Efficacy and Safety of Benralizumab in EGPA Compared to Mepolizumab.

Eosinophilic Granulomatous Vasculitis Clinical Trial

— MANDARA  

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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04157348
• Other study ID #: D3253C00001
• Secondary ID: 2023-510248-19-0
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 29, 2019
• Est. completion date: March 31, 2026

Study information

• Verified date: April 2024
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 140
• Est. completion date: March 31, 2026
• Est. primary completion date: August 10, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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-a 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.

Related Conditions & MeSH terms

• Churg-Strauss Syndrome
• Eosinophilic Granulomatous Vasculitis
• Vasculitis

Intervention

Biological:
• Benralizumab
30 mg/mL solution for injection in a single accessorized prefilled syringe (APFS) will be administered subcutaneously (SC)
• 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)
• 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)
• Placebo to Benralizumab
Matching placebo solution for injection in APFS, 1 mL fill volume. Placebo solution will be administered subcutaneously (SC)

Locations

Country	Name	City	State
Belgium	Research Site	Brussel
Belgium	Research Site	Brussels
Canada	Research Site	Calgary	Alberta
Canada	Research Site	Hamilton	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Toronto	Ontario
France	Research Site	Dijon Cedex
France	Research Site	Marseille
France	Research Site	Montpellier
France	Research Site	Nantes Cedex 1
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Suresnes Cedex
France	Research Site	Toulouse
Germany	Research Site	Bamberg
Germany	Research Site	Freiburg
Germany	Research Site	Hamburg
Germany	Research Site	Kirchheim
Germany	Research Site	Lübeck
Israel	Research Site	Ashkelon
Israel	Research Site	Beer Sheva
Israel	Research Site	Jerusalem
Israel	Research Site	Ramat Gan
Israel	Research Site	Rehovot
Israel	Research Site	Tel Aviv
Italy	Research Site	Cuneo
Italy	Research Site	Firenze
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Roma
Italy	Research Site	Torino
Japan	Research Site	Chiba-shi
Japan	Research Site	Kita-gun
Japan	Research Site	Sagamihara-shi
Japan	Research Site	Sendai-shi
Japan	Research Site	Shinjuku-ku
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	London
United Kingdom	Research Site	Portsmouth
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Denison	Texas
United States	Research Site	Denver	Colorado
United States	Research Site	Great Neck	New York
United States	Research Site	New York	New York
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Rochester	Minnesota
United States	Research Site	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  France,  Germany,  Israel,  Italy,  Japan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Numbers of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)		Minimum of 52 weeks
Other	Change from baseline in systolic and diastolic blood pressure		Minimum of 52 weeks
Other	Change from baseline in pulse rate		Minimum of 52 weeks
Other	Change from baseline in hematology parameters of hemoglobin, leukocytes, lymphocytes, monocytes, basophils, eosinophils, neutrophils, and platelets		Minimum of 52 weeks
Other	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		Minimum of 52 weeks
Other	Overall interpretation of ECG by Investigator	Triplicate measurements of 12-lead electrocardiograms recorded at rest.	Minimum of 52 weeks
Other	Serum benralizumab concentration as a measure of pharmacokinetics		Minimum of 52 weeks
Other	Anti-drug antibodies (ADA) titers as measure of immunogenicity		Minimum of 52 weeks
Other	Cumulative OCS use	Total OCS use (measured in mg) as measured by sum of all daily prednisolone/prednisone doses, over the 52-week double-blind treatment period.	Up to 52 weeks
Other	Number of EGPA related hospitalisations		Up to 52 weeks
Other	Length of hospital stay		Up to 52 weeks
Other	ICU (Intensive Care Unit) days		Up to 52 weeks
Other	Number of EGPA related ER visits		Up to 52 weeks
Other	Number of EGPA related outpatient visits		Up to 52 weeks
Other	Number of EGPA related procedures/tests (by specific procedure/test)		Up to 52 weeks
Primary	Proportion of patients who are in remission at both weeks 36 and 48	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
Secondary	Number of patients in each category of accrued duration of remission	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.	Up to 52 weeks
Secondary	Time from randomisation to first EGPA relapse	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.	During first 52 weeks
Secondary	Based on the average daily prednisolone/prednisone dose during Weeks 48 through 52:	Proportion of patients in each category of average daily prednisolone/prednisone dose during Weeks 48 through 52 using the following categories: 0 mg; > 0 to =4 mg; > 4 to = 7.5 mg and > 7.5 mg.; Proportion of patients in each category of percent reduction from baseline: no reduction or withdrawal from treatment; < 25% reduction; 25 to < 50% reduction; 50 to < 75% reduction; 75 to < 100% reduction; 100% reduction.; Proportion of patients with = 50% reduction from baseline.; Proportion of patients with 100% reduction from baseline.; Proportion of patients with = 4 mg in average daily dose.	week 48 through week 52
Secondary	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.	Remission (defined as BVAS = 0 and prednisolone/prednisone dose = 4 mg/day) at any time during the double-blind treatment period; = 50% reduction in average daily prednisolone/prednisone dose during Weeks 48 through 52; EGPA relapse free during the double-blind treatment period. Analysis will be repeated for the supportive remission definition.	Up to 52 weeks
Secondary	Annualized relapse rate		Over first 52 weeks
Secondary	Proportion of patients who have achieved remission within the first 24 weeks and remained in remission for remainder of the double-blind treatment period	Analysis will be repeated based on main and supportive remission definitions.	Up to 52 weeks
Secondary	Change from baseline in VDI	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
Secondary	Change from baseline in BVAS	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
Secondary	Change from baseline in pulmonary function	As measured by Forced vital capacity (FVC) and Forced Expiratory Volume during first second (FEV1), unit L	Up to 52 weeks
Secondary	Change from baseline in ACQ-6	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
Secondary	Change from baseline in sino-nasal symptoms (SSQ)	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
Secondary	Change from baseline in SNOT-22	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
Secondary	Change from baseline in SF-36v2	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
Secondary	Change from baseline in PGIS	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
Secondary	Change from baseline in WPAI	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
Secondary	Change from baseline in blood eosinophil counts		Up to 52 weeks
Secondary	Proportion of PGIC responders at each weekly assessment	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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