Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab. (MANDARA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04157348
Recruitment Status : Recruiting
First Posted : November 8, 2019
Last Update Posted : April 8, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE September 29, 2019
First Posted Date  ICMJE November 8, 2019
Last Update Posted Date April 8, 2021
Actual Study Start Date  ICMJE October 29, 2019
Estimated Primary Completion Date December 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 3, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
  • 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 to 52 [ Time Frame: 48 to 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.
Current Other Pre-specified Outcome Measures
 (submitted: December 10, 2019)
  • 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 ]
Original Other Pre-specified Outcome Measures
 (submitted: November 5, 2019)
  • 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) as a 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 ]
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab.
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Eosinophilic Granulomatous Vasculitis
Intervention  ICMJE
  • Biological: Benralizumab
    30 mg/mL solution for injection in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC)
  • Biological: Mepolizumab
    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 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)
  • Biological: Placebo to Benralizumab
    Matching placebo solution for injection in APFS, 1 mL fill volume. Placebo solution will be administered subcutaneously (SC)
Study Arms  ICMJE
  • Experimental: Benralizumab arm
    1x benralizumab SC injection + 3x placebo to mepolizumab SC injections
    Interventions:
    • Biological: Benralizumab
    • Biological: Placebo to Mepolizumab
  • Active Comparator: Mepolizumab arm
    3x mepolizumab SC injections + 1x placebo to benralizumab SC injection
    Interventions:
    • Biological: Mepolizumab
    • Biological: Placebo to Benralizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 5, 2019)
140
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 27, 2024
Estimated Primary Completion Date December 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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. Stable doses of OCS other than prednisolone or prednisone may be acceptable, but must be discussed with the AstraZeneca study physician.
  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 signing the informed consent 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 and through randomisation.
  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 antiinfective 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, receipt of of any other marketed or investigational biologic products within 4 months or 5 half-lives prior to screening, whichever is longer . Or receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to screening (V1), whichever is longer, prior to screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Belgium,   Canada,   France,   Germany,   Israel,   Italy,   Japan,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04157348
Other Study ID Numbers  ICMJE D3253C00001
2019-001832-77 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Michael Wechsler, MD National Jewish Health, 1400 Jackson St Denver, CO 80206
PRS Account AstraZeneca
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP