Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab. (MANDARA)
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|ClinicalTrials.gov Identifier: NCT04157348|
Recruitment Status : Recruiting
First Posted : November 8, 2019
Last Update Posted : February 5, 2021
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).
|Condition or disease||Intervention/treatment||Phase|
|Eosinophilic Granulomatous Vasculitis||Biological: Benralizumab Biological: Mepolizumab Biological: Placebo to Mepolizumab Biological: Placebo to Benralizumab||Phase 3|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||140 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||A Randomized, 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|
|Actual Study Start Date :||October 29, 2019|
|Estimated Primary Completion Date :||December 30, 2022|
|Estimated Study Completion Date :||January 27, 2024|
Experimental: Benralizumab arm
1x benralizumab SC injection + 3x placebo to mepolizumab SC injections
30 mg/mL solution for injection in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC)
Biological: Placebo to Mepolizumab
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)
Active Comparator: Mepolizumab arm
3x mepolizumab SC injections + 1x placebo to benralizumab SC injection
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)
Biological: Placebo to Benralizumab
Matching placebo solution for injection in APFS, 1 mL fill volume. Placebo solution will be administered subcutaneously (SC)
- Proportion of patients who are in remission at both weeks 36 and 48 [ Time Frame: 36 and 48 weeks ]
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.
- Number of patients in each category of accrued duration of remission [ Time Frame: Up to 52 weeks ]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.
- Time from randomisation to first EGPA relapse [ Time Frame: During first 52 weeks ]
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 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.
- Number of patients in each category of average daily prednisolone/prednisone dose during weeks 48 through 52 [ Time Frame: 48 through 52 weeks ]The categories of average daily prednisolone/prednisone dose are: 0; >0 to ≤4 mg; >4 to ≤7.5 mg and > 7.5 mg.
- Annualized relapse rate [ Time Frame: Over first 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 [ Time Frame: Up to 52 weeks ]Analysis will be repeated based on main and supportive remission definitions.
- Change from baseline in VDI [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in BVAS [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in pulmonary function [ Time Frame: Up to 52 weeks ]As measured by Forced vital capacity (FVC), unit L
- Change from baseline in pulmonary function [ Time Frame: Up to 52 weeks ]As measured by Forced Expiratory Volume during first second (FEV1), unit L
- Change from baseline in ACQ-6 [ Time Frame: Up to 52 weeks ]
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 well controlled. Higher scores indicate worse disease control.
- Change from baseline in sino-nasal symptoms (SSQ) [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in SNOT-22 [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in SF-36v2 [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in PGIS [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in WPAI [ Time Frame: Up to 52 weeks ]
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.
- Change from baseline in blood eosinophil counts [ Time Frame: Up to 52 weeks ]
- Proportion of PGIC responders at each weekly assessment [ Time Frame: Up to 4 weeks ]
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.
- Numbers of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Minimum of 52 weeks ]
- Change from baseline in systolic and diastolic blood pressure [ Time Frame: Minimum of 52 weeks ]
- Change from baseline in pulse rate [ Time Frame: Minimum of 52 weeks ]
- Change from baseline in hematology parameters of hemoglobin, leukocytes, lymphocytes, monocytes, basophils, eosinophils, neutrophils, and platelets [ Time Frame: Minimum of 52 weeks ]
- 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 ]
- Change from baseline in QT Interval Corrected by Fridericia's Method (QTcF) [ Time Frame: Minimum of 52 weeks ]Triplicate measurements of 12-lead electrocardiograms recorded at rest.
- Serum benralizumab concentration as a measure of pharmacokinetics [ Time Frame: Minimum of 52 weeks ]
- Anti-drug antibodies (ADA) titers as measure of immunogenicity [ Time Frame: Minimum of 52 weeks ]
- Cumulative OCS use [ Time Frame: Up to 52 weeks ]Total OCS use (measured in mg) as measured by sum of all daily doses during the 52-week double-blind period.
- Number of EGPA related hospitalisations [ Time Frame: Up to 52 weeks ]
- Length of hospital stay [ Time Frame: Up to 52 weeks ]
- ICU (Intensive Care Unit) days [ Time Frame: Up to 52 weeks ]
- Number of EGPA related ER visits [ Time Frame: Up to 52 weeks ]
- Number of EGPA related outpatient visits [ Time Frame: Up to 52 weeks ]
- Number of EGPA related procedures/tests (by specific procedure/test) [ Time Frame: Up to 52 weeks ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04157348
|Contact: AstraZeneca Clinical Study Information Centerfirstname.lastname@example.org|
|Principal Investigator:||Michael Wechsler, MD||National Jewish Health, 1400 Jackson St Denver, CO 80206|