Clinical Trials Register

Summary
EudraCT Number:	2019-001832-77
Sponsor's Protocol Code Number:	D3253C00001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2020-10-22
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

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

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.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	AstraZeneca AB
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 AB
B.5.2	Functional name of contact point	Information Center
B.5.3	Address:
B.5.3.1	Street Address	N/A
B.5.3.2	Town/ city	Sodertalje
B.5.3.3	Post code	SE-151 85
B.5.3.4	Country	Sweden
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	No
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.3.9.4	EV Substance Code	AS1
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	Dose 1
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
D.2.1.1.2	Name of the Marketing Authorisation holder	GSK
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	EU/3/13/1116
D.3 Description of the IMP
D.3.1	Product name	NUCALA
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.3.9.4	EV Substance Code	AS2
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.1.3

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.
Primary endpoint: Proportion of patients with relapsing or refractory EGPA, achieving
remission, defined as BVAS=0 (BVAS is a physician completed score based on disease activity in multiple parts of the body) and OCS (Oral corticosteroid) dose less or equal to 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 less or equal to 7.5 mg/day (Supportive remission definition) at both weeks 36 and 48.

E.2.2

Secondary objectives of the trial

Double blind period Objectives
1. To assess the efficacy of benralizumab compared with mepolizumab on duration of clinical remission, defined as accrued duration in weeks where a patient achieves remission 2. To assess the efficacy of benralizumab compared with mepolizumab on time to first relapse. 3. To assess the average daily dose of corticosteroid required during weeks 48 to 52 in patients receiving benralizumab compared to mepolizumab
4. To assess the annualized relapse rate in patients receiving benralizumab compared to mepolizumab. 5. To assess the proportion of patients who achieve remission within the first 24 weeks and remain in remission for the remainder of the double-blind period in patients receiving benralizumab compared to mepolizumab 6. To assess additional measures of the efficacy and health status/health-related quality of life in patients receiving benralizumab compared to mepolizumab.
7. To assess the safety and tolerability of benralizumab compared to mepolizum

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

Patient Interview Sub-study
To characterize the patient-reported experience and treatment benefits of benralizumab compared with mepolizumab through patient interviews

Mechanistic Sub-study
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, through analysis of tissue biopsies and sputum.

Both sub-studies are part of the main study protocol V1.0, 11Jun2019

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 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 screenin, 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.
- Proportion of patients in each category of average daily
prednisolone/prednisone dose during weeks 48 to 52 using the following
categories: 0; >0 to ≤4 mg; >4 to ≤7.5 mg and > 7.5 mg
- 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 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
- 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,
physical 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

Belgium

Canada

France

Germany

Israel

Italy

Japan

United Kingdom

United States

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

LSLV

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1