NATRON: A Phase 3 Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)

Sponsor

AstraZeneca (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04191304

Collaborator

(none)

120

Enrollment

Locations

Arms

51.5

Anticipated Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase 3 study to compare the efficacy and safety of benralizumab versus placebo administered by SC injection Q4W in patients with hypereosinophilic syndrome (HES). This study comprises 2 distinct periods (together defined as the 'main study'): A 24-week, DB treatment period, during which patients will be randomised to receive either benralizumab or placebo, in addition to prior stable HES background therapy, and an open-label (OLE) treatment period, during which all patients will receive benralizumab. Patients will not continue to be recruited after 47 patients have had their first HES worsening/flare.The primary database lock (DBL) will occur when at least 47 patients have had their first HES worsening/flare event and all randomised patients have been followed up for the 24-week DB treatment period. The target patient population is male and female patients 12 years of age and older with symptomatic active HES. Approximately 120 eligible patients will be randomised at a 1:1 ratio to receive either benralizumab or matching placebo

Condition or Disease	Intervention/Treatment	Phase
Hypereosinophilic Syndrome	Biological: Benralizumab Biological: Placebo	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

All eligible patients will be centrally randomly assigned in a 1:1 ratio to receive either benralizumab or placebo. Randomisation will be done using an IWRS/IVRS. Benralizumab and placebo will not be visually distinct from each other. All packaging and labelling of the IP will be done in such a way as to ensure blinding for all Sponsor and investigational site staff. Neither the patient nor any of the Investigators or Sponsor staff who are involved in the treatment, clinical evaluation, and monitoring of the patients will be aware of the treatment received. Since benralizumab and placebo are not visually distinct, IP will be handled by an appropriately qualified member of the study team (e.g., pharmacist, Investigator, or designee) at the site.

Primary Purpose:

Treatment

Official Title:

A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 24-week Phase 3 Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)

Actual Study Start Date :

Jul 20, 2020

Anticipated Primary Completion Date :

Nov 2, 2023

Anticipated Study Completion Date :

Nov 4, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Benralizumab arm 1x Benralizumab SC injection	Biological: Benralizumab Benralizumab solution for injection in an accessorised prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks
Placebo Comparator: Placebo arm 1x Benralizumab matching placebo SC injection	Biological: Placebo Matching placebo solution for injection in an APFS will be administered SC every 4 weeks

Arm

Intervention/Treatment

Experimental: Benralizumab arm

1x Benralizumab SC injection

Biological: Benralizumab

Benralizumab solution for injection in an accessorised prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks

Placebo Comparator: Placebo arm

1x Benralizumab matching placebo SC injection

Biological: Placebo

Matching placebo solution for injection in an APFS will be administered SC every 4 weeks

Outcome Measures

Primary Outcome Measures

Time to first HES worsening/flare [Up to 24 weeks]
An HES worsening or flare is defined as HES clinical manifestations or lab abnormalities that result in an increase/burst of OCS ≥10 mg/day for at least 2 days, OR in increase or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalisation

Secondary Outcome Measures

Time to first haematologic relapse [Up to 24 weeks]
A haematologic relapse is defined as AEC ≥1000 cells/μL
Proportion of patients who experience HES worsening/flare [Up to 24 weeks]
Proportion of patients who have haematologic relapse [Up to 24 weeks]
Proportion of patients who have AEC<500 cells/µL for 24 weeks [Up to 24 weeks]
Proportion of patients who require an increase in corticosteroid dose [Up to 24 weeks]
Change from baseline in fatigue [Up to 24 weeks]
The PROMIS Fatigue Short Form 7a will be used which contains 7 questions assessing a range of patient-reported symptoms, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles
Change from baseline in HRQoL [Up to 24 weeks]
Derived from the SF-36v2 questionnaires which contains 36 questions measuring patients' general functional health and well-being, both physically and mentally
PGIS [Up to 24 weeks]
The PGIS is a single question evaluating patients' perception of overall symptom severity
PGIC [Up to 24 weeks]
The PGIC is a single question evaluating whether there has been an improvement or decline in patients' overall health status after start of treatment.
Serum benralizumab concentration as a measure of pharmacokinetics [Up to 24 weeks]
Anti-drug antibodies (ADA) titers and neutralizing antibodies (nAb) testing for all ADA-positive samples as measure of immunogenicity [Up to 24 weeks]
Percentage of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 24 weeks]
Change from baseline in systolic and diastolic blood pressure [Up to 24 weeks]
Change from baseline in pulse rate [Up to 24 weeks]
Change from baseline in respiratory rate [Up to 24 weeks]
Change from baseline in hematology parameters of hemoglobin, leukocytes, lymphocytes, monocytes, basophils, eosinophils, neutrophils, and platelets [Up to 24 weeks]
Change from baseline in clinical chemistry parameters of Alanine Aminotransferase (ALT), alkaline phosphatase, Aspartate Aminotransferase (AST), creatinine kinase, direct, indirect and total bilirubin, uric acid, albumin, creatinine and glucose [Up to 24 weeks]

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 130 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

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.
Males and females 12 years of age and older at the time of signing the ICF.
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).
Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation.
Stable HES treatment dose(s) and regimen for ≥4 weeks at the time of Visit 1
Signs or symptoms of HES worsening/flare and/or laboratory abnormalities indicative of HES worsening/flare (other than isolated eosinophilia) at Visit 1.
AEC ≥1000 cells/μL at Visit 1 (assessed by local laboratory).
Corticosteroid responsiveness defined as an AEC <1000 cells/μL after a 2-day course of OCS 1 mg/kg/day at Visit 2 (assessed by local laboratory).
Women of childbearing potential (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

Exclusion Criteria

Life-threatening HES and/or HES complication(s) as judged by the Investigator:
Medical intervention for HES-related life-threatening event(s) within 12 weeks prior to randomisation OR
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
Disease severity that, in the opinion of the Investigator, makes the patient inappropriate for inclusion in the study.
Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation.
Definitive diagnosis of eosinophilic granulomatosis with polyangiitis.
Known, pre-existing, 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.
Hypereosinophilia of unknown significance.
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.
Known currently active liver disease.
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.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3× the upper limit of normal (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.
Current malignancy, or history of malignancy, except:
Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided the patient is in remission and curative therapy was completed at least 12 months prior to the date that informed consent, and assent when applicable, was obtained.
Patients who have had other malignancies are eligible provided the patient is in remission and curative therapy was completed at least 5 years prior to the date informed consent, and assent when applicable, was obtained.
Diagnosis of systemic mastocytosis.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	La Jolla	California	United States	92037
2	Research Site	Atlanta	Georgia	United States	30324
3	Research Site	Bethesda	Maryland	United States	20892
4	Research Site	Ann Arbor	Michigan	United States	48105
5	Research Site	Rochester	Minnesota	United States	55905-0001
6	Research Site	Durham	North Carolina	United States	27705
7	Research Site	Cleveland	Ohio	United States	44106
8	Research Site	Columbus	Ohio	United States	43212
9	Research Site	Salt Lake City	Utah	United States	84112
10	Research Site	Milwaukee	Wisconsin	United States	53226
11	Research Site	Innsbruck		Austria	6020
12	Research Site	Brussels		Belgium	1070
13	Research Site	Edegem		Belgium	2650
14	Research Site	Leuven		Belgium	3000
15	Research Site	København Ø		Denmark	2100
16	Research Site	Lille Cedex		France	59037
17	Research Site	Pessac		France	33604
18	Research Site	Strasbourg		France	67091
19	Research Site	Suresnes		France	92150
20	Research Site	Toulouse Cedex 9		France	31059
21	Research Site	Hannover		Germany	30625
22	Research Site	Kirchheim		Germany	73230
23	Research Site	Mannheim		Germany	68167
24	Research Site	Haifa		Israel	34362
25	Research Site	Holon		Israel	58100
26	Research Site	Jerusalem		Israel	91120
27	Research Site	Kfar Saba		Israel	44218
28	Research Site	Petah Tiqva		Israel	49100
29	Research Site	Ramat Gan		Israel	5265601
30	Research Site	Rehovot		Israel	76100
31	Research Site	Tel-Aviv		Israel	64239
32	Research Site	Bologna		Italy	40138
33	Research Site	Milano		Italy	20132
34	Research Site	Bunkyo-ku		Japan	113-8431
35	Research Site	Chiba-shi		Japan	260-0852
36	Research Site	Hamamatsu-shi		Japan	431-3192
37	Research Site	Ichikawa-shi		Japan	272-8516
38	Research Site	Kawasaki-shi		Japan	211-8510
39	Research Site	Nishinomiya-shi		Japan	663-8501
40	Research Site	Osaka-shi		Japan	530-8480
41	Research Site	Sendai-shi		Japan	980-8574
42	Research Site	Rotterdam		Netherlands	3015 GD
43	Research Site	Gdańsk		Poland	80-214
44	Research Site	Łódź		Poland	90-153
45	Research Site	Bern		Switzerland	3010
46	Research Site	Zürich		Switzerland	8091

Sponsors and Collaborators

AstraZeneca

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.

Responsible Party:

AstraZeneca

ClinicalTrials.gov Identifier:

NCT04191304

Other Study ID Numbers:

D3254C00001
2019-002039-27

First Posted:

Dec 9, 2019

Last Update Posted:

Jul 6, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by AstraZeneca

benralizumab

Hypereosinophilic Syndrome (HES)

Additional relevant MeSH terms:

Hypereosinophilic Syndrome

Syndrome

Benralizumab

Study Results

No Results Posted as of Jul 6, 2022