BENRALIZUMAB for Eosinophilic granulomatosis with polyangiitis (EGPA)

Inclusion criteria

• {"criterion_text":"- 1. Male or female subjects age 18 years or older."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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)."}
• {"criterion_text":"- 6. QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle branch block."}
• {"criterion_text":"- 7. Females of childbearing potential must use an acceptable method of birth control from randomisation for at least 12 weeks after the last study drug administration."}

Exclusion criteria

• {"criterion_text":"- 1. Diagnosed with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)."}
• {"criterion_text":"- 10. Known immunodeficiency disorder or positive HIV test."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 2. Organ or life-threatening EGPA < 3 months prior to screening."}
• {"criterion_text":"- 3. Currently pregnant or breastfeeding, or planning to become pregnant during study participation."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 5. An untreated or refractory helminth parasitic infection < 24 weeks prior to screening."}
• {"criterion_text":"- 6. Unstable liver disease."}
• {"criterion_text":"- 7. Severe or clinically significant, uncontrolled cardiovascular disease."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 9. Chronic or ongoing infectious disease requiring systemic anti-infective treatment."}

Primary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Remission defined as BVAS = 0 and oral corticosteroid (OCS) dose ≤ 4 mg/day; assessed at both Weeks 36 and 48; proportion of patients meeting this definition is primary outcome."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Supportive remission defined as BVAS = 0 and OCS dose ≤ 7.5 mg/day; assessed at Weeks 36 and 48; proportion meeting this supportive definition."}

Secondary endpoints

• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Total accrued duration of remission categorized in specified time bands during double-blind period; analyses repeated for main and supportive remission definitions."}
• {"endpoint_text":"- (Part 1/2) - 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","definition_or_measurement_approach":"Time-to-event (from randomisation to first relapse) where relapse is defined by criteria including BVAS > 0 or worsening ACQ-6 for asthma; (text continues in next endpoint part)."}
• {"endpoint_text":"- (Part 2/2) *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.","definition_or_measurement_approach":"Relapse definition continued: active nasal/sinus disease with worsening symptoms that lead to increased OCS (>4 mg prednisolone/day), increased/additional immunosuppressive therapy, or hospitalisation."}
• {"endpoint_text":"- (Part 1*/2*) -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.","definition_or_measurement_approach":"Categorical assessment of average daily prednisolone/prednisone dose during Weeks 48–52 with specified dose bands; proportion in each category reported."}
• {"endpoint_text":"- (Part 2*/2*) *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.","definition_or_measurement_approach":"Assess percent reduction from baseline prednisolone/prednisone dose across specified categories; report proportions meeting ≥50% and 100% reduction and proportion with ≤4 mg average daily dose."}
• {"endpoint_text":"- (Part 1**/2**) - 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.","definition_or_measurement_approach":"Composite clinical benefit and complete response definitions described in protocol; proportion meeting any vs all criteria will be reported."}
• {"endpoint_text":"- (Part 2**/2**) *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.","definition_or_measurement_approach":"Endpoints include remission at any time during DB period (BVAS=0 and pred ≤4 mg/day), ≥50% reduction in average daily steroid dose (Weeks 48–52), and relapse-free status during DB period; analyses repeated for supportive remission definition."}
• {"endpoint_text":"- Annualized relapse rate","definition_or_measurement_approach":"Annualized count of EGPA relapses per patient-year during the specified assessment period."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Proportion achieving remission within 24 weeks and sustaining it through end of DB period; analyses with main and supportive definitions."}
• {"endpoint_text":"- 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. 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.","definition_or_measurement_approach":"Various clinical assessments and PROs measured as change from baseline over 52-week DB period; PGIS/WPAI descriptive statistics; PGIC measured as weekly response proportions between specified visits."}
• {"endpoint_text":"- Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and electrocardiogram (ECG).","definition_or_measurement_approach":"Safety endpoints captured by adverse events, vital signs, physical exams, laboratory tests, and ECG assessments."}
• {"endpoint_text":"- Study end point(s) for open label extension (OLE) period: - Remission, relapse (as defined in the secondary endpoints), OCS use","definition_or_measurement_approach":"OLE endpoints include remission and relapse using the same definitions as DB period and assessment of oral corticosteroid use."}
• {"endpoint_text":"- Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and ECG .","definition_or_measurement_approach":"OLE safety assessed by AEs, vitals, physical exam, labs and ECG."}
• {"endpoint_text":"- Serum benralizumab concentrations, Anti-benralizumab antibodies and neutralizing antibodies.","definition_or_measurement_approach":"Pharmacokinetic and immunogenicity assessments including serum benralizumab concentrations and anti-drug/neutralizing antibody measurements."}

France

Earliest CTIS Part Ii Submission Date

09-04-2024

Latest Decision Or Authorization Date

06-08-2024

Processing Time Days

119

Number Of Sites

7

Number Of Participants

33

Germany

Earliest CTIS Part Ii Submission Date

15-04-2024

Latest Decision Or Authorization Date

06-08-2024

Processing Time Days

113

Number Of Sites

4

Number Of Participants

17

Belgium

Earliest CTIS Part Ii Submission Date

09-04-2024

Latest Decision Or Authorization Date

02-08-2024

Processing Time Days

115

Number Of Sites

2

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

02-04-2024

Latest Decision Or Authorization Date

09-03-2026

Processing Time Days

706

Number Of Sites

6

Number Of Participants

18

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden