Clinical Trials Register

Summary
EudraCT Number:	2019-001832-77
Sponsor's Protocol Code Number:	D3253C00001
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-08-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2019-001832-77

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Efficacy and Safety of Benralizumab in EGPA compared to mepolizumab.

A.4.1

Sponsor's protocol code number

D3253C00001

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04157348

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZenecaAB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca
B.5.2	Functional name of contact point	Clinical Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	1800 Concorde Pike
B.5.3.2	Town/ city	Wilmington
B.5.3.3	Post code	19803
B.5.3.4	Country	United States
B.5.4	Telephone number	+1877240 9479
B.5.6	E-mail	information.center@astrazeneca.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Fasenra
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca AB
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	benralizumab
D.3.2	Product code	MEDI-563
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	benralizumab
D.3.9.1	CAS number	1044511-01-4
D.3.9.2	Current sponsor code	MEDI-563
D.3.9.3	Other descriptive name	Benralizumab
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Nucala 100 mg powder for solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline Trading Services Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	mepolizumab
D.3.2	Product code	L04AC06
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Mepolizumab
D.3.9.1	CAS number	0196078-29-2
D.3.9.2	Current sponsor code	Mepolizumab
D.3.9.3	Other descriptive name	Nucala
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

E.1.1.1

Medical condition in easily understood language

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10078117
E.1.2	Term	Eosinophilic granulomatosis with polyangiitis
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

DB
To assess:
-the efficacy of benralizumab compared with mepolizumab on duration f 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 OLE
- To assess the safety and tolerability of benralizumab

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A. Mechanistic Sub-study
Objective: To evaluate the effect of benralizumab compared to mepolizumab on biomarkers related to the mechanism of action (MoA), eosinophilic inflammation and EGPA disease pathogenesis, as well as baseline predictors of response to benralizumab or mepolizumab.

B. Patient Qualitative Interview Sub-study
Objective: To characterize the impact of EGPA on patients’ lives and their experiences with study treatment.

E.3

Principal 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 signing the informed consent for at least 12 weeks after the last study drug administration.

E.4

Principal 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-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.

E.5 End points

E.5.1

Primary end point(s)

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.

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.

E.5.1.1

Timepoint(s) of evaluation of this end point

Both weeks 36&48

E.5.2

Secondary end point(s)

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.

- 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
*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.

-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.

- 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.

- Annualized relapse rate

- 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.

- 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. escriptive 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.

- Safety and tolerability will be evaluated based on AEs, Vital signs, physical exam, Clinical laboratory, and electrocardiogram (ECG).

Study end point(s) for open label extension (OLE) period:
- Remission, relapse (as defined in the secondary endpoints), OCS use

-Safety and tolerability will be evaluated based on AEs, Vital signs, hysical exam, Clinical laboratory, and ECG .

-Serum benralizumab concentrations, Anti-benralizumab antibodies and neutralizing antibodies

E.5.2.1

Timepoint(s) of evaluation of this end point

Varies depending on the endpoint/objective

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Israel

Japan

United States

Belgium

France

Germany

Italy

United Kingdom

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

For the purpose of Clinical Trial Transparency, the definition of the end of the study differs under FDA and EU regulatory requirements: EU requirements define study completion as the last visit of the last
subject for any protocol related activity.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

120

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

140

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Upon completion of the initial 52-week treatment period, patients will be offered an additional Open Label Extension of benralizumab Dosing
Regimen for at least one year, with ongoing study assessments. After the end of the study, patients should be given standard of care therapy,
at the discretion of the Investigator, per local practice.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-11-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-15

P. End of Trial
P.	End of Trial Status	Trial now transitioned

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials