.	Week 28
Secondary	Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils >=300/uL	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.	Week 28
Secondary	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	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.	Week 28
Secondary	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	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.	Week 28
Secondary	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.	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.	Week 28
Secondary	The Proportion of Patients With Average Final OCS Dose =5.0 mg Daily at Visit 14, While Maintaining Asthma Control	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.	Week 28
Secondary	Number and Percentage of Patients With =1 Asthma Exacerbation	Number and percentage of patients with at least one post randomisation asthma exacerbation.	Immediately following the randomisation through Study Week 28
Secondary	Time to the First Asthma Exacerbation	Time to the first occurrence of asthma exacerbation post randomisation	The time from randomisation to the date of first asthma exacerbation over 28 weeks
Secondary	Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit	Time to the first exacerbation requiring hospitalization or ER visit post randomisation	The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks.
Secondary	The Annualized Rate of Asthma Exacerbation	The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator adjusted by the time of follow-up.	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
Secondary	The Annualized Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization	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.	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
Secondary	Number of Days in Hospital Due to Asthma	Number of days in hospital due to asthma, if none, 0 day is considered	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
Secondary	Change From Baseline to Week 28 in Pre-bronchodilator FEV1	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.	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in Asthma Symptom Scores (Total)	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.	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime)	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.	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime)	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.	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in Rescue Medication Use	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].	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow)	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.	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow)	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	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication	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.	Change from baseline at week 28
Secondary	Change From Baseline to Week 28 in ACQ-6	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.	Change from baseline at week 28
Secondary	ACQ-6 Responders (Improvement) at 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.	Week 28
Secondary	Change From Baseline at Week 28 in AQLQ(S)+12 (Overall)	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.	Change from baseline at week 28
Secondary	AQLQ(s)+12 Responders (Improvement) at 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.	Week 28
Secondary	Extent of Exposure	Duration of exposure from first dose date to last dose date.	From first dose to Week 24
Secondary	Serum Concentration of Benralizumab	Pre-dose serum concentrations at each visit	Pre-first dose to Week 36
Secondary	Anti-drug Antibody Response	Number and percentage of patients in different ADA response categories	From baseline to follow-up Week 36
Secondary	Percent Change From Baseline in Blood Eosinophil Counts	Percent change from baseline in blood eosinophil counts at week 28	Change from baseline at Week 28
Secondary	Total Lung Capacity	Change from baseline in total lung capacity	From baseline to Week 28
Secondary	Residual Volume	Change from baseline in residual volume	From baseline to Week 28
Secondary	Vital Capacity	Change from baseline in vital capacity	From baseline to Week 28
Secondary	Functional Residual Capacity	Change from baseline in functional residual capacity	From baseline to Week 28
Secondary	Inspiratory Capacity	Change from baseline in inspiratory capacity	From baseline to Week 28

External Links

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