Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab.

Phase 3Active Not RecruitingNCT04157348

AstraZeneca140 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

140

Conditions

Eosinophilic Granulomatous Vasculitis

Interventions

MepolizumabBIOLOGICAL

3x100 mg vials of powder for solution for injection reconstituted into 3 separate 1 mL syringes for administration on each dosing occasion. Injection volume per syringe is 1 mL. Mepolizumab active solution will be administered subcutaneously (SC)

Placebo to MepolizumabBIOLOGICAL

Matching placebo: 0.9% sodium chloride, solutions for injection in 1mL syringes (3 syringes will be used on each dosing occasion). Injection volume per syringe is 1mL. Placebo to Mepolizumban will be administered subcutaneously (SC)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 130 Years

Medical Language ↔ Plain English

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 randomization for at least 12 weeks after the last study drug administration. 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.

Locations (50)

Research Site

Denver, Colorado, United States

Research Site

Ann Arbor, Michigan, United States

Research Site

Rochester, Minnesota, United States

Research Site

Albuquerque, New Mexico, United States

Research Site

Great Neck, New York, United States

Research Site

Outcomes

Primary Outcomes

Number of Subjects Who Achieved Main Remission at Both Weeks 36 and 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.

Time frame: Week 36 and Week 48

Supportive Endpoint: Proportion of Subjects Who Achieved Supportive Remission at Both Weeks 36 and 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.

Time frame: Week 36 and Week 48

Secondary Outcomes

Total Accrued Duration of Remission During DB Treatment Period

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.

Time frame: from baseline to end of DB period, 52 Weeks.

Total Accrued Duration of Sustained Remission During DB Treatment Period

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 frame: from baseline to end of DB period, 52 Weeks

Time From Randomization to First Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse

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.

Time frame: from baseline to end of DB period, 52 Weeks

Annualized Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse Rate

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.

Time frame: from baseline to end of DB period, 52 Weeks

Average Daily Dose of Prednisolone/Prednisone and Change From Baseline During Week 48 Through 52

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

Time frame: last 4 weeks of DB period

Proportion of Patients With Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52

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

Time frame: last 4 weeks of DB period

Percentage Reduction From Baseline in Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52

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.

Time frame: 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

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.

Time frame: last 4 weeks of DB period

Proportion of Subjects Who Achieve Clinical Benefit

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.)

Time frame: 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

Proportion of patients who have achieved remission within the first 24 weeks and remained in remission for remainder of the double-blind treatment period

Time frame: from baseline to end of DB period, 52 Weeks

Change From Baseline in Birmingham Vasculitis Activity Score (BVAS)

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.

Time frame: from baseline to end of DB period, 52 Weeks

Spirometry Change From Baseline by Timepoint up to Week 52: Pre-BD FEV1 (L)

Pre-bronchodilator (BD) Forced Expiratory Volume during first second (FEV1) change from baseline by timepoint up to week 52

Time frame: from baseline to end of DB period, 52 Weeks

Spirometry Change From Baseline by Timepoint up to Week 52: Pre-BD FVC (L)

Pre-bronchodilator (BD) Forced vital capacity (FVC) change from baseline by timepoint up to week 52

Time frame: from baseline to end of DB period, 52 Weeks

Change From Baseline in Vasculitis Damage Index (VDI)

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.

Time frame: from baseline to end of DB period, 52 Weeks

Change From Baseline in Asthma Control Questionnaire (6-item Version) (ACQ-6)

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).

Time frame: from baseline to end of DB period, 52 Weeks

Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) Component: Physical Component Summary (PCS)

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.

Time frame: from baseline to end of DB period, 52 Weeks

Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) Component: Mental Component Summary (MCS)

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.

Time frame: from baseline to end of DB period, 52 Weeks

Change From Baseline in Sino-nasal Outcome Test-22 (SNOT-22) Total Score

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).

Time frame: from baseline to end of DB period, 52 Weeks

Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Runny Nose

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).

Time frame: from baseline to end of DB period, 52 Weeks

Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Post-nasal Discharge

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).

Time frame: from baseline to end of DB period, 52 Weeks

Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Facial Pain/Pressure

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).

Time frame: from baseline to end of DB period, 52 Weeks

Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Loss or Reduction in Sense of Taste/Smell

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).

Time frame: from baseline to end of DB period, 52 Weeks

Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Blockage/Congestion of Nose

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).

Time frame: from baseline to end of DB period, 52 Weeks

Patient Global Impression of Severity (PGIS) Category

Patient Global Impression of Severity (PGIS) category by timepoint

Time frame: from baseline to end of DB period, 52 Weeks

Patient Global Impression of Change (PGIC) Category

Patient Global Impression of Change (PGIC) category by timepoint

Time frame: from baseline to week 4

WPAI-GH Endpoint, Change From Baseline by Timepoint: Absenteeism (%)

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.

Time frame: from baseline to end of DB period, 52 Weeks

WPAI-GH Endpoint, Change From Baseline by Timepoint up to Week 52: Subscale: Presenteeism (Impairment at Work) (%), Range 0-100.

Time frame: from baseline to end of DB period, 52 Weeks

WPAI-GH Endpoint, Change From Baseline by Timepoint: Work Productivity Loss (%)

Time frame: from baseline to end of DB period, 52 Weeks

WPAI-GH Endpoint, Change From Baseline by Timepoint: Activity Impairment (%)

Time frame: from baseline to end of DB period, 52 Weeks

Absolute Eosinophil Count, Change From Baseline

Absolute eosinophil count, change from baseline by timepoint up to week 52

Time frame: from baseline to end of DB period, 52 Weeks