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
Latest Information Update: 13 Jul 2023
At a glance
- Drugs Benralizumab (Primary)
- Indications Asthma
- Focus Registrational; Therapeutic Use
- Acronyms ZONDA
- Sponsors AstraZeneca
- 24 May 2023 Results of an analysis assessing rates of clinical remission after treatment with benralizumab in patients with SEA with or without CRSwNP from 5 clinical studies (SIROCCO, CALIMA, ZONDA, ANDHI and PONENTE) presented at the 119th International Conference of the American Thoracic Society
- 14 Mar 2022 Results of post-hoc pooled analysis assessing composite remission definition to characterize individual responses to benralizumab after 6 and 12 months in 3 phase III studies (SIROCCO (NCT01928771); CALIMA (NCT01914757); ZONDA (NCT02075255)) were published in the Advances in Therapy.
- 21 Oct 2020 Results of post-hoc analysis assessing fficacy of benralizumab in reducing AER for patients with and without early clinically meaningful improvements above baseline in pre-bronchodilator FEV1, presented at the CHEST Annual Meeting 2020 by Annual Meeting of the American College of Chest Physicians.
Most Recent Events
Trial Overview
Outcome
Purpose
The purpose of this trial is to confirm if benralizumab can reduce oral corticosteroid (OCS) dependence (after dose optimisation) in patients who are uncontrolled on high-dose inhaled corticosteroid-long-acting beta agonist, and chronically dependent on OCS as part of their regular asthma controller regimen.
Comments
Health Canada has approved Fasenra (benralizumab injection) as an add-on maintenance treatment for adult patients with severe eosinophilic asthma, based on results from the WINDWARD clinical program.
Based on the data from SIROCCO CALIMA and ZONDA, US Food and Drug Administration (FDA) has approved FASENRA™ (benralizumab) for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. The European Commission (EC) has also approved Fasenra (benralizumab) as an add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists. In January 2018, Fasnera has been approved by the Japanese Ministry of Health, Labour and Welfare.
ZONDA is part of the phase III Windward programme for benralizumab for severe uncontrolled asthma. Other studies in the programme include CALIMA, SIROCCO, PAMPERO and BORA [see trial profiles 700235439, 700236411, 700237155 and 700238596]. The data from ZONDA, SIROCCO and CALIMA trials were included in regulatory submission for benralizumab which is under regulatory review in the US, EU, Japan and several other countries with a US PDUFA data in the fourth quarter of 2017.
Primary Endpoints
Percentage reduction of Oral Corticosteroid dose
The effect of 2 dosing regimens of benralizumab on percentage reduction of Oral Corticosteroid dose in the terms of percentage reduction in final Oral Corticosteroid dose compared with week 0, while maintaining asthma control
Time Frame: Starting from week 0 following the first administration of study drug through study week 28. [1]
Other Endpoints
Number and Percentage of Patients in Different Categories of Percent Reduction From Baseline in Final OCS Dose While Maintaining Asthma Control
description: Number and percentage of patients in different categories of percent reduction from baseline in final OCS dose. time_frame: Week 28
Percentage Reduction in Final OCS Dose Compared With Baseline While Maintaining Asthma Control for Patients With Baseline Eosinophils ≥300/uL
description: 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. time_frame: Week 28
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
description: 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. time_frame: Week 28
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
description: 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. time_frame: Week 28
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.
description: 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. time_frame: Week 28
The Proportion of Patients With Average Final OCS Dose ≤5.0 mg Daily at Visit 14, While Maintaining Asthma Control
description: 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. time_frame: Week 28
Number and Percentage of Patients With ≥1 Asthma Exacerbation
description: Number and percentage of patients with at least one post randomisation asthma exacerbation. time_frame: Immediately following the randomisation through Study Week 28
Time to the First Asthma Exacerbation
description: Time to the first occurrence of asthma exacerbation post randomisation time_frame: The time from randomisation to the date of first asthma exacerbation over 28 weeks
Time to the First Asthma Exacerbation Requiring Hospitalization or ER Visit
description: Time to the first exacerbation requiring hospitalization or ER visit post randomisation time_frame: The time from randomisation to the date of first asthma exacerbation associated with hospitalization or ER over 28 weeks.
The Annualized Rate of Asthma Exacerbation
description: The annualized exacerbation rate is based on unadjudicated exacerbation reported by the investigator adjusted by the time of follow-up. 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 Rate of Asthma Exacerbations That Are Associated With an Emergency Room Visit or a Hospitalization
description: 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. 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
description: Number of days in hospital due to asthma, if none, 0 day is considered 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
Change From Baseline to Week 28 in Pre-bronchodilator FEV1
description: 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. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in Asthma Symptom Scores (Total)
description: 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. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in Asthma Symptom Scores (Daytime)
description: 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. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in Asthma Symptom Scores (Nighttime)
description: 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. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in Rescue Medication Use
description: 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]. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in Home Lung Function (Morning Peak Expiratory Flow)
description: 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. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in Home Lung Function (Evening Peak Expiratory Flow)
description: 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 time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in the Proportion of Nights With Awakening Due to Asthma Requiring Rescue Medication
description: 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. time_frame: Change from baseline at week 28
Change From Baseline to Week 28 in ACQ-6
description: 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. time_frame: Change from baseline at week 28
ACQ-6 Responders (Improvement) at Week 28
description: 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. time_frame: Week 28
Change From Baseline at Week 28 in AQLQ(S)+12 (Overall)
description: 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. time_frame: Change from baseline at week 28
AQLQ(s)+12 Responders (Improvement) at Week 28
description: 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. time_frame: Week 28
Extent of Exposure
description: Duration of exposure from first dose date to last dose date. time_frame: From first dose to Week 24
Serum Concentration of Benralizumab
description: Pre-dose serum concentrations at each visit time_frame: Pre-first dose to Week 36
Anti-drug Antibody Response
description: Number and percentage of patients in different ADA response categories time_frame: From baseline to follow-up Week 36
Percent Change From Baseline in Blood Eosinophil Counts
description: Percent change from baseline in blood eosinophil counts at week 28 time_frame: Change from baseline at Week 28
Total Lung Capacity
description: Change from baseline in total lung capacity time_frame: From baseline to Week 28
Residual Volume
description: Change from baseline in residual volume time_frame: From baseline to Week 28
Vital Capacity
description: Change from baseline in vital capacity time_frame: From baseline to Week 28
Functional Residual Capacity
description: Change from baseline in functional residual capacity time_frame: From baseline to Week 28
Inspiratory Capacity
description: Change from baseline in inspiratory capacity time_frame: From baseline to Week 28 [2]
Diseases Treated
Indication | Qualifiers | Patient Segments |
---|---|---|
Asthma | treatment | disease exacerbations, severe |
Subjects
- Subject Type patients
-
Number
Planned: 210
Actual: 220
- Sex male & female
- Age Group 18-75 (Mean 51) years; adult; elderly
Patient 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)
Patient 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
Trial Details
Identifiers
Identifier | Owner |
---|---|
D3250C00020 | AstraZeneca |
NCT02075255 | ClinicalTrials.gov: US National Institutes of Health |
EudraCT2013-002523-42 | European Clinical Trials Database |
14-002961 | Mayo Clinic |
P018-2015 | Paediatric Investigation Plan EMA Decision number |
P020-2014 | Paediatric Investigation Plan EMA Decision number |
Organisations
- Sponsors AstraZeneca
- Affiliations AstraZeneca; Covance; Labcorp Drug Development
Trial Dates
-
Initiation Dates
Planned : 01 Apr 2014
Actual : 28 Apr 2014
-
Primary Completion Dates
Planned : 01 Jul 2016
Actual : 08 Aug 2016
-
End Dates
Planned : 01 Jul 2016
Actual : 08 Aug 2016
Other Details
- Design double-blind; multicentre; parallel; prospective; randomised
- Phase of Trial Phase III
- Location Argentina; Bulgaria; Canada; Chile; France; Germany; Poland; South Korea; Spain; Turkey; Ukraine; USA
- Focus Registrational; Therapeutic Use
Interventions
Drugs | Route | Formulation |
---|---|---|
BenralizumabPrimary Drug | Subcutaneous | Injection |
Benralizumab Arm A
Patients received benralizumab 30 mg subcutaneously every 4 weeks
Biological: Benralizumab (Benralizumab administered subcutaneously every 4 weeks)
Placebo
Placebo administered subcutaneously every 4 weeks
Biological: Placebo (Placebo subcutaneously on study week 0 until study week 24 inclusive.)
Benralizumab Arm B
Patients received benralizumab 30 mg 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.
Biological: 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.)
Results
Therapeutic efficacy
Pooled analysis : Pooled data from the patients severe eosinophilic asthma in the phase III SIROCCO/CALIMA/BORA and ZONDA trials showed that treatment with benralizumab, led to a sustained improvement in the exacerbation rates, lung function, asthma control and health-related quality of life of the patients for up to two years. Improvements in prebronchodilator FEV1, ACQ-6 scores, and AQLQ+12 scores were reported in the trials. Benralizumab also reduced the use of oral corticosteroids (OCS) in these patients. The integrated analysis 1,030 patients in the SIROCCO/CALIMA/BORA full analysis set and 131 patients in the ZONDA/BORA analysis set. Among patients in the ZONDA and BORA trials, after 84 weeks, about 75% of patients experienced at least a 50% reduction in the OCS dosages from baseline and 39% of patients had at least a 90% reduction. By the end of the study OCS dosage was reduced by 67%, which was similar to reductions seen in the ZONDA trial of 75% from baseline compared with 25% for placebo. Results were reported from a total of 1,161 patients [3] .
Results from the phase III ZONDA study demonstrated that the trial met its primary efficacy endpoint with statistically significant reductions in daily maintenance oral corticosteroid doses as compared to the placebo group. Median reduction in the OCS dose was 75% for patients treated with benralizumab versus 25% with placebo. Patients treated with benralizumab were four times more likely to reduce OCS dose relative to placebo. Out of the benralizumab-treated patients, 66% patients reduced OCS doses by about 50% compared to 37% patients receiving placebo. Thirty seven percent of benralizumab-treated patients reduced OCS doses by =90% compared to 12% receiving placebo. Fifty two percent of benralizumab patients, eligible to discontinue OCS use per protocol stopped OCS use completely, relative to 19% receiving placebo. There was a reduction of 70% in the overall annual exacerbation rate relative to placebo while a reduction of 93% in emergency room visits or hospitalisations due to exacerbations was observed in the benralizumab group compared to the placebo group [4] .
Adverse events
Pooled analysis : Pooled data from the patients severe eosinophilic asthma in the phase III SIROCCO/CALIMA/BORA and ZONDA trials showed that safety profile of benralizumab was similar to that observed in individual trials, with no increase in the frequencies of overall or serious adverse events. Viral upper respiratory infection, upper respiratory tract infection and bronchitis were the three most common adverse events reported for patients in the SIROCCO or CALIMA trials and entered the BORA study. Rates of all treatment-emergent adverse events and serious AEs observed in SIROCCO/CALIMA FAS and ZONDA groups, were similar with that of BORA extension and SIROCCO/CALIMA and ZONDA study periods. No increase in risk of infection over time were observed with benralizumab, and the malignancy rate was low. Results were reported from a total of 1,161 patients [5] [3] .
Results from the phase III ZONDA trial demonstrated that benralizumab was generally well tolerated and displayed a safety profile similar to that of placebo and consistent with previous phase III studies. The most common adverse events (=10%) in benralizumab-treated patients were nasopharyngitis, worsening asthma and bronchitis [4] .
Publications
-
Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N-Engl-J-Med 2017;.
PubMed | CrossRef Fulltext -
AstraZeneca. Fasenra reduces oral corticosteroid use and maintains long-term efficacy and safety profile in severe eosinophilic asthma. Media-Rel 2019;.
Media Release -
AstraZeneca. Phase III ZONDA Trial for benralizumab Shows Ability to Reduce Oral Steroid Use in Severe Asthma Patients. Media-Rel 2017;.
Media Release -
Fitzgerald JM, Bleecker ER, Bourdin A, Busse WW, Ferguson GT, Brooks L, et al. Two-Year Integrated Efficacy and Safety Analysis of Benralizumab SIROCCO, CALIMA, ZONDA, and BORA Trials in Severe Asthma. ATS-2019 2019; abstr. A2676/511.
Available from: URL: http://www.abstractsonline.com/pp8/#!/5789/presentation/12667 -
Nair P, Wenzel SE, Rabe K, Bourdin A, Lugogo N, Kuna P, et al. Benralizumab Significantly Reduced Oral Corticosteroid Dosages and Asthma Exacerbation Rates for Patients with Severe, Uncontrolled Asthma: Results of the ZONDA Phase III Trial. ATS-2017 2017; abstr. A4678.
Available from: URL: https://cms.psav.com/ats2017/confcal -
Bourdin A, Shaw D, Menzies-Gow A, FitzGerald JM, Bleecker ER, Busse WW, et al. Two-year integrated steroid-sparing analysis and safety of benralizumab for severe asthma. J-Asthma 2021;58(4):514-522.
PubMed | CrossRef Fulltext -
Sehmi R. Benralizumab attenuates airway eosinophilopoietic processes in prednisone-dependent asthma. ERS-2017 2017; abstr. 3217.
Available from: URL: http://www.ers-education.org/Media/Media.aspx?idMedia=354237 -
Yan L, Wang B, Chia YL, Roskos LK. Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma. Clin-Pharmacokinet 2019;.
PubMed | CrossRef Fulltext -
Maselli DJ, Peters JI. In severe asthma, benralizumab reduced daily oral glucocorticoid dose and asthma exacerbations at 6 months. Ann-Intern-Med 2017;167(8):JC43.
PubMed | CrossRef Fulltext -
Lugogo N, Kreindler J, Katial R, Barker P, Gil EG. Benralizumab Reduces Exacerbations for Patients with Ocs-Dependent Severe Asthma Regardless of Early Improvement in Fev1. CHEST-2020 2020; abstr. N/A.
Available from: URL: https://journal.chestnet.org/article/S0012-3692(20)32263-7/fulltext -
Andersson M, Janson C, Kristensen T, Szende A, Golam S. Cost Effectiveness of Benralizumab for Severe, Uncontrolled Oral Corticosteroid-Dependent Asthma in Swededn. EISPOR-2019 2019; abstr. PRS24.
Available from: URL: https://www.ispor.org/heor-resources/presentations-database/presentation/euro2019-3120/96149 -
Louis RE, Harrison T, Shavit A, Kwiatek J, Cohen D, Keeling N, et al. Approaching Clinical Remission in Severe Asthma: An Analysis of Patients With Comorbid Chronic Rhinosinusitis With Nasal Polyps (CRSwNP) Treated With Benralizumab Across Five Clinical Trials. ATS-2023 2023; abstr. P602.
Available from: URL: https://www.abstractsonline.com/pp8/#!/10703/presentation/10588 -
Chupp G, Lugogo NL, Kline JN, Ferguson GT, Hirsch I, Goldman M, et al. Rapid Onset of Effect of Benralizumab on Morning Peak Expiratory Flow in Severe, Uncontrolled Asthma. Ann-Allergy-Asthma-Immunol 2019;.
PubMed | CrossRef Fulltext -
Jackson DJ, Korn S, Mathur SK, Barker P, Meka VG, Martin UJ, et al. Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab. Drug-Safety 2020;.
PubMed | CrossRef Fulltext -
Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, et al. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. . Adv-Ther 2022;.
PubMed | CrossRef Fulltext -
Lugogo N, Kline JN, Hirsch I, Goldman M, Zangrilli JG, Trudo F. Benralizumab Improves Morning Peak Expiratory Flow While Reducing Oral Corticosteroid Dosages for Patients with Severe, Uncontrolled Asthma in the ZONDA Phase III Trial. ATS-2018 2018; abstr. A2488.
Available from: URL: http://files.abstractsonline.com/CTRL/e9/2/07d/67b/67f/4ff/aa3/f1b/54c/494/a91/43/g9823_1.jpg?noCache=43
Trial Centres
Investigators
Investigator | Centre Name | Trial Centre Country |
---|---|---|
AstraZeneca Clinical Study Information Center
Phone: 1-877-240-9479
show details
information.center@astrazeneca.com |
, AstraZeneca |
-
|
Clinical Study Information
Phone: +1 800-236-9933
show details
information.center@astrazeneca.com |
, AstraZeneca |
-
|
Parameswaran Nair, MD,PhD,FRCP,FRCPC | St Joseph's Healthcare Hamilton Firestone Institute for Respiratory Health 50 Charlton Avenue East Hamilton |
-
|
Centres
Centre Name | Location | Trial Centre Country |
---|---|---|
- |
-
|
-
|
- | Łódź | Poland |
- | Adana | Turkey |
- | Ankara | Turkey |
- | Bamberg | Germany |
- | Barcelona | Spain |
- | Berlin | Germany |
- | Białystok | Poland |
- | Brest Cedex 2 | France |
- | Bronx, New York | USA |
- | Buenos Aires | Argentina |
- | Bursa | Turkey |
- | Bydgoszcz | Poland |
- | Bystra Śląska | Poland |
- | Caba | Argentina |
- | Calgary, Alberta | Canada |
- | Centennial, Colorado | USA |
- | Cheongju-si | South-Korea |
- | Chicago, Illinois | USA |
- | Cincinnati, Ohio | USA |
- | Denver, Colorado | USA |
- | Dnipropetrovsk | Ukraine |
- | Durham, North Carolina | USA |
- | Everett, Washington | USA |
- | Florida | Argentina |
- | Fort Lauderdale, Florida | USA |
- | Fort Mitchell, Kentucky | USA |
- | Freiburg | Germany |
- | Galveston, Texas | USA |
- | Gdańsk | Poland |
- | Greenville, South Carolina | USA |
- | Grosshansdorf | Germany |
- | Hamilton, Ontario | Canada |
- | Hannover | Germany |
- | Hialeah, Florida | USA |
- | Iowa City, Iowa | USA |
- | Istanbul | Turkey |
- | Ivano-Frankivsk | Ukraine |
- | Karczew | Poland |
- | Kharkiv | Ukraine |
- | Koszalin | Poland |
- | Kozloduy | Bulgaria |
- | Kraków | Poland |
- | Kyiv | Ukraine |
- | Las Vegas, Nevada | USA |
- | Leipzig | Germany |
- | Los Angeles, California | USA |
- | Lubin | Poland |
- | Lublin | Poland |
- | Lyon Cedex 04 | France |
- | Málaga | Spain |
- | Madison, Wisconsin | USA |
- | Mainz | Germany |
- | Marseille | France |
- | Mendoza | Argentina |
- | Miami, Florida | USA |
- | Middleburg Heights, Ohio | USA |
- | Mobile, Alabama | USA |
- | Monroe, Michigan | USA |
- | Montpellier | France |
- | Montreal, Quebec | Canada |
- | Mt Pleasant, South Carolina | USA |
- | Oklahoma City, Oklahoma | USA |
- | Orlando, Florida | USA |
- | Ottawa, Ontario | Canada |
- | Pazardzhik | Bulgaria |
- | Petrich | Bulgaria |
- | Philadelphia, Pennsylvania | USA |
- | Phoenix, Arizona | USA |
- | Pittsburgh, Pennsylvania | USA |
- | Plano, Texas | USA |
- | Quebec | Canada |
- | Quillota | Chile |
- | Rancagua | Chile |
- | Rochester, Minnesota | USA |
- | Ruse | Bulgaria |
- | Samokov | Bulgaria |
- | Santiago | Chile |
- | Seoul | South-Korea |
- | Sliven | Bulgaria |
- | Sofia | Bulgaria |
- | Strasbourg Cedex | France |
- | Suwon-si | South-Korea |
- | Szczecin | Poland |
- | Talca | Chile |
- | Talcahuano | Chile |
- | Tamow | Poland |
- | Tarnów | Poland |
- | Toulouse | France |
- | Valencia | Spain |
- | Valparaiso | Chile |
- | Vancouver, British Columbia | Canada |
- | Vinnytsia | Ukraine |
- | Vratsa | Bulgaria |
- | Winston Salem, North Carolina | USA |
- | Wrocław | Poland |
- | Wroclaw | Poland |
AstraZeneca |
-
|
-
|
St Joseph's Healthcare Hamilton Firestone Institute for Respiratory Health 50 Charlton Avenue East Hamilton |
-
|
-
|
Trial History
Event Date | Event Type | Comment |
---|---|---|
24 May 2023 | Results | Results of an analysis assessing rates of clinical remission after treatment with benralizumab in patients with SEA with or without CRSwNP from 5 clinical studies (SIROCCO, CALIMA, ZONDA, ANDHI and PONENTE) presented at the 119th International Conference of the American Thoracic Society Updated 13 Jul 2023 |
14 Mar 2022 | Results | Results of post-hoc pooled analysis assessing composite remission definition to characterize individual responses to benralizumab after 6 and 12 months in 3 phase III studies (SIROCCO (NCT01928771); CALIMA (NCT01914757); ZONDA (NCT02075255)) were published in the Advances in Therapy. Updated 17 Mar 2022 |
25 Jun 2021 | Other trial event | According to a Labcorp company website, Covance has changed its name to LabCorp Drug Development Updated 26 Sep 2022 |
01 Apr 2021 | Results | Results of integrated analysis of BORA and ZONDA studies were published in the Journal of Asthma. Updated 13 Oct 2021 |
21 Oct 2020 | Results | Results of post-hoc analysis assessing fficacy of benralizumab in reducing AER for patients with and without early clinically meaningful improvements above baseline in pre-bronchodilator FEV1, presented at the CHEST Annual Meeting 2020 by Annual Meeting of the American College of Chest Physicians. Updated 11 Dec 2020 |
02 Apr 2020 | Results | Results doing integrated analyses of benralizumab safety data from the phase III SIROCCO and CALIMA trials and subsequent BORA extension trial and ZONDA for patients with asthma, and the phase III GALATHEA and TERRANOVA trials for patients with chronic obstructive pulmonary disease, published in the Drug Safety Updated 07 Apr 2020 |
06 Nov 2019 | Results | Results presented at the 22nd Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research Updated 13 Nov 2019 |
22 May 2019 | Results | Results presented at the 115th International Conference of the American Thoracic Society. Updated 23 Sep 2019 |
20 May 2019 | Results | According to a AstraZeneca media release, pooled analysis data for phase III SIROCCO, CALIMA exacerbation trials, the BORA extension trial and the 28-week phase III ZONDA OCS-sparing trial were presented at the American Thoracic Society (ATS) 2019 International Conference. Updated 24 May 2019 |
20 May 2019 | Results | Pooled analysis data for phase III SIROCCO, CALIMA exacerbation trials, the BORA extension trial and the 28-week phase III ZONDA OCS-sparing trial presented in a AstraZenec media release. Updated 24 May 2019 |
11 Mar 2019 | Results | Results assessing pharmacokinetic (PK) data from nine clinical trials (NCT00512486, NCT00659659, NCT00768079, NCT00783289, NCT01238861, NCT01928771, NCT01914757, NCT02322775, NCT02075255) for patients with asthma, published in the Clinical Pharmacokinetics. Updated 15 Mar 2019 |
22 Feb 2019 | Results | Results assessing the onset of action of benralizumab by examining change in morning PEF following initiation of treatment in the SIROCCO, CALIMA, and ZONDA clinical trials, published in the Annals of Allergy, Asthma and Immunology Updated 01 Mar 2019 |
10 Jun 2018 | Other trial event | Last checked against the ClinicalTrials.gov record. Updated 10 Jun 2018 |
23 May 2018 | Results | Results presented at the 114th International Conference of the American Thoracic Society Updated 05 Jul 2018 |
26 Feb 2018 | Other trial event | According to an AstraZeneca media release, health Canada has approved Fasenra (benralizumab injection) as an add-on maintenance treatment for adult patients with severe eosinophilic asthma, based on results from the WINDWARD clinical program. Updated 27 Feb 2018 |
19 Jan 2018 | Other trial event | According to an AstraZeneca media release, the Japanese Ministry of Health, Labour and Welfare has approved Fasenra (benralizumab) as an add-on treatment for bronchial asthma in patients who continue to experience asthma exacerbations despite treatment with high-dose inhaled corticosteroid and other asthma controllers. The approval is based on the results from the WINDWARD programme, including the SIROCCO, CALIMA and ZONDA trials. Updated 24 Jan 2018 |
10 Jan 2018 | Other trial event | According to an AstraZeneca media release, based on the results from the WINDWARD programme, including the pivotal Phase III exacerbation trials, SIROCCO and CALIMA, and the Phase III OCS-sparing trial, ZONDA, the European Commission (EC) has approved Fasenra (benralizumab) as an add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting beta-agonists. Updated 15 Jan 2018 |
14 Nov 2017 | Other trial event | According to an AstraZeneca media release, US Food and Drug Administration (FDA) has approved FASENRA (benralizumab) for the add-on maintenance treatment of patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype. Updated 21 Nov 2017 |
10 Nov 2017 | Other trial event | The positive opinion from the CHMP will now be reviewed by the European Commission, as reported in a MedImmune media release. Updated 17 Nov 2017 |
10 Nov 2017 | Other trial event | Based on the data from the WINDWARD programme including the pivotal Phase III exacerbation trials, SIROCCO and CALIMA, and Phase III oral corticosteroid (OCS)-sparing trial, ZONDA, the CHMP of the EMA has adopted a positive opinion, recommending the marketing authorisation of benralizumab as an add-on maintenance treatment in adult patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting b-agonists. Updated 17 Nov 2017 |
17 Oct 2017 | Results | Results published in the Annals of Internal Medicine. Updated 30 Oct 2017 |
13 Sep 2017 | Results | Results of a Canadian substudy of Zonda, presented at the 27th Annual Congress of the European Respiratory Society. Updated 15 Nov 2017 |
24 May 2017 | Results | Results presented at the 113th International Conference of the American Thoracic Society Updated 09 Jul 2017 |
22 May 2017 | Other trial event | According to an AstraZeneca media release, the data from ZONDA, SIROCCO and CALIMA trials were included in regulatory submission for benralizumab which is under regulatory review in the US, EU, Japan and several other countries with a US PDUFA data in the fourth quarter of 2017. Updated 29 May 2017 |
22 May 2017 | Results | Results presented at the American Thoracic Society (ATS) 2017 International Congress, according to an AstraZeneca media release. Updated 29 May 2017 |
22 May 2017 | Results | Results published in an AstraZeneca media release. Updated 29 May 2017 |
22 May 2017 | Endpoint met | Primary endpoint (Percentage reduction of Oral Corticosteroid dose) has been met. Updated 26 May 2017 |
22 May 2017 | Results | Results published in the New England Journal of Medicine Updated 26 May 2017 |
28 Jan 2017 | Other trial event | Last checked against European Clinical Trials Database. Updated 28 Jan 2017 |
23 Aug 2016 | Status change - completed | Status changed from active, no longer recruiting to completed. Updated 30 Aug 2016 |
20 Aug 2016 | Other trial event | This trial has been completed in Bulgaria (end date: 6 Jul 2016). Updated 23 Aug 2016 |
05 Aug 2016 | Other trial event | This trial has been completed in Spain according to the European Clinical Trials Database. Updated 05 Aug 2016 |
26 Apr 2016 | Other trial event | This trial was completed in Poland according to the European Clinical Trials Database. Updated 26 Apr 2016 |
18 Mar 2016 | Completion date | Planned End Date changed from 1 Sep 2016 to 1 Jul 2016 as reported by ClinicalTrials.gov. Updated 23 Mar 2016 |
18 Mar 2016 | Other trial event | Planned primary completion date changed from 1 Sep 2016 to 1 Jul 2016 as reported by ClinicalTrials.gov. Updated 23 Mar 2016 |
04 Feb 2016 | Other trial event | According to an AstraZeneca media release, regulatory submissions to the agencies in US and EU for benralizumab for the treatment of severe asthma are anticipated in the second half of 2016. Updated 15 Feb 2016 |
22 Dec 2015 | Status change - active, no longer recruiting | Status changed from recruiting to active, no longer recruiting as reported by ClinicalTrials.gov. Updated 08 Jan 2016 |
22 Apr 2015 | Other trial event | Planned number of patients changed from 120 to 210, as reported by ClinicalTrials.gov. Updated 30 Apr 2015 |
22 Apr 2015 | Completion date | Planned End Date changed from 1 May 2016 to 1 Sep 2016, as reported by ClinicalTrials.gov. Updated 30 Apr 2015 |
22 Apr 2015 | Other trial event | Planned primary completion date changed from 1 May 2016 to 1 Sep 2016, as reported by ClinicalTrials.gov. Updated 30 Apr 2015 |
14 Jan 2015 | Completion date | Planned End Date changed from 1 Jan 2016 to 1 May 2016 as reported by ClinicalTrials.gov record. Updated 23 Jan 2015 |
14 Jan 2015 | Other trial event | Planned primary completion date changed from 1 Jan 2016 to 1 May 2016 as reported by ClinicalTrials.gov record. Updated 23 Jan 2015 |
19 Sep 2014 | Other trial event | Planned number of patients changed from 240 to 120 according to ClinicalTrials.gov record. Updated 30 Sep 2014 |
25 Aug 2014 | Other trial event | New source identified and integrated (Mayo Clinic; 14-002961) Updated 25 Aug 2014 |
09 Jul 2014 | Other trial event | New source identified and integrated (European Clinical Trials Database; EudraCT2013-002523-42) Updated 09 Jul 2014 |
27 May 2014 | Status change - recruiting | Status changed from not yet recruiting to recruiting; according to ClinicalTrials.gov record. Updated 09 Jul 2014 |
10 Mar 2014 | New trial record | New trial record Updated 10 Mar 2014 |
Table of Contents
References
-
Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral Glucocorticoid-Sparing Effect of Benralizumab in Severe Asthma. N-Engl-J-Med 2017;.
PubMed | CrossRef Fulltext -
ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.
Available from: URL: http://clinicaltrials.gov -
AstraZeneca. Fasenra reduces oral corticosteroid use and maintains long-term efficacy and safety profile in severe eosinophilic asthma. Media-Rel 2019;.
Media Release -
AstraZeneca. Phase III ZONDA Trial for benralizumab Shows Ability to Reduce Oral Steroid Use in Severe Asthma Patients. Media-Rel 2017;.
Media Release -
Fitzgerald JM, Bleecker ER, Bourdin A, Busse WW, Ferguson GT, Brooks L, et al. Two-Year Integrated Efficacy and Safety Analysis of Benralizumab SIROCCO, CALIMA, ZONDA, and BORA Trials in Severe Asthma. ATS-2019 2019; abstr. A2676/511.
Available from: URL: http://www.abstractsonline.com/pp8/#!/5789/presentation/12667 -
Nair P, Wenzel SE, Rabe K, Bourdin A, Lugogo N, Kuna P, et al. Benralizumab Significantly Reduced Oral Corticosteroid Dosages and Asthma Exacerbation Rates for Patients with Severe, Uncontrolled Asthma: Results of the ZONDA Phase III Trial. ATS-2017 2017; abstr. A4678.
Available from: URL: https://cms.psav.com/ats2017/confcal -
AstraZeneca. Fasenra receives approval in Japan. Media-Rel 2018;.
Media Release -
AstraZeneca Canada. Health Canada approves Fasenra(R) (benralizumab injection) for patients with severe eosinophilic asthma. Media-Rel 2018;.
Media Release -
Bourdin A, Shaw D, Menzies-Gow A, FitzGerald JM, Bleecker ER, Busse WW, et al. Two-year integrated steroid-sparing analysis and safety of benralizumab for severe asthma. J-Asthma 2021;58(4):514-522.
PubMed | CrossRef Fulltext -
Sehmi R. Benralizumab attenuates airway eosinophilopoietic processes in prednisone-dependent asthma. ERS-2017 2017; abstr. 3217.
Available from: URL: http://www.ers-education.org/Media/Media.aspx?idMedia=354237 -
European Clinical Trials Database. Trial-Reg 2023;.
Available from: URL: https://www.clinicaltrialsregister.eu -
Yan L, Wang B, Chia YL, Roskos LK. Population Pharmacokinetic Modeling of Benralizumab in Adult and Adolescent Patients with Asthma. Clin-Pharmacokinet 2019;.
PubMed | CrossRef Fulltext -
Maselli DJ, Peters JI. In severe asthma, benralizumab reduced daily oral glucocorticoid dose and asthma exacerbations at 6 months. Ann-Intern-Med 2017;167(8):JC43.
PubMed | CrossRef Fulltext -
AstraZeneca, MedImmune. FASENRA (benralizumab) Receives US FDA Approval For Severe Eosinophilic Asthma. Media-Rel 2017;.
Media Release -
AstraZeneca. AstraZeneca Full-Year and Q4 2015 Results. Media-Rel 2016;.
Media Release -
Lugogo N, Kreindler J, Katial R, Barker P, Gil EG. Benralizumab Reduces Exacerbations for Patients with Ocs-Dependent Severe Asthma Regardless of Early Improvement in Fev1. CHEST-2020 2020; abstr. N/A.
Available from: URL: https://journal.chestnet.org/article/S0012-3692(20)32263-7/fulltext -
MedImmune. Benralizumab receives positive EU CHMP opinion for severe, uncontrolled eosinophilic asthma. Media-Rel 2017;.
Media Release -
Labcorp. Pharm-Biotech-Companies 2022;.
Available from: URL: https://www.labcorp.com/ -
Andersson M, Janson C, Kristensen T, Szende A, Golam S. Cost Effectiveness of Benralizumab for Severe, Uncontrolled Oral Corticosteroid-Dependent Asthma in Swededn. EISPOR-2019 2019; abstr. PRS24.
Available from: URL: https://www.ispor.org/heor-resources/presentations-database/presentation/euro2019-3120/96149 -
Louis RE, Harrison T, Shavit A, Kwiatek J, Cohen D, Keeling N, et al. Approaching Clinical Remission in Severe Asthma: An Analysis of Patients With Comorbid Chronic Rhinosinusitis With Nasal Polyps (CRSwNP) Treated With Benralizumab Across Five Clinical Trials. ATS-2023 2023; abstr. P602.
Available from: URL: https://www.abstractsonline.com/pp8/#!/10703/presentation/10588 -
Mayo Clinic. Clin-Res-Organ 2014;.
Available from: URL: http://clinicaltrials.mayo.edu -
Chupp G, Lugogo NL, Kline JN, Ferguson GT, Hirsch I, Goldman M, et al. Rapid Onset of Effect of Benralizumab on Morning Peak Expiratory Flow in Severe, Uncontrolled Asthma. Ann-Allergy-Asthma-Immunol 2019;.
PubMed | CrossRef Fulltext -
Jackson DJ, Korn S, Mathur SK, Barker P, Meka VG, Martin UJ, et al. Safety of Eosinophil-Depleting Therapy for Severe, Eosinophilic Asthma: Focus on Benralizumab. Drug-Safety 2020;.
PubMed | CrossRef Fulltext -
Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, et al. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. . Adv-Ther 2022;.
PubMed | CrossRef Fulltext -
AstraZeneca. AstraZeneca advances MedImmune's benralizumab to Phase III in severe asthma. Media-Rel 2013;.
Media Release -
AstraZeneca. AstraZeneca receives EU approval of Fasenra for severe eosinophilic asthma. Media-Rel 2018;.
Media Release -
Lugogo N, Kline JN, Hirsch I, Goldman M, Zangrilli JG, Trudo F. Benralizumab Improves Morning Peak Expiratory Flow While Reducing Oral Corticosteroid Dosages for Patients with Severe, Uncontrolled Asthma in the ZONDA Phase III Trial. ATS-2018 2018; abstr. A2488.
Available from: URL: http://files.abstractsonline.com/CTRL/e9/2/07d/67b/67f/4ff/aa3/f1b/54c/494/a91/43/g9823_1.jpg?noCache=43
Adis International Ltd. Part of Springer Science+Business Media
© Springer Nature Switzerland AG