Clinical Trials Register

Summary
EudraCT Number:	2019-002039-27
Sponsor's Protocol Code Number:	D3254C00001
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-02-20
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

Austria - BASG

A.2

EudraCT number

2019-002039-27

A.3

Full title of the trial

A Multicentre, Randomised, Double-blind, Parallel-group,
Placebo-controlled, 24-Week Phase III Study with an Open-label
Extension to Evaluate the Efficacy and Safety of Benralizumab in
Patients with Hypereosinophilic Syndrome (HES)

A.3.1

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

A study to evaluate if benralizumab may be beneficial in the treatment of Hypereosinophilic Syndrome (HES)

A.3.2

Name or abbreviated title of the trial where available

NATRON

A.4.1

Sponsor's protocol code number

D3254C00001

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/035/2022

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 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	Södertälje
B.5.3.3	Post code	SE-151 85
B.5.3.4	Country	Sweden
B.5.4	Telephone number	46701010974
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	Fasrena
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.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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hypereosinophilic Syndrome (HES)

E.1.1.1

Medical condition in easily understood language

Hypereosinophilic Syndrome (HES)

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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	10048643
E.1.2	Term	Hypereosinophilic syndrome
E.1.2	System Organ Class	10005329 - Blood and lymphatic 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 evaluate the effect of benralizumab on the time to first HES worsening/flare

E.2.2

Secondary objectives of the trial

For DB period to evaluate the effect of benralizumab on:
- the proportion of patients who experience an HES worsening/flare
- the number of HES worsenings/flares
- time to first haematological relapse
- patient reported measure of fatigue
- the proportion of patients with haematologic relapse
- the number of patients who maintain AEC < 500 cells/μL for 24 weeks
- corticosteroid use
- health status/HRQoL measures
And also to evaluate the PK, immunogenicity, safety and tolerability of
benralizumab in patients with HES
For OLE extension period to evaluate the effect of benralizumab on:
- the proportion of patients who experience an HES worsening/flare and
on the number of HES worsening/flare (a)
- patient reported measure of fatigue (b)
- HRQoL (c)
(a) Applicable to full duration of OLE
(b) for HES worsening/flare
(c) Applicable to 1st year of OLE only
And also the safety, tolerability, PK and immunogenicity of benralizumab
in patients with HES (a)

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

Mechanistic sub-study: To support identifying predictors and
mechanisms of response to benralizumab in adults. The additional
exploratory analyses will be performed from three whole blood samples:
- for DNA analysis to determine clinical subtype of HES by targeted PCR
(all study sites).
- for more in-depth phenotyping of lymphocytes and other leukocytes by
flow cytometry of peripheral blood mononuclear cells (PBMC) (all study
sites).
- for phenotyping of eosinophils by flow cytometry (only selected
mechanistic sub-study sites)

Patient qualitative interview sub-study: to characterise the impact of
HES on patients´lives and their experiences with the study treatment
(selected sites only).

E.3

Principal inclusion criteria

1. Provision of the signed and dated written informed consent of the
patient or the patient's legally authorised representative, and informed
assent from the patient (per local regulations) prior to any mandatory
study-specific procedures, sampling, and analyses
2. Males and females 12 years of age and older at the time of signing the
ICF
3. Documented diagnosis of HES (history of persistent eosinophilia
>1500 cells/μL without
secondary cause on 2 examinations [interval ≥1 month; Valent et al
2012] and evidence of end organ manifestations attributable to the
eosinophilia)
4. Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine
kinase gene translocation
5. Stable HES treatment dose(s) and regimen for for ≥4 weeks at the
time of Visit 1
6. Signs or symptoms of HES worsening/flare and/or laboratory
abnormalities indicative of HES worsening/flare (other than isolated
eosinophilia) at Visit 1 or a documented history of 2 or more HES
worsening/flares within 12 months prior to Visit 1 requiring an
escalation in therapy.
-At least one flare within the past 12 months must not be related to a
decrease in HES therapy during the 4 weeks prior to the flare.
7. AEC ≥1000 cells/μL at Visit 1 (assessed by local laboratory)
8. Corticosteroid responsiveness defined as an AEC <1000 cells/μL after
a 2-day course of OCS (prednisone/prednisolone) 1 mg/kg/day at Visit
2 (assessed by local laboratory). Other OCSs in equivalent doses are
permitted.
9. WOCBP must agree to use a highly
effective method of birth control (confirmed by the Investigator) from
enrolment, throughout the study duration, and within 12 weeks after
last dose of IP and have a negative urine dipstick pregnancy test result
on Visit 1
10. Women not of childbearing potential are defined as women who are
either permanently sterilised (hysterectomy, bilateral oophorectomy, or
bilateral salpingectomy) or who are postmenopausal. Women will be
considered postmenopausal if they have been amenorrhoeic for ≥12
months prior to the planned date of enrolment without an alternative
medical cause

E.4

Principal exclusion criteria

1. Life-threatening HES and/or HES complication(s) as judged by the
Investigator:
(a) Medical intervention for HES-related life-threatening event(s) within
12 weeks prior to randomization, (b) History of thrombotic
complications, stroke, or significant cardiac damage related to HES, if
the respective events were life threatening and currently represent a
risk of life-threatening disease complications. Events that occurred in
the past but considered resolved or stable, can be accepted if, as per
Investigator's judgment participation in the study will not put the
patient at risk c) Disease severity that, in the opinion of the Investigator,
makes the patient inappropriate for inclusion in the study
2. Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation
or other known imatinib-sensitive mutation
3. Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
4. Known, preexisting, clinically significant endocrine, autoimmune,
metabolic, neurological, renal, gastrointestinal, hepatic, haematological,
respiratory, or any other system abnormalities that are not associated
with HES and are uncontrolled with standard treatment which, in the
opinion of the Investigator, may put the patient at risk because of
his/her participation in the study, or may influence the results of the
study, or the patient's ability to complete the entire duration of the study
5.Hypereosinophilia of unknown significance
6. Cardiovascular: Documented history of any clinically significant
cardiac damage, clinically significant echocardiography (if available) or
ECG findings within 12 months prior to Visit 1 or clinically significant ECG
findings at screening that, in the opinion of the Investigator, may put the
patients at risk.
7. Known currently active liver disease
(a) Chronic stable hepatitis B and C (including positive testing for
hepatitis B surface antigen or hepatitis C antibody) or other stable
chronic liver disease are acceptable if patient otherwise meets eligibility
criteria. Stable chronic liver disease should generally be defined by the
absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia,
oesophageal or gastric varices, or persistent jaundice, or cirrhosis
(b) ALT or AST level ≥3× ULN during the screening period
(AST or ALT >5× ULN if documented HES with liver manifestations).
Transient increase of AST/ALT level that resolves by the time of
randomisation is acceptable if, in the Investigator's opinion, the patient
does not have an active liver disease and meets other eligibility criteria
8. Current or history of malignancy within 5 years before the screening
visit with the following exceptions:
(a) Patients treated for in situ carcinoma of the cervix who have
completed curative therapy and are in remission for at least 12 months
prior to signing the informed consent and
(b) Patients with basal cell or superficial squamous skin cancer.
(c) Patients who have had other malignancies are eligible provided that
the patient is in remission and curative therapy was completed at least 5
years prior to the date informed consent was obtained.
9. Diagnosis of systemic mastocytosis
10. Chronic or ongoing active infections requiring systemic treatment, as
well as clinically significant viral, bacterial, or fungal infection within 4
weeks prior to Visit 1
11. A helminth parasitic infection diagnosed within 24 weeks prior to
Visit 1 that has not been treated or has failed to respond to standard of
care therapy. A confirmation of a complete resolution of any helminth
parasitic infection prior to Visit 1 should be available
12. A history of known immunodeficiency disorder other than that
explained by the use of
OCS or other therapy taken for HES. Positive HIV test.
13. Any clinically significant abnormal findings in HES physical
examination, vital signs, haematology or clinical chemistry during the
screening period, which, in the
opinion of the investigator, may put the patient at risk because of
his/her participation in
the study or may influence the results of the study or the patient's ability
to complete the entire duration of the study.
14. For women only: Currently pregnant, breastfeeding, or lactating
women
15.Treatment with injectable (SC, IV, or IM) corticosteroids in the 4-week period prior to randomisation

E.5 End points

E.5.1

Primary end point(s)

Time to first HES worsening/flare
- Population b: Full analysis set
- Intercurrent event strategy b: Included in analysis regardless of
treatment discontinuation (treatment policy)
- Population-level summary: Hazard ratio
(HES worsening/flare: HES clinical manifestations or lab abnormalities
that result in an increase/burst of oral corticosteroids (OCS) ≥10
mg/day for at least 2 days OR an increase, or addition of new cytotoxic
and/or immunosuppressive therapy, OR hospitalization)

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout the 24wk double-blind treatment period

E.5.2

Secondary end point(s)

DB treatment period
- Key: Proportion of patients who experience an HES worsening/flare
during the DB period
- Key: Number of HES worsenings/flares (annualised rate/year) during
the DB period
- Key: Time to first haematologic relapse (AEC ≥ 1000 cells/μL) during
the DB period
- Key: Fatigue severity (PROMIS fatigue short form 7a) at Week 24
- Proportion of patients who:
- have haematologic relapse during the DB period
- have AEC < 500 cells/μL for 24 weeks
- require an increase in corticosteroid dose from baseline at any point
in the DB treatment period
- HRQoL (SF-36v2, PGIS, PGIC)
- Serum benralizumab concentrations Anti-benralizumab antibodies and
nAbs
- Safety and tolerability will be evaluated in terms of AEs, vital signs, and
clinical laboratory assessments
OLE treatment period
- Proportion of patients who experience an HES worsening/flare
- Annualized rate of HES worsening/flare
- Fatigue (PROMIS fatigue short form 7a)
- Safety and tolerability will be evaluated in terms of AEs, vital signs and
clinical laboratory assessments
- Serum benralizumab concentrations, anti-benralizumab antibodies and
nAbs
- HES symptom questionnaire
- HRQoL (SF-36v2)

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

Yes

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)

E.8.2.2

Placebo

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

Argentina

Switzerland

India

Israel

Japan

Korea, Republic of

United Kingdom

United States

Austria

Belgium

Denmark

France

Germany

Italy

Netherlands

Poland

Spain

E.8.7

Trial has a data monitoring committee

Yes

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

The end of study is defined as the last expected visit/contact of the last patient undergoing the
study.

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

Yes

F.1.1