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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

10 Jun 2020 → ongoing

Decision date (initial)

2024-07-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2023-510455-28-00

EudraCT number

2019-002039-27

ClinicalTrials.gov

NCT04191304

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Pharmacokinetic, Therapy, Pharmacogenomic, Efficacy

To evaluate the effect of benralizumab on the time to first HES worsening/flare

Secondary objectives 1

1. "For DB period to evaluate the effect of benralizumab on: - the proportion of patients who experience an HES worse - 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 "

Conditions and MedDRA coding

Hypereosinophilic Syndrome (HES)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

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 ≥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.

Exclusion criteria 15

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 x 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. "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)"

Secondary endpoints 2

1. "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 [...]
2. "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)"

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

-

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca AB Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca AB Information Center

Third parties 7

Locations

9 EU/EEA countries · 21 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 80 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications