Clinical trial NCT04157348: Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab.
Official title: A Randomised, Double-blind, Active-controlled 52-week Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab Compared to Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis (EGPA) in Patients Receiving Standard of Care Therapy (MANDARA Study)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Eosinophilic Granulomatous Vasculitis
Keywords: Benralizumab
Inhaled corticosteroids
Eosinophilic Granulomatous Vasculitis
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-11-08
Enrollment: 140
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Subjects Who Achieved Main Remission at Both Weeks 36 and 48
timeFrame: Week 36 and Week 48
measure: Supportive Endpoint: Proportion of Subjects Who Achieved Supportive Remission at Both Weeks 36 and 48
timeFrame: Week 36 and Week 48
Secondary outcomes:
measure: Total Accrued Duration of Remission During DB Treatment Period
timeFrame: from baseline to end of DB period, 52 Weeks.
measure: Total Accrued Duration of Sustained Remission During DB Treatment Period
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Time From Randomization to First Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Annualized Eosinophilic Granulomatosis With Polyangiitis (EGPA) Relapse Rate
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Average Daily Dose of Prednisolone/Prednisone and Change From Baseline During Week 48 Through 52
timeFrame: last 4 weeks of DB period
measure: Proportion of Patients With Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52
timeFrame: last 4 weeks of DB period
measure: Percentage Reduction From Baseline in Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52
timeFrame: last 4 weeks of DB period
measure: Proportion of Subjects With Reduction From Baseline in Average Daily Dose of Prednisolone/Prednisone During Week 48 Through 52
timeFrame: last 4 weeks of DB period
measure: Proportion of Subjects Who Achieve Clinical Benefit
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Proportion of Patients Who Have Achieved Remission Within the First 24 Weeks and Remained in Remission for Remainder of the Double-blind Treatment Period
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Change From Baseline in Birmingham Vasculitis Activity Score (BVAS)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Spirometry Change From Baseline by Timepoint up to Week 52: Pre-BD FEV1 (L)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Spirometry Change From Baseline by Timepoint up to Week 52: Pre-BD FVC (L)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Change From Baseline in Vasculitis Damage Index (VDI)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Change From Baseline in Asthma Control Questionnaire (6-item Version) (ACQ-6)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) Component: Physical Component Summary (PCS)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Change From Baseline in Short Form 36-item Health Survey (Version 2, Acute Recall) (SF-36v2) Component: Mental Component Summary (MCS)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Change From Baseline in Sino-nasal Outcome Test-22 (SNOT-22) Total Score
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Runny Nose
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Post-nasal Discharge
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Facial Pain/Pressure
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Loss or Reduction in Sense of Taste/Smell
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Sino-nasal Symptoms Questionnaire (SSQ) Scores: Symptom Blockage/Congestion of Nose
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Patient Global Impression of Severity (PGIS) Category
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Patient Global Impression of Change (PGIC) Category
timeFrame: from baseline to week 4
measure: WPAI-GH Endpoint, Change From Baseline by Timepoint: Absenteeism (%)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: WPAI-GH Endpoint, Change From Baseline by Timepoint up to Week 52: Subscale: Presenteeism (Impairment at Work) (%), Range 0-100.
timeFrame: from baseline to end of DB period, 52 Weeks
measure: WPAI-GH Endpoint, Change From Baseline by Timepoint: Work Productivity Loss (%)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: WPAI-GH Endpoint, Change From Baseline by Timepoint: Activity Impairment (%)
timeFrame: from baseline to end of DB period, 52 Weeks
measure: Absolute Eosinophil Count, Change From Baseline
timeFrame: from baseline to end of DB period, 52 Weeks
Other outcomes:
Locations:
city: Denver
country: United States
facility: Research Site
state: Colorado
city: Ann Arbor
country: United States
facility: Research Site
state: Michigan
city: Rochester
country: United States
facility: Research Site
state: Minnesota
city: Albuquerque
country: United States
facility: Research Site
state: New Mexico
city: Great Neck
country: United States
facility: Research Site
state: New York
city: New York
country: United States
facility: Research Site
state: New York
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Denison
country: United States
facility: Research Site
state: Texas
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Brussels
country: Belgium
facility: Research Site
city: Brussel
country: Belgium
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Hamilton
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Dijon Cedex
country: France
facility: Research Site
city: Marseille
country: France
facility: Research Site
city: Montpellier
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Paris
country: France
facility: Research Site
city: Suresnes Cedex
country: France
facility: Research Site
city: Toulouse
country: France
facility: Research Site
city: Bamberg
country: Germany
facility: Research Site
city: Freiburg
country: Germany
facility: Research Site
city: Hamburg
country: Germany
facility: Research Site
city: Kirchheim
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Ashkelon
country: Israel
facility: Research Site
city: Beer Sheva
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Rehovot
country: Israel
facility: Research Site
city: Tel Aviv
country: Israel
facility: Research Site
city: Cuneo
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Chiba-shi
country: Japan
facility: Research Site
city: Kita-gun
country: Japan
facility: Research Site
city: Sagamihara-shi
country: Japan
facility: Research Site
city: Sendai-shi
country: Japan
facility: Research Site
city: Shinjuku-ku
country: Japan
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Portsmouth
country: United Kingdom
facility: Research Site
Study officials:
affiliation: National Jewish Health, 1400 Jackson St Denver, CO 80206
name: Michael Wechsler, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Serling-Boyd N, Wallace ZS. Management of primary vasculitides with biologic and novel small molecule medications. Curr Opin Rheumatol. 2021 Jan;33(1):8-14. doi: 10.1097/BOR.0000000000000756.