E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Eosinophilic Granulomatosis with Polyangiitis (EGPA) |
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E.1.1.1 | Medical condition in easily understood language |
Eosinophilic Granulomatosis with Polyangiitis (EGPA) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the durability of response to treatment with benralizumab compared with mepolizumab in patients with relapsing or refractory EGPA who are receiving Standard of Care Therapy, assessed by the proportion of patients in remission at both Weeks 36 and 48.
Primary endpoint: Proportion of patients with relapsing or refractory EGPA, achieving
remission, defined as BVAS=0 (BVAS is a physician completed score based on disease activity in multiple parts of the body) and OCS (Oral corticosteroid) dose less or equal to 4mg/day (Main Remission definition) at both weeks 36 and 48.
Supportive endpoint: Proportion of patients who have achieved remission defined by BVAS =0 and OCS dose less or equal to 7.5 mg/day (Supportive remission definition) at both weeks 36 and 48. |
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E.2.2 | Secondary objectives of the trial |
Double blind period Objectives
1. To assess the efficacy of benralizumab compared with mepolizumab on duration of clinical remission, defined as accrued duration in weeks where a patient achieves remission 2. To assess the efficacy of benralizumab compared with mepolizumab on time to first relapse. 3. To assess the average daily dose of corticosteroid required during weeks 48 to 52 in patients receiving benralizumab compared to mepolizumab
4. To assess the annualized relapse rate in patients receiving benralizumab compared to mepolizumab. 5. To assess the proportion of patients who achieve remission within the first 24 weeks and remain in remission for the remainder of the double-blind period in patients receiving benralizumab compared to mepolizumab 6. To assess additional measures of the efficacy and health status/health-related quality of life in patients receiving benralizumab compared to mepolizumab.
7. To assess the safety and tolerability of benralizumab compared to mepolizum |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Patient Interview Sub-study
To characterize the patient-reported experience and treatment benefits of benralizumab compared with mepolizumab through patient interviews
Mechanistic Sub-study
To evaluate the effect of benralizumab compared to mepolizumab on biomarkers related to the mechanism of action (MoA), eosinophilic
inflammation and EGPA disease pathogenesis, as well as baseline predictors of response to benralizumab or mepolizumab, through analysis of tissue biopsies and sputum.
Both sub-studies are part of the main study protocol V1.0, 11Jun2019
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E.3 | Principal inclusion criteria |
1. Male or female subjects age 18 years or older.
2. EGPA diagnosis based on history or presence asthma and
eosinophilia (>1.0x10^9/L and/or >10% of leucocytes) and at least 2
of; biopsy with eosinophilic vasculitis or perivascular/granulomatous
inflammation; mono-or polyneuropathy, non-fixed pulmonary infiltrates,
sino-nasal abnormality; cardiomyopathy; glomerulonephritis; alveolar
haemorrhage; palpable purpura; anti neutrophil cytoplasmic anti-body
(ANCA) positivity (Myeloperoxidase or proteinease 3).
3. History of relapsing (at least 1 confirmed EGPA relapse within last 2
years and > 12 weeks prior to screening, or refractory (failure to attain
remission, defined as BVAS=0 and oral corticosteroid (OCS) dose <=7.5
mg/day of prednisolone or equivalent, following standard induction
regimen for at least 3 months and within 6 months prior to screening, or
recurrence of symptoms upon OCS tapering at any dose of ≥7.5 mg/day
prednisolone or equivalent.
If induction with glucocorticoidsalone, patient must have failed to attain
remission after 3 months and the glucocorticoid dose must be ≥15
mg/day prednisolone or equivalent for the 4 weeks prior to
randomization.
4. Must be on a stable dose of oral prednisolone or prednisone of ≥7.5
mg/day (but not >50mg/day) for at least 4 weeks prior to
randomization.
5. If receiving immunosuppressive therapy (excluding
cyclophosphamide) the dose must be stable for the 4 weeks prior to
randomization and during the study (dose reductions for safety reasons
will be permitted).
6. QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle
branch block.
7. Females of childbearing potential must use an acceptable method of
birth control from signing the informed consent for at least 12 weeks after the
last study drug administration. |
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E.4 | Principal exclusion criteria |
1. Diagnosed with granulomatosis with polyangiitis (GPA) or
microscopic polyangiitis (MPA)
2. Organ or life-threatening EGPA < 3 months prior to screening
3. Currently pregnant or breastfeeding, or planning to become pregnant
during study participation.
4. Current malignancy or history of malignancy, unless received
curative therapy >5 years ago, or >1 year ago for basal cell carcinoma,
localized squamous cell carcinoma of the skin or in situ carcinoma of the
cervix
5. An untreated or refractory helminth parasitic infection < 24 weeks
prior to screening
6. Unstable liver disease
7. Severe or clinically significant, uncontrolled cardiovascular disease
8. Other concurrent disease that may put the patient at risk, or may
influence the results of the study, or the patients' ability to complete
entire duration of the study
9. Chronic or ongoing infectious disease requiring systemic antiinfective
treatment
10. Known immunodeficiency disorder or positive HIV test
11. Prior receipt of mepolizumab, reslizumab, dupilumab or
benralizumab. Receipt of intravenous/intramuscular/subcutaneous
corticosteroids within 4 weeks prior to randomization, receipt of
omalizumab within 130 days prior to screenin, rituximab within 6
months prior to screening (or B-cells not recovered), interferon-α or
alemtuzumab within 6 months prior to screening, receipt of anti-tumor
necrosis factor therapy within 12 weeks prior to screening or an
investigational non-biologic product within 30 days or 5 half-lives prior to screening, whichever is longer. Receipt of any other marketed or investigational biologic products within 4 months or 5 half-lives prior to screening, whichever is longer. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS=0 and OCS dose ≤ 4mg/day (Main Remission definition) at both weeks 36 and 48.
Supportive endpoint: Proportion of patients who have achieved remission defined by BVAS =0 and OCS dose ≤ 7.5 mg/day (Supportive remission definition) at both weeks 36 and 48.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Study secondary end point(s) – double-blind period:
- Total accrued duration of remission for the following categories: 0 wk,
>0 to <12 wk, 12 to <24 wk, 24 to <36 wk, ≥36 wk. Analysis will be
repeated based on main and supportive remission definitions.
- Time from randomisation to first EGPA relapse, where relapse is
defined as any of the following:
*Active vasculitis (BVAS >0); OR
*Active asthma symptoms and/or signs with a corresponding worsening
in ACQ-6 score; OR
*Active nasal and/or sinus disease, with a corresponding worsening in
at least one of the sino-nasal symptom questions warranting any of the
following:
an increase of OCS therapy (>4mg prednisolone total daily dose or
equivalent);
an increased dose or addition of an immunosuppressive agent;
Hospitalisation related to EGPA worsening.
- Proportion of patients in each category of average daily
prednisolone/prednisone dose during weeks 48 to 52 using the following
categories: 0; >0 to ≤4 mg; >4 to ≤7.5 mg and > 7.5 mg
- Annualized relapse rate
- Proportion of patients who have achieved remission within the first 24
weeks and remained in remission for remainder of the double-blind
treatment period. Analysis will be repeated based on main and
supportive remission definitions.
- BVAS, VDI, pulmonary function testing, asthma symptoms (ACQ-6), SNOT-22 questionnaire, health-related
quality of life (SF-36v2), WPAI and blood eosinophil counts will be
assessed as change from baseline over the 52-week treatment period. Descriptive statistics will be provided for PGIS and WPAI to assess change from baseline over the 52 week double-blind period.
PGIC will be assessed as response proportions at each weekly
assessment between Visits 2 and 4
- Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and electrocardiogram (ECG).
Study end point(s) for open label extension (OLE) period:
- Remission, relapse (as defined in the secondary endpoints), OCS use
-Safety and tolerability will be evaluated based on AEs, Vital signs,
physical exam, Clinical laboratory, and ECG .
-Serum benralizumab concentrations, Anti-benralizumab antibodies and
neutralizing antibodies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Varies depending on the endpoint/objective |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 34 |
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 |
Belgium |
Canada |
France |
Germany |
Israel |
Italy |
Japan |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 17 |