E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Asthma (an illness that causes breathing difficulty) that is not fully controlled, so that episodes of breathing difficulty are still occuring despite the use of other available treatments |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003553 |
E.1.2 | Term | Asthma |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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 |
|
E.2.2 | Secondary objectives of the trial |
To assess the effect of 2 dosing regimens of benralizumab on:
-OCS dose in adult patients with uncontrolled asthma
-parameters associated with asthma exacerbations
-pulmonary function
-asthma symptoms and other asthma control metrics
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 a
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 prednisone or prednisolone therapy for at least 6 continuous months
directly preceding Visit 1, and on a stable dose for at least one month prior to Visit 1
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. Either documented post bronchodilator (post-BD) reversibility of ≥ 12% and ≥ 200 mL in FEV1 or PC20 FEV1
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
period
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)
16. No documented asthma exacerbations during the screening/dose optimization period |
|
E.4 | Principal 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, haematological, 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, haematology, clinical chemistry, or urinalysis during screening/run-in 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 dexamethasone as the maintenance oral steroid controller for asthma symptoms |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Percentage reduction in final OCS dose compared with baseline (Visit 6), while maintaining asthma control |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The effect of 2 dosing regimens of benralizumab on:
-OCS dose in terms of proportion of patients with ≥50% reduction in average daily OCS dose at week 28 compared with dose at week 0 while maintaining asthma control average final OCS dose ≤5.0 mg daily at week 28, while maintaining asthma control.
-OCS dose in terms of proportion of patients with ≤5.0 mg reduction on daily OCS dose at week 28 compared with dose at week 0, while maintaining asthma control.
-Proportion of patients with ≥1 asthma exacerbation after randomization, time to the first
asthma exacerbation after randomization and annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization after randomization
-pulmonary function in terms of change from week 0 in prebronchodilator Forced Expiratory Volume in 1 second (FEV1) and in prebronchodilator Inspiratory Capacity (IC), Expiratory Reserve Volume (ERV) and Inspiratory Reserve Volume (IRV).
-asthma symptoms and other asthma control metrics in the terms of change from week 0 in asthma symptom score (total, daytime, and night time) and in rescue medication use.
-asthma symptoms and other asthma control metrics in the terms of change from week 0 in the number of nights with awakening due to asthma requiring rescue medication.
- asthma symptoms and other asthma control metrics in the terms of change from week 0 in Asthma Control Questionnaire 6 (ACQ-6).
-asthma related health related quality of life in the terms of change from week 0 in Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12).
-The pharmacokinetics (PK) of 2 dosing regimens of benralizumab in the terms of PK parameters
-The immunogenicity of 2 dosing regimens of benralizumab in the terms of
Anti-drug antibodies (ADA) presence or absence
-The safety and tolerability of 2 dosing regimens of benralizumab in terms of Adverse Event (AE)/Serious Adverse Event (SAE)
-The safety and tolerability of 2 dosing regimens of benralizumab in terms of laboratory variables
-The safety and tolerability of 2 dosing regimens of benralizumab in terms of electrocardiogram (ECG) evaluation
-The safety and tolerability of 2 dosing regimens of benralizumab in terms of physical examination results
-The impact of 2 dosing regimens of benralizumab on blood eosinophil count.
- The impact of 2 dosing regimens of benralizumab on biomarkers (subset of patients) in terms of quantification of sputum cytokines and biomarkers
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Canada |
Chile |
France |
Germany |
Poland |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 16 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |