- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04157348
Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab. (MANDARA)
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)
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 Overview
Status
Conditions
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
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Brussel, Belgium, 1090
- Research Site
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Brussels, Belgium, 1070
- Research Site
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Alberta
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Calgary, Alberta, Canada, T2N 4Z6
- Research Site
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Ontario
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Hamilton, Ontario, Canada, L8N 4A6
- Research Site
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Toronto, Ontario, Canada, M5T 3A9
- Research Site
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Toronto, Ontario, Canada, M5G 1E2
- Research Site
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Dijon Cedex, France, 21079
- Research Site
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Marseille, France, 13915
- Research Site
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Montpellier, France, 34090
- Research Site
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Nantes Cedex 1, France, 44093
- Research Site
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Paris, France, 75014
- Research Site
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Paris, France, 75877
- Research Site
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Suresnes Cedex, France, 92151
- Research Site
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Toulouse, France, 31059
- Research Site
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Bamberg, Germany, 96049
- Research Site
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Freiburg, Germany, 79106
- Research Site
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Hamburg, Germany, 20251
- Research Site
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Kirchheim, Germany, 73230
- Research Site
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Lübeck, Germany, 23538
- Research Site
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Ashkelon, Israel, 7830604
- Research Site
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Beer Sheva, Israel, 84101
- Research Site
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Jerusalem, Israel, 91120
- Research Site
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Ramat Gan, Israel, 52621
- Research Site
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Rehovot, Israel, 7661041
- Research Site
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Tel Aviv, Israel, 6423906
- Research Site
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Cuneo, Italy, 12100
- Research Site
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Firenze, Italy, 50141
- Research Site
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Milano, Italy, 20132
- Research Site
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Milano, Italy, 20162
- Research Site
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Napoli, Italy, 80131
- Research Site
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Roma, Italy, 00168
- Research Site
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Torino, Italy, 10128
- Research Site
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Chiba-shi, Japan, 260-0877
- Research Site
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Kita-gun, Japan, 761-0793
- Research Site
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Sagamihara-shi, Japan, 228-0815
- Research Site
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Sendai-shi, Japan, 980-8574
- Research Site
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Shinjuku-ku, Japan, 162-8666
- Research Site
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Cambridge, United Kingdom, CB2 0QQ
- Research Site
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Leicester, United Kingdom, LE3 9QP
- Research Site
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London, United Kingdom, SE19RT
- Research Site
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Portsmouth, United Kingdom, PO6 3LY
- Research Site
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Colorado
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Denver, Colorado, United States, 80206
- Research Site
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Michigan
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Ann Arbor, Michigan, United States, 48109
- Research Site
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Minnesota
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Rochester, Minnesota, United States, 55905-0001
- Research Site
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New Mexico
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Albuquerque, New Mexico, United States, 87106
- Research Site
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New York
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Great Neck, New York, United States, 11021
- Research Site
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New York, New York, United States, 10021
- Research Site
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Research Site
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Texas
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Denison, Texas, United States, 75020
- Research Site
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Washington
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Seattle, Washington, United States, 98115
- Research Site
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Benralizumab arm
1x benralizumab SC injection + 3x placebo to mepolizumab SC injections
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30 mg/mL solution for injection in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC)
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)
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Active Comparator: Mepolizumab arm
3x mepolizumab SC injections + 1x placebo to benralizumab SC injection
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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)
Matching placebo solution for injection in APFS, 1 mL fill volume.
Placebo solution will be administered subcutaneously (SC)
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Proportion of patients who are in remission at both weeks 36 and 48
Time Frame: week 36 and week 48
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Patients must be in remission at both of these timepoints of weeks 36 and 48. Main definition: Remission is defined as BVAS=0 and OCS dose ≤ 4mg/day. Supportive definition: Remission is defined by BVAS =0 and OCS dose ≤ 7.5 mg/day. Analysis will be repeated based on main and supportive remission definitions. |
week 36 and week 48
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Number of patients in each category of accrued duration of remission
Time Frame: Up to 52 weeks
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The categories of accrued duration of remission are: 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.
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Up to 52 weeks
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Time from randomisation to first EGPA relapse
Time Frame: During first 52 weeks
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Relapse is defined as any of the following:
warranting any of the following:
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During first 52 weeks
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Annualized relapse rate
Time Frame: Over first 52 weeks
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Over first 52 weeks
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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: Up to 52 weeks
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Analysis will be repeated based on main and supportive remission definitions.
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Up to 52 weeks
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Change from baseline in VDI
Time Frame: Up to 52 weeks
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Vasculitis Damage Index (VDI) Vasculitis Damage Index measures accrued damage across 11 organ systems since diagnosis. Total score is sum of all systems and ranges from 0 to 64 with higher scores indicating more damage. |
Up to 52 weeks
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Change from baseline in BVAS
Time Frame: Up to 52 weeks
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Birmingham Vasculitis Activity Score (BVAS) Birmingham Vasculitis Activity Score (BVAS) measures vasculitis disease activity across 9 organ systems. Total score is sum of the weighted organ scores and ranges from 0 to 63 with higher scores indicating higher disease activity. |
Up to 52 weeks
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Change from baseline in sino-nasal symptoms (SSQ)
Time Frame: Up to 52 weeks
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Sino-nasal Symptoms Questionnaire (SSQ) SSQ captures 5 different sino-nasal symptoms over the previous week as scored as none, mild, moderate, severe, or very severe. Higher scores indicate greater severity. |
Up to 52 weeks
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Change from baseline in SNOT-22
Time Frame: Up to 52 weeks
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Sino-nasal Outcome Test-22 (SNOT-22) The 22 items in SNOT-22 have a 6-point scale ranging from 0=no problem to 5=problem as bad as it can be. The total score is the sum of item scores and has a range from 0 to 110. Higher scores indicate poorer outcomes. |
Up to 52 weeks
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Change from baseline in SF-36v2
Time Frame: Up to 52 weeks
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Short Form 36-item health survey (version 2, acute recall) (SF-36v2) The short form 36-item health survey, version 2 (SF-36v2) is a 36-item, self-report survey of functional health and well-being. The assessment yields 8-domain profile consisting of the following: Physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE), and mental health (MH). Psychometrically-based physical and mental health component summary scores (PCS and MCS, respectively) are computed from subscale scores to give a broader metric of physical and mental health-related quality of life. The score range is 0 to 100 with higher scores indicating better health status. |
Up to 52 weeks
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Change from baseline in PGIS
Time Frame: Up to 52 weeks
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Patient Global Impression of Severity (PGIS) PGIS is a 6-point categorical response scale ranging from 0=no symptoms to 6= very severe symptoms. Higher scores indicate worse severity. |
Up to 52 weeks
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Change from baseline in WPAI
Time Frame: Up to 52 weeks
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Work productivity and Activity Impairment Questionnaire (WPAI) WPAI consists of 6 questions regarding absenteeism, presenteeism (reduced effectiveness while working), overall work productivity loss (absenteeism plus presenteeism), and activity impairment. WPAI outcomes are scored as impairment percentages, with a higher percentage indicating greater impairment and less productivity. |
Up to 52 weeks
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Change from baseline in blood eosinophil counts
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Proportion of PGIC responders at each weekly assessment
Time Frame: Up to 4 weeks
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Patient Global Impression of Change (PGIC) Patient Global Impression of Change (PGIC) measures the patient´s overall impression of response to treatment since the initial dose using a 7-point scale ranging from "much better", "about the same" to "much worse". Lower scores indicate better health status. |
Up to 4 weeks
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Based on the average daily prednisolone/prednisone dose during Weeks 48 through 52:
Time Frame: week 48 through week 52
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week 48 through week 52
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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.
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Change from baseline in pulmonary function
Time Frame: Up to 52 weeks
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As measured by Forced vital capacity (FVC) and Forced Expiratory Volume during first second (FEV1), unit L
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Up to 52 weeks
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Change from baseline in ACQ-6
Time Frame: Up to 52 weeks
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Asthma Control Questionnaire (6-item version) (ACQ-6 ) The 6 items in ACQ-6 have a 7-point scale ranging from 0=no impairment to 6=maximum impairment. The ACQ-6 score is calculated by taking the mean of the 6 equally weighted items ranging from 0=well controlled to 6=extremely poorly controlled. Higher scores indicate worse disease control. |
Up to 52 weeks
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Numbers of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Change from baseline in systolic and diastolic blood pressure
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Change from baseline in pulse rate
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Change from baseline in hematology parameters of hemoglobin, leukocytes, lymphocytes, monocytes, basophils, eosinophils, neutrophils, and platelets
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Change from baseline in clinical chemistry parameters of Alanine Aminotransferase (ALT), alkaline phosphatase, Aspartate Aminotransferase (AST), creatinine kinase, indirect and total bilirubin, creatinine and glucose
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Serum benralizumab concentration as a measure of pharmacokinetics
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Anti-drug antibodies (ADA) titers as measure of immunogenicity
Time Frame: Minimum of 52 weeks
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Minimum of 52 weeks
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Number of EGPA related hospitalisations
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Length of hospital stay
Time Frame: Up to 52 weeks
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Up to 52 weeks
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ICU (Intensive Care Unit) days
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Number of EGPA related ER visits
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Number of EGPA related outpatient visits
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Number of EGPA related procedures/tests (by specific procedure/test)
Time Frame: Up to 52 weeks
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Up to 52 weeks
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Overall interpretation of ECG by Investigator
Time Frame: Minimum of 52 weeks
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Triplicate measurements of 12-lead electrocardiograms recorded at rest.
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Minimum of 52 weeks
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Cumulative OCS use
Time Frame: Up to 52 weeks
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Total OCS use (measured in mg) as measured by sum of all daily prednisolone/prednisone doses, over the 52-week double-blind treatment period.
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Up to 52 weeks
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Michael Wechsler, MD, National Jewish Health, 1400 Jackson St Denver, CO 80206
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Cardiovascular Diseases
- Vascular Diseases
- Skin Diseases
- Immune System Diseases
- Lymphoproliferative Disorders
- Lymphatic Diseases
- Autoimmune Diseases
- Skin Diseases, Vascular
- Systemic Vasculitis
- Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis
- Granuloma
- Vasculitis
- Churg-Strauss Syndrome
- Anti-Asthmatic Agents
- Respiratory System Agents
- Benralizumab
Other Study ID Numbers
- D3253C00001
- 2019-001832-77 (EudraCT Number)
- 2023-510248-19-00 (Other Identifier: EU Trial (CTIS) Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
"Yes", indicates that AZ are accepting requests for IPD, but this does not mean all requests will be approved.
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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