Hypereosinophilic SyndromePhase 3NATRONNCT04191304
A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)
A Phase 3 study testing Benralizumab in people with Hypereosinophilic Syndrome, run by AstraZeneca at 52 sites in 17 countries.
Trial summary
This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab versus placebo administered by SC injection Q4W in patients with hypereosinophilic syndrome (HES). Read more about this study
- Who is it for?
- Ages 12 to 130 years
- Conditions the study is for
- Hypereosinophilic Syndrome
- What is being tested?
- Benralizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 134 participants
- Where
- 52 sitesin 17 countries
- Study dates
- 20 Jul 2020to 28 Feb 2027
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 130 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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 OR a documented history of 2 or more HES worsening/flares within 12 months prior to Visit 1 requiring an escalation in therapy
Show all 17Show fewer
- 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
- 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 (prednisone/prednisolone) 1 mg/kg/day at Visit 2 (assessed by local laboratory). Other OCSs in equivalent doses are permitted
- 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. Highly effective methods of birth control (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include:
- Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal
- Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable
- Intrauterine device
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient)
- Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomised partner has received medical assessment of the surgical success)
Who cannot join
- 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 randomization
- 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
Show all 21Show fewer
- 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
- 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
- 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
- Current or history of malignancy within 5 years before the screening visit with the following exceptions:
- 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
- Patients with basal cell or superficial squamous skin cancer
- 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
- 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
- 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
- A history of known immunodeficiency disorder other than that explained by the use of OCS or other therapy taken for HES. Positive HIV test
- 14. Evidence of prior benralizumab treatment failure
Trial locations and contacts
52 sites in 17 countries.
52 sites in 17 countries
United States8 sites
Research Site
Ann Arbor, Michigan, 48105
Research Site
Atlanta, Georgia, 30324
Research Site
Bethesda, Maryland, 20892
Research Site
Cleveland, Ohio, 44106
Research Site
Columbus, Ohio, 43212
Research Site
Durham, North Carolina, 27705
Research Site
La Jolla, California, 92037
Research Site
Salt Lake City, Utah, 84112
Israel8 sites
Research Site
Haifa, 34362
Research Site
Holon, 58100
Research Site
Jerusalem, 91120
Research Site
Kfar Saba, 44218
Research Site
Petah Tikva, 49100
Research Site
Ramat Gan, 5265601
Research Site
Rehovot, 76100
Research Site
Tel Aviv, 64239
Japan7 sites
Research Site
Chiba, 260-0852
Research Site
Hamamatsu, 431-3192
Research Site
Ichikawa-shi, 272-8516
Research Site
Kawasaki-shi, 211-8510
Research Site
Nishinomiya-shi, 663-8501
Research Site
Osaka, 530-8480
Research Site
Sendai, 980-8574
China5 sites
Research Site
Chengdu, 610041
Research Site
Shanghai, 200040
Research Site
Tianjin, 300020
Research Site
Xiamen, 361015
Research Site
Zhengzhou, 450008
France5 sites
Research Site
Lille, 59037
Research Site
Pessac, 33604
Research Site
Strasbourg, 67091
Research Site
Suresnes, 92151
Research Site
Toulouse, 31059
Germany3 sites
Research Site
Hanover, 30625
Research Site
Kirchheim, 73230
Research Site
Mannheim, 68167
India3 sites
Research Site
Ahmedabad, 380013
Research Site
Ajmer, 305001
Research Site
Delhi, 110029
Poland3 sites
Research Site
Chęciny, 26-060
Research Site
Gdansk, 80-214
Research Site
Lodz, 90-153
About this study
Official title: 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)
This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase III 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 their prior stable HES background therapy, and an open-label extension (OLE) period, during which all patients will receive benralizumab.
The primary database lock (DBL) will occur when approximately 38 patients have had their first HES worsening/flare event during the DB treatment period and all randomised patients have had the opportunity to be followed up for the 24-week DB treatment period.
A patient must complete the 24-week DB treatment period on investigational product (IP) to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE.
Read the detailed description
This is a multicentre, randomised, DB, parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab 30 mg versus placebo administered by SC injection Q4W in patients with HES. This study will be conducted at approximately 68 sites in 18 countries.
The target patient population is male and female patients 12 years of age and older with symptomatic active HES. Eligible patients must be negative for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation.
Potentially eligible patients will enter a 3-day screening period and will be required to have documented stable HES therapy for at least 4 weeks prior to Visit 1 and AEC ≥ 1000 cells/μL at local laboratory testing to proceed to the second day of the screening period. Patients will be assessed for corticosteroid responsiveness (defined as an AEC < 1000 cells/μL after 2 days of OCS [prednisone/prednisolone] 1 mg/kg/day given on top of the patient's background therapy for HES) prior to randomisation; other OCSs in equivalent doses are permitted. Patients who are not corticosteroid responsive or fail any other eligibility criteria will be screen failed.
It is expected that approximately 120 patients will be randomised at a 1:1 ratio at the randomisation/baseline visit (Visit 3) to receive either benralizumab or matching placeboQ4W for a 24-week DB treatment period. Recruitment may continue beyond 120 patients if required to achieve the target number of HES worsening/flares. Recruitment of adolescent patients is targeted to be broadly in line with expected prevalence rates of adolescents in the overall population. Approximately 4 to 6 adolescent patients (aged 12 to 17) are targeted to be randomised. Randomisation will be stratified. Approximately 40 patients will participate in a noninterventional interview to collect data on HRQoL and the patients' experience during the DB portion of the study.
All patients will remain on stable dose(s) and regimen of background HES therapy during the screening period and throughout 36 weeks of treatment (until Visit 12/Week 36 when the therapy can be adjusted). During this time, background HES therapy may only be modified if a patient has an HES clinical worsening/flare or an AE thought to be due to background therapy.
AstraZeneca, sites, and patients will be blinded to the absolute eosinophil, basophil, and monocyte counts, differential blood counts (percentages) for all WBCs (eosinophils, basophils, monocytes, neutrophils, and lymphocytes), and biopsy cell counts (if applicable) after randomisation/baseline (Visit 3/Week 0), during the entire DB treatment period, and for the first 4 weeks of the OLE treatment period (until Visit 10/Week 28) after which no blinding to WBC counts or biopsy cell counts is required. After the primary DBL, AstraZeneca will become unblinded to all patients' blood and biopsy cell counts obtained during DB treatment period.
The final dose of the DB treatment period will be given at Week 20, and the DB treatment period will complete at Week 24.
All patients who complete the DB treatment period on IP may be eligible to continue into an OLE treatment period on benralizumab (30 mg SC Q4W). The OLE is intended to allow treatment with open-label benralizumab for at least 1 year for adults and at least 2 years for adolescents after completion of the DB treatment period of the study (earlier enrolled patients may therefore be in the OLE for longer than 1 year). AstraZeneca may choose to extend the study depending on the overall development program. Moreover, AstraZeneca reserves the right of terminating the OLE early (eg, if development of the asset is terminated or marketing authorisation is obtained).
The primary DBL will occur when approximately 38 patients have had their first HES worsening/flare event during the DB treatment period and all randomised patients have had the opportunity to be followed up for the 24-week DB treatment period. Treatment allocation will remain blinded until the primary DBL. A patient must complete the 24-week DB treatment period on IP to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE. Data from the OLE treatment period of the study will be presented in an addendum to the primary analysis CSR and/or a separate OLE treatment period CSR.
- Conditions
- Hypereosinophilic Syndrome
- Being tested
- Benralizumab, Placebo
- Keywords
- benralizumab, Hypereosinophilic Syndrome (HES)
- Medical subject headings
- Hypereosinophilic Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BenralizumabBiological
Benralizumab solution for injection in an accessorised prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks
PlaceboBiological
Matching placebo solution for injection in an APFS will be administered SC every 4 weeks
| Study group | Role | What they receive |
|---|---|---|
| Benralizumab arm | Experimental | 1x Benralizumab SC injection Receives: Biological: Benralizumab |
| Placebo arm | Placebo comparator | 1x Benralizumab matching placebo SC injection Receives: Biological: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to First HES Worsening/Flare During the DB Treatment Period
The time to first HES worsening/flare is calculated as: start date of the first HES worsening - date of randomisation + 1. For participants who do not experience a HES worsening/flare, the time to first HES worsening/flare is right censored at the end of the DB period corresponding to the earliest date (date of the first of Benra open label dose, study day 183, date of last contact, and data cut-off date).
The number of participants with events and censored observations is presented.
Measured: DB period (Baseline to Week 24)
Secondary outcomes (12)
Proportion of Patients Who Experience an HES Worsening/Flare During the DB Treatment Period
The proportion of participants who experience an HES worsening/flare or who withdraw from the study prior to completing the 24-week DB treatment period. The proportion is calculated as the number of participants with an HES worsening/flare or withdrawal divided by the total number of participants in the analysis population.
The number and proportion (expressed as percentage) or participants who experienced HES worsening/flare is presented.
Measured: DB period (Baseline to Week 24)
Number of HES Worsenings/Flares (Annualised Rate) During the DB Period
The annualised rate of HES worsening/flare events was analysed using a negative binomial regression model adjusted for region, with the logarithm of follow-up time included as an offset variable. Annualized flare rates are model estimated marginal rates.
A separate HES worsening/flare is considered if the start date of an HES worsening/flare is at least 14 days apart from the stop date of a preceding HES worsening/flare.
Measured: DB period (Baseline to Week 24)
Time to First Haematologic Relapse (AEC ≥ 1000 Cells/μL) During the DB Period
Time to first haematologic relapse is calculated as start date of the first haematologic relapse - date of randomisation + 1. Haematologic relapse is defined as the first occurrence of an absolute eosinophil count (AEC) ≥ 1000 cells/μL post-baseline.
For participants who do not experience haematologic relapse, the time to first haematologic relapse is right censored at the end of the DB period corresponding to the earliest date of (date of the first of Benra open label dose, study day 183, date of last contact, and data cut-off date).
The number of participants with events and censored observations is presented.
Measured: DB period (Baseline to Week 24)
Fatigue Severity (PROMIS Fatigue Short Form 7a) at Week 24
Fatigue severity was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a questionnaire. Each item is scored on a 5-point Likert scale (1 to 5), and the total raw score is converted to a T-score.
T-scores are standardized such that 50 represents the population mean with a standard deviation of 10. Standardized T-score range is from 29.4 to 83.2, with higher scores indicating more severe fatigue. A reduction in T-score indicates an improvement in fatigue severity.
The least squares (LS) mean (95% CI) change from baseline in T-score at Week 24 is presented.
Measured: Week 24
Proportion of Patients Who Have Haematologic Relapse During the DB Treatment Period
The proportion of patients who have a haematologic relapse or withdraw from the study over the DB treatment period is defined as the number of participants who have a first haematologic relapse or withdraw prior to completing in the DB period divided by the number of participants in the the analysis. Haematologic relapse is defined when AEC post baseline is ≥ 1,000 cells/Ul for the first time.
The number and proportion (expressed as percentage) of participants who experienced haematologic relapse is presented.
Measured: DB period (Baseline to Week 24)
Proportion of Patients Who Have AEC < 500 Cells/μL for 24 Weeks
The proportion of participants who maintained an AEC of < 500 cells/µL throughout the 24-week DB treatment period. The proportion is defined as the number of participants who maintained AEC < 500 cells/µL divided by the total number of participants in the analysis population.
The number and proportion (expressed as percentage) of participants who maintained AEC < 500 cells/µL is presented.
Measured: DB period (Baseline to Week 24)
Proportion of Patients Who Require an Increase in Corticosteroid Dose From Baseline at Any Point in the DB Treatment Period
The proportion of patients who required an increase in systemic corticosteroids (SCS) from baseline during the 24-week DB treatment period. An increase in SCS includes an increase of at least 1 mg prednisone equivalent for participants receiving oral corticosteroids at baseline, or initiation of a new or additional course of systemic corticosteroids for treatment of HES or a closely related condition. Baseline is defined as the last valid value on or prior to randomisation.
The number and proportion (expressed as percentage) of participants who require an increase in SCS from baseline.
Measured: DB period (Baseline to Week 24)
Health-Related Quality of Life (HRQoL) (Short Form-36 Version 2 [SF-36v2])
HRQoL was assessed using the 36 Item Short Form Health Survey, version 2 (SF 36v2). Change from baseline in HRQoL was evaluated using the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores at Week 12 and Week 24 during the DB treatment period.
PCS and MCS scores are norm-based and standardized to a general population with a mean of 50 and a standard deviation of 10, with higher scores indicating better HRQoL. Scores generally range from 0 to 100.
PCS and MCS scores are derived from weighted combinations of domain scores using standard scoring algorithms. An increase in score indicates an improvement.
LS mean (95% CI) changes from baseline for PCS and MCS scores are presented.
Measured: DB period (Baseline to Week 24)
Patient Global Impression of Severity (PGI-S)
Patient Global Impression of Severity (PGI-S) is a single-item, participant-reported assessment of disease severity during the DB treatment period. PGI-S captures the participant's perception of overall symptom severity at the time of assessment using categorical response options ranging from "No symptoms" to "Very severe".
The number and percentage of participants in each response category are presented at each timepoint.
Measured: DB period (Baseline to Week 24)
Patient Global Impression of Change (PGI-C)
Patient Global Impression of Change (PGI-C) is a single-item, participant-reported assessment that captures the participant's overall evaluation of response to treatment during the DB treatment period. PGI-C reflects the participant's perception of change in disease status compared with baseline using categorical response options ranging from "Much better" to "Much worse." The number and percentage of participants in each response category are presented at each time point.
Measured: DB period (Baseline to Week 24)
Serum Benralizumab Concentrations
Serum concentrations of benralizumab measured over time during the DB period to characterise the pharmacokinetics of benralizumab in participants with HES.
Baseline is defined as the last valid value on or prior to the date of randomisation.
Measured: DB period (Baseline to Week 24)
Anti-Benralizumab Antibodies and Neutralizing Antibodies (nAbs)
Immunogenicity of benralizumab, as assessed by the incidence and prevalence of anti-drug antibodies (ADA), including nAbs, measured from baseline through the 24-week DB treatment period in participants with HES.
Measured: DB period (Baseline to Week 24)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Dec 2019
- Study start20 Jul 2020
- Primary completion7 May 2025
- Study completion28 Feb 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hypereosinophilic SyndromeStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 134 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04191304
- Sponsor's protocol ID
- D3254C00001
- Other IDs
- 2023-510455-28-00, 2019-002039-27, 2019, 2023
- Acronym
- NATRON
- Status last verified
- Jul 2026
- First submitted
- 20 Nov 2019
- Last updated
- 10 Jul 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Publications
Ogbogu PU, Roufosse F, Akuthota P, Kuna P, Groh M, Reiter A, Yokota A, Siddiqui SH, Mutsaers PGNJ, Li B, Khoury P, Bahadori LM, Bednarczyk A, Bouma G, Brooks LG, Ferreira J, Grindebacke H, Ho CN, Jain P, Palmer RL, Jison ML, Klion AD; NATRON study group. Benralizumab versus placebo for hypereosinophilic syndrome: a randomized, placebo-controlled phase 3 trial. Nat Med. 2026 Jun;32(6):2017-2025. doi: 10.1038/s41591-026-04315-8. Epub 2026 Mar 31.
PubMed 41917160
Study at a glance
From the registry record, last updated by the sponsor on 10 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT04191304
- Acronym / sponsor ID
- NATRON / D3254C00001
- Conditions
- Hypereosinophilic Syndrome
- Keywords
- benralizumab, Hypereosinophilic Syndrome (HES)
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 134 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Study start
- 20 Jul 2020 (actual)
- Primary completion
- 7 May 2025 (actual)
- Study completion
- 28 Feb 2027 (estimated)
- First posted
- 9 Dec 2019 (actual)
- Results
- Posted 10 Jul 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a multicentre, randomised, double-blind (DB), parallel-group, placebo-controlled, 24-week Phase III 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 their prior stable HES background therapy, and an open-label extension (OLE) period, during which all patients will receive benralizumab.
The primary database lock (DBL) will occur when approximately 38 patients have had their first HES worsening/flare event during the DB treatment period and all randomised patients have had the opportunity to be followed up for the 24-week DB treatment period.
A patient must complete the 24-week DB treatment period on investigational product (IP) to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE.
Detailed description
This is a multicentre, randomised, DB, parallel-group, placebo-controlled, 24-week Phase III study to compare the efficacy and safety of benralizumab 30 mg versus placebo administered by SC injection Q4W in patients with HES. This study will be conducted at approximately 68 sites in 18 countries.
The target patient population is male and female patients 12 years of age and older with symptomatic active HES. Eligible patients must be negative for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation.
Potentially eligible patients will enter a 3-day screening period and will be required to have documented stable HES therapy for at least 4 weeks prior to Visit 1 and AEC ≥ 1000 cells/μL at local laboratory testing to proceed to the second day of the screening period. Patients will be assessed for corticosteroid responsiveness (defined as an AEC < 1000 cells/μL after 2 days of OCS [prednisone/prednisolone] 1 mg/kg/day given on top of the patient's background therapy for HES) prior to randomisation; other OCSs in equivalent doses are permitted. Patients who are not corticosteroid responsive or fail any other eligibility criteria will be screen failed.
It is expected that approximately 120 patients will be randomised at a 1:1 ratio at the randomisation/baseline visit (Visit 3) to receive either benralizumab or matching placeboQ4W for a 24-week DB treatment period. Recruitment may continue beyond 120 patients if required to achieve the target number of HES worsening/flares. Recruitment of adolescent patients is targeted to be broadly in line with expected prevalence rates of adolescents in the overall population. Approximately 4 to 6 adolescent patients (aged 12 to 17) are targeted to be randomised. Randomisation will be stratified. Approximately 40 patients will participate in a noninterventional interview to collect data on HRQoL and the patients' experience during the DB portion of the study.
All patients will remain on stable dose(s) and regimen of background HES therapy during the screening period and throughout 36 weeks of treatment (until Visit 12/Week 36 when the therapy can be adjusted). During this time, background HES therapy may only be modified if a patient has an HES clinical worsening/flare or an AE thought to be due to background therapy.
AstraZeneca, sites, and patients will be blinded to the absolute eosinophil, basophil, and monocyte counts, differential blood counts (percentages) for all WBCs (eosinophils, basophils, monocytes, neutrophils, and lymphocytes), and biopsy cell counts (if applicable) after randomisation/baseline (Visit 3/Week 0), during the entire DB treatment period, and for the first 4 weeks of the OLE treatment period (until Visit 10/Week 28) after which no blinding to WBC counts or biopsy cell counts is required. After the primary DBL, AstraZeneca will become unblinded to all patients' blood and biopsy cell counts obtained during DB treatment period.
The final dose of the DB treatment period will be given at Week 20, and the DB treatment period will complete at Week 24.
All patients who complete the DB treatment period on IP may be eligible to continue into an OLE treatment period on benralizumab (30 mg SC Q4W). The OLE is intended to allow treatment with open-label benralizumab for at least 1 year for adults and at least 2 years for adolescents after completion of the DB treatment period of the study (earlier enrolled patients may therefore be in the OLE for longer than 1 year). AstraZeneca may choose to extend the study depending on the overall development program. Moreover, AstraZeneca reserves the right of terminating the OLE early (eg, if development of the asset is terminated or marketing authorisation is obtained).
The primary DBL will occur when approximately 38 patients have had their first HES worsening/flare event during the DB treatment period and all randomised patients have had the opportunity to be followed up for the 24-week DB treatment period. Treatment allocation will remain blinded until the primary DBL. A patient must complete the 24-week DB treatment period on IP to be eligible to enter the OLE treatment period. The final DBL will occur after the last patient completes the OLE. Data from the OLE treatment period of the study will be presented in an addendum to the primary analysis CSR and/or a separate OLE treatment period CSR.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Benralizumab arm | Experimental | Biological: Benralizumab1x Benralizumab SC injection |
| Placebo arm | Placebo comparator | Biological: Placebo1x Benralizumab matching placebo SC injection |
Who may qualify
- Ages
- 12 to 130 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (17 listed)
- 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
Key exclusion criteria (21 listed)
- Life-threatening HES and/or HES complication(s) as judged by the investigator:
- Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation
- Definitive diagnosis of eosinophilic granulomatosis with polyangiitis
- 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
- Hypereosinophilia of unknown significance
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BenralizumabBenralizumab solution for injection in an accessorised prefilled syringe (APFS) will be administered subcutaneously (SC) every 4 weeks | Biological | Benralizumab arm |
| PlaceboMatching placebo solution for injection in an APFS will be administered SC every 4 weeks | Biological | Placebo arm |
Primary outcome
Time to First HES Worsening/Flare During the DB Treatment Period
Time frame: DB period (Baseline to Week 24)
The time to first HES worsening/flare is calculated as: start date of the first HES worsening - date of randomisation + 1. For participants who do not experience a HES worsening/flare, the time to first HES worsening/flare is right censored at the end of the DB period corresponding to the earliest date (date of the first of Benra open label dose, study day 183, date of last contact, and data cut-off date). The number of participants with events and censored observations is presented.
12 secondary outcomes
Proportion of Patients Who Experience an HES Worsening/Flare During the DB Treatment Period
Time frame: DB period (Baseline to Week 24)
Number of HES Worsenings/Flares (Annualised Rate) During the DB Period
Time frame: DB period (Baseline to Week 24)
Time to First Haematologic Relapse (AEC ≥ 1000 Cells/μL) During the DB Period
Time frame: DB period (Baseline to Week 24)
Fatigue Severity (PROMIS Fatigue Short Form 7a) at Week 24
Time frame: Week 24
Proportion of Patients Who Have Haematologic Relapse During the DB Treatment Period
Time frame: DB period (Baseline to Week 24)
Proportion of Patients Who Have AEC < 500 Cells/μL for 24 Weeks
Time frame: DB period (Baseline to Week 24)
Proportion of Patients Who Require an Increase in Corticosteroid Dose From Baseline at Any Point in the DB Treatment Period
Time frame: DB period (Baseline to Week 24)
Health-Related Quality of Life (HRQoL) (Short Form-36 Version 2 [SF-36v2])
Time frame: DB period (Baseline to Week 24)
Patient Global Impression of Severity (PGI-S)
Time frame: DB period (Baseline to Week 24)
Patient Global Impression of Change (PGI-C)
Time frame: DB period (Baseline to Week 24)
Serum Benralizumab Concentrations
Time frame: DB period (Baseline to Week 24)
Anti-Benralizumab Antibodies and Neutralizing Antibodies (nAbs)
Time frame: DB period (Baseline to Week 24)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Jul 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41917160Ogbogu PU, Roufosse F, Akuthota P, Kuna P, Groh M, Reiter A, Yokota A, Siddiqui SH, Mutsaers PGNJ, Li B, Khoury P, Bahadori LM, Bednarczyk A, Bouma G, Brooks LG, Ferreira J, Grindebacke H, Ho CN, Jain P, Palmer RL, Jison ML, Klion AD; NATRON study group. Benralizumab versus placebo for hypereosinophilic syndrome: a randomized, placebo-controlled phase 3 trial. Nat Med. 2026 Jun;32(6):2017-2025. doi: 10.1038/s41591-026-04315-8. Epub 2026 Mar 31.
- CSR SynopsisLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
52 sites in 17 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Benralizumab in people with Hypereosinophilic Syndrome, run by AstraZeneca at 52 sites in 17 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 10 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 52 sites in United States, Israel, Japan, China, France and 12 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 10 Jul 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to First HES Worsening/Flare During the DB Treatment Period (time frame: DB period (Baseline to Week 24)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04191304, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2026.