Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab.

Phase 3

Active, not recruiting

Conditions: Eosinophilic Granulomatous Vasculitis

Interventions: Biological: Benralizumab
Biological: Mepolizumab
Biological: Placebo to Mepolizumab
Biological: Placebo to Benralizumab

Registration Number: NCT04157348

Lead Sponsor: AstraZeneca

Brief Summary: This is a randomized, double blind, active-controlled, parallel group, multicenter 52-week Phase 3 study to compare the efficacy and safety of benralizumab 30 mg versus mepolizumab 300 mg administered by subcutaneous (SC) injection in patients with relapsing or refractory EGPA on corticosteroid therapy with or without stable immunosuppressive therapy.

All patients who complete the 52-week double-blind treatment period on IP may be eligible to continue into an open label extension (OLE) period. The OLE period is intended to allow each patient at least 1 year of treatment with open-label benralizumab 30 mg administered SC (earlier enrolled patients may therefore be in the OLE for longer than 1 year).

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 140

Inclusion Criteria

Male or female subjects age 18 years or older.
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).
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.
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.
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).
QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle branch block.
Females of childbearing potential must use an acceptable method of birth control from randomization for at least 12 weeks after the last study drug administration.

Exclusion Criteria

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Benralizumab arm	Benralizumab	1x benralizumab SC injection + 3x placebo to mepolizumab SC injections
Mepolizumab arm	Mepolizumab	3x mepolizumab SC injections + 1x placebo to benralizumab SC injection
Benralizumab arm	Placebo to Mepolizumab	1x benralizumab SC injection + 3x placebo to mepolizumab SC injections
Mepolizumab arm	Placebo to Benralizumab	3x mepolizumab SC injections + 1x placebo to benralizumab SC injection

Primary Outcome Measures

Name	Time	Method
Number of Subjects Who Achieved Main Remission at Both Weeks 36 and 48	Week 36 and Week 48	Percentage of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS = 0 and OCS dose ≤ 4 mg/day (main remission definition) at both Weeks 36 and 48.
Supportive Endpoint: Proportion of Subjects Who Achieved Supportive Remission at Both Weeks 36 and 48	Week 36 and Week 48	Supportive endpoint: Proportion of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS = 0 and OCS dose ≤ 7.5 mg/day (supportive remission definition) at both Weeks 36 and 48.

Secondary Outcome Measures

Name	Time	Method
Spirometry Change From Baseline by Timepoint up to Week 52: Pre-BD FVC (L)	from baseline to end of DB period, 52 Weeks	Pre-bronchodilator (BD) Forced vital capacity (FVC) change from baseline by timepoint up to week 52
Proportion of Patients Who Have Achieved Remission Within the First 24 Weeks and Remained in Remission for Remainder of the Double-blind Treatment Period	from baseline to end of DB period, 52 Weeks	Proportion of patients who have achieved remission within the first 24 weeks and remained in remission for remainder of the double-blind treatment period
Total Accrued Duration of Remission During DB Treatment Period	from baseline to end of DB period, 52 Weeks.	Total accrued duration of remission for the following categories: 0 week, \> 0 to \< 12 week, 12 to \< 24 week, 24 to \< 36 week, ≥ 36 week.
Total Accrued Duration of Sustained Remission During DB Treatment Period	from baseline to end of DB period, 52 Weeks	Total accrued duration of sustained remission for the following categories: 0 week, \> 0 to \< 12 week, 12 to \< 24 week, 24 to \< 36 week, ≥ 36 week.
Time From Randomization to First Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse	from baseline to end of DB period, 52 Weeks	Time from randomization to first Eosinophilic Granulomatosis with Polyangiitis (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 increased dose of OCS therapy to \> 4 mg/day prednisolone total daily dose; OR * An increased dose or addition of immunosuppressive therapy; OR * Hospitalization related to EGPA worsening Calculated using the Kaplan-Meier technique.
Annualized Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse Rate	from baseline to end of DB period, 52 Weeks	Annualized Eosinophilic Granulomatosis with Polyangiitis (EGPA) relapse rate through end of DB treatment period. The estimate of annualized relapse rate (relapses per year) and the corresponding 95% CIs were calculated using a negative binomial model. The response variable in the model is the number of relapses experienced by a subject up to Week 52. The logarithm of the subject's corresponding follow-up time up to Week 52 was used as an offset variable to adjust for subjects having different follow-up times during which the events occur. The covariates in the model include treatment arm, baseline dose of prednisone, baseline BVAS and region.
Average Daily Dose of Prednisolone/Prednisone and Change From Baseline During Week 48 Through 52	last 4 weeks of DB period	Average daily dose of prednisolone/prednisone and change from baseline during Week 48 through 52, or last 28 days prior to last double-blind assessment for those that withdrew
Proportion of Patients With Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52	last 4 weeks of DB period	Proportion of patients with average daily dose of prednisolone/prednisone during Week 48 through 52 in each category: 0 mg; \>0 to ≤ 4 mg; \> 4 to ≤ 7.5 mg and \> 7.5 mg
Percentage Reduction From Baseline in Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52	last 4 weeks of DB period	Percentage reduction from baseline in average daily dose of prednisolone/prednisone during Week 48 through 52 in each category: no reduction or withdrawal from treatment; \< 25% reduction; 25 to \< 50% reduction; 50 to \<75% reduction; 75 to \< 100% reduction; 100% reduction.
Proportion of Subjects With Reduction From Baseline in Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52	last 4 weeks of DB period	Proportion of subjects with reduction from baseline in average daily dose of prednisolone/prednisone during Week 48 through 52 in each category: \>= 50% reduction; 100% reduction; OCS dose \<= 4 mg/day.
Proportion of Subjects Who Achieve Clinical Benefit	from baseline to end of DB period, 52 Weeks	Proportion of subjects who achieved any clinical benefit definition 1 (defined as any of the following: * Main remission at any time in DB period * \>= 50% reduction in OCS dose in Weeks 48 to 52 * EGPA relapse free in DB period) and subjects who achieved complete response definition 1 (defined as meeting all the definition 1 criteria above.)
Change From Baseline in Birmingham Vasculitis Activity Score (BVAS)	from baseline to end of DB period, 52 Weeks	Birmingham Vasculitis Activity Score (BVAS) change from baseline by timepoint up to week 52. The BVAS form is divided into 9 organ-based systems, with each section including symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. The total score on all 9 organ systems gives an indication of the disease activity of each patient at the time of scoring. Total scores range from 0 to 63, with higher scores indicating more active vasculitis.
Spirometry Change From Baseline by Timepoint up to Week 52: Pre-BD FEV1 (L)	from baseline to end of DB period, 52 Weeks	Pre-bronchodilator (BD) Forced Expiratory Volume during first second (FEV1) change from baseline by timepoint up to week 52
Change From Baseline in Vasculitis Damage Index (VDI)	from baseline to end of DB period, 52 Weeks	Vasculitis Damage Index (VDI) change from baseline by timepoint up to week 52. The VDI is divided into 11 organ systems and records items of damage, due to vasculitis, treatment or unrelated, that have occurred since the onset of vasculitis. Completion of the form provides a numerical score, ranging from 0 to 64, with a higher score indicating more damage.
Change From Baseline in Asthma Control Questionnaire (6-item Version) (ACQ-6)	from baseline to end of DB period, 52 Weeks	Asthma Control Questionnaire (6-item version) (ACQ-6) change from baseline by timepoint up to week 52. The ACQ-6 score is calculated by taking the mean of 6 equally weighted domains, with a range of 0 (well controlled) to 6 (extremely poorly controlled).
Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) Component: Physical Component Summary (PCS)	from baseline to end of DB period, 52 Weeks	Short Form 36-item health survey (version 2, acute recall) (SF-36v2) component Physical Component Summary (PCS) change from baseline by timepoint up to week 52. PCS score ranges from 10.8 to 75.5, where a higher score indicates better health.
Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) Component: Mental Component Summary (MCS)	from baseline to end of DB period, 52 Weeks	Short Form 36-item health survey (version 2, acute recall) (SF-36v2) component Mental Component Summary (MCS) change from baseline by timepoint up to week 52. MCS score ranges from 5.6 to 69.7, where a higher score indicates better health.
Change From Baseline in Sino-nasal Outcome Test-22 (SNOT-22) Total Score	from baseline to end of DB period, 52 Weeks	Sino-nasal Outcome Test-22 (SNOT-22) total score change from baseline by timepoint up to week 52. Patient reported symptom severity and symptom impact over the previous 2 weeks on 22 items are captured via a 6-point scale (0 = no problem to 5 = problem as bad as it can be). The total score is the sum of item scores and ranges from 0 to 110 (higher scores indicate poorer outcomes).
Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Runny Nose	from baseline to end of DB period, 52 Weeks	Sino-nasal Symptoms Questionnaire (SSQ) scores : symptom runny nose by timepoint. For the SSQ, participants rate each symptom against the following categories: very severe, severe, moderate, mild, none. Higher scores indicate greater severity (0 = none to 4 = very severe).
Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Post-nasal Discharge	from baseline to end of DB period, 52 Weeks	Sino-nasal Symptoms Questionnaire (SSQ) scores : symptom Post-nasal discharge by timepoint. For the SSQ, participants rate each symptom against the following categories: very severe, severe, moderate, mild, none. Higher scores indicate greater severity (0 = none to 4 = very severe).
Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Facial Pain/Pressure	from baseline to end of DB period, 52 Weeks	Sino-nasal Symptoms Questionnaire (SSQ) scores: symptom Facial pain/pressure by timepoint. For the SSQ, participants rate each symptom against the following categories: very severe, severe, moderate, mild, none. Higher scores indicate greater severity (0 = none to 4 = very severe).
Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Loss or Reduction in Sense of Taste/Smell	from baseline to end of DB period, 52 Weeks	Sino-nasal Symptoms Questionnaire (SSQ) scores: symptom Loss or reduction in sense of taste/smell by timepoint. For the SSQ, participants rate each symptom against the following categories: very severe, severe, moderate, mild, none. Higher scores indicate greater severity (0 = none to 4 = very severe).
Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Blockage/Congestion of Nose	from baseline to end of DB period, 52 Weeks	Sino-nasal Symptoms Questionnaire (SSQ) scores: symptom Blockage/congestion of nose by timepoint. For the SSQ, participants rate each symptom against the following categories: very severe, severe, moderate, mild, none. Higher scores indicate greater severity (0 = none to 4 = very severe).
Patient Global Impression of Severity (PGIS) Category	from baseline to end of DB period, 52 Weeks	Patient Global Impression of Severity (PGIS) category by timepoint
Patient Global Impression of Change (PGIC) Category	from baseline to week 4	Patient Global Impression of Change (PGIC) category by timepoint
WPAI-GH Endpoint, Change From Baseline by Timepoint: Absenteeism (%)	from baseline to end of DB period, 52 Weeks	The Work Productivity and Activity Impairment questionnaire (WPAI-GH) has 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment for the 7 days prior to the assessment. WPAI outcomes are presented as impairment percentages (a higher percentage indicating greater impairment and less productivity). Subscale: Absenteeism (work time missed) (%) score, range 0-100.
WPAI-GH Endpoint, Change From Baseline by Timepoint up to Week 52: Subscale: Presenteeism (Impairment at Work) (%), Range 0-100.	from baseline to end of DB period, 52 Weeks	The Work Productivity and Activity Impairment questionnaire (WPAI-GH) has 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment for the 7 days prior to the assessment. WPAI outcomes are presented as impairment percentages (a higher percentage indicating greater impairment and less productivity). Presenteeism (%) score.
WPAI-GH Endpoint, Change From Baseline by Timepoint: Work Productivity Loss (%)	from baseline to end of DB period, 52 Weeks	The Work Productivity and Activity Impairment questionnaire (WPAI-GH) has 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment for the 7 days prior to the assessment. WPAI outcomes are presented as impairment percentages (a higher percentage indicating greater impairment and less productivity). Work productivity loss (%) score, range 0-100.
WPAI-GH Endpoint, Change From Baseline by Timepoint: Activity Impairment (%)	from baseline to end of DB period, 52 Weeks	The Work Productivity and Activity Impairment questionnaire (WPAI-GH) has 6 questions which address absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment for the 7 days prior to the assessment. WPAI outcomes are presented as impairment percentages (a higher percentage indicating greater impairment and less productivity). Activity impairment (%) score, range 0-100.
Absolute Eosinophil Count, Change From Baseline	from baseline to end of DB period, 52 Weeks	Absolute eosinophil count, change from baseline by timepoint up to week 52