E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Eosinophilic Granulomatosis with Polyangiitis (EGPA) |
|
E.1.1.1 | Medical condition in easily understood language |
Eosinophilic Granulomatosis with Polyangiitis (EGPA) |
|
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10078117 |
E.1.2 | Term | Eosinophilic granulomatosis with polyangiitis |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
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. |
|
E.2.2 | Secondary objectives of the trial |
DB To assess: -the efficacy of benralizumab compared with mepolizumab on duration f clinical remission -the efficacy of benralizumab compared with mepolizumab on time to first relapse -the effect of benralizumab on corticosteroid dose required during Weeks 48 through 52 compared to mepolizumab -the clinical benefit of benralizumab compared to mepolizumab -the annualized relapse rate in benralizumab compared to mepolizumab group -the proportion of patients achieving remission within the first 24 wks and remain in remission for the remainder of the DB period in benralizumab compared to mepolizumab group -additional measures of efficacy and health status/health-related quality of life in patients receiving benralizumab compared to mepolizumab -the safety and tolerability of benralizumab compared to mepolizumab -the pharmacokinetics and immunogenicity of benralizumab OLE - To assess the safety and tolerability of benralizumab |
|
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 |
A. Mechanistic Sub-study Objective: 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.
B. Patient Qualitative Interview Sub-study Objective: To characterize the impact of EGPA on patients’ lives and their experiences with study treatment. |
|
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. |
|
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 anti-infective 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 screening, 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. |
|
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. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
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.
-Based on the average daily prednisolone/prednisone dose during Weeks 48 through 52: *Proportion of patients in each category of average daily prednisolone/prednisone dose during Weeks 48 through 52 using the following categories: 0 mg; > 0 to ≤ 4 mg; > 4 to ≤ 7.5 mg and > 7.5 mg. *Proportion of patients in each category of percent reduction from baseline: no reduction or withdrawal from treatment; < 25% reduction; 25 to < 50% reduction; 50 to < 75% reduction; 75 to < 100% reduction; 100% reduction. *Proportion of patients with ≥ 50% reduction from baseline. *Proportion of patients with 100% reduction from baseline. *Proportion of patients with ≤ 4 mg in average daily dose.
- Proportion of patients who have achieved any clinical benefit when meeting any of the criteria below. Proportion of patients who have achieved complete response when meeting all of the criteria below. *Remission (defined as BVAS = 0 and prednisolone/prednisone dose ≤ 4 mg/day) at any time during the double-blind treatment period *≥ 50% reduction in average daily prednisolone/prednisone dose during Weeks 48 through 52 *EGPA relapse free during the double-blind treatment period. Analysis will be repeated for the supportive remission definition.
- 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 double-blind treatment period. escriptive 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, hysical exam, Clinical laboratory, and ECG .
-Serum benralizumab concentrations, Anti-benralizumab antibodies and neutralizing antibodies |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Varies depending on the endpoint/objective |
|
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Canada |
Israel |
Japan |
United States |
Belgium |
France |
Germany |
Italy |
United Kingdom |
|
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
|
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs under FDA and EU regulatory requirements: EU requirements define study completion as the last visit of the last subject for any protocol related activity. |
|
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 | 10 |
E.8.9.1 | In the Member State concerned days | |
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 | 10 |