Efficacy and Safety of Benralizumab in EGPA compared to mepolizumab.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

21 Jan 2020 → ongoing

Decision date (initial)

2024-04-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-510248-19-00

EudraCT number

2019-001832-77

ClinicalTrials.gov

NCT04157348

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Pharmacodynamic, Pharmacokinetic, Therapy

To assess the durability of response to treatment with benralizumab
compared with mepolizumab in patients with relapsing or refractory
EGPA who are receiving Standard of Care Therapy, assessed by the
proportion of patients in remission at both Weeks 36 and 48.

Secondary objectives 2

1. To assess (DB): -the efficacy of benralizumab compared with mepolizumab on duration of clinical remission -the efficacy of benralizumab compared with mepolizumab on time to first relapse -the effect of benralizumab on corticosteroid dose required during Weeks 48 through 52 compared to mepolizumab -the clinical benefit of benralizumab compared to mepolizumab -the annualized relapse rate in benralizumab compared to mepolizumab group -the proportion of patients achieving remission within the first 24 wks and remain in remission for the remainder of the DB period in benralizumab compared to mepolizumab group -additional measures of efficacy and health status/health-related quality of life in patients receiving benralizumab compared to mepolizumab -the safety and tolerability of benralizumab compared to mepolizumab -the pharmacokinetics and immunogenicity of benralizumab.
2. To assess (OLE): the safety and tolerability of benralizumab.

Conditions and MedDRA coding

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Study design 2 periods

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-001214-PIP09-21

Plan to share IPD

Yes

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 shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. 1. Male or female subjects age 18 years or older.
2. 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. 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. 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. 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. 6. QTc(F)<450 msec or QTc(F)<480 msec for patients with bundle branch block.
7. 7. Females of childbearing potential must use an acceptable method of birth control from randomisation for at least 12 weeks after the last study drug administration.

Exclusion criteria 11

1. 1. Diagnosed with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA).
2. 2. Organ or life-threatening EGPA < 3 months prior to screening.
3. 3. Currently pregnant or breastfeeding, or planning to become pregnant during study participation.
4. 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. 5. An untreated or refractory helminth parasitic infection < 24 weeks prior to screening.
6. 6. Unstable liver disease.
7. 7. Severe or clinically significant, uncontrolled cardiovascular disease.
8. 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. 9. Chronic or ongoing infectious disease requiring systemic anti-infective treatment.
10. 10. Known immunodeficiency disorder or positive HIV test.
11. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Proportion of patients with relapsing or refractory EGPA, achieving remission, defined as BVAS=0 and OCS dose ≤ 4mg/day (Main Remission definition) at both weeks 36 and 48.
2. Supportive endpoint: Proportion of patients who have achieved remission defined by BVAS =0 and OCS dose ≤ 7.5 mg/day (Supportive remission definition) at both weeks 36 and 48.

Secondary endpoints 14

1. Study secondary end point(s) – double-blind period: - Total accrued duration of remission for the following categories: 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.
2. (Part 1/2) - Time from randomisation to first EGPA relapse, where 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
3. (Part 2/2) *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.
4. (Part 1*/2*) -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.
5. (Part 2*/2*) *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.
6. (Part 1**/2**) - 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.
7. (Part 2**/2**) *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.
8. - Annualized relapse rate
9. - 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.
10. - BVAS, VDI, pulmonary function testing, asthma symptoms (ACQ-6), SNOT-22 questionnaire, health-related quality of life (SF-36v2), WPAI and blood eosinophil counts will be assessed as change from baseline over the 52-week double-blind treatment period. Descriptive statistics will be provided for PGIS and WPAI to assess change from baseline over the 52 week double-blind period. PGIC will be assessed as response proportions at each weekly assessment between Visits 2 and 4.
11. - Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and electrocardiogram (ECG).
12. Study end point(s) for open label extension (OLE) period: - Remission, relapse (as defined in the secondary endpoints), OCS use
13. -Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and ECG .
14. -Serum benralizumab concentrations, Anti-benralizumab antibodies and neutralizing antibodies.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Placebo 2

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

Clinical Study Information Center

Locations

4 EU/EEA countries · 19 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications