BENRALIZUMAB for Hypereosinophilic syndrome

Inclusion criteria

• {"criterion_text":"- 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\n- 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.\n- Males and females 12 years of age and older at the time of signing the ICF\n- 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)\n- Documented negative testing for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation.\n- Stable HES treatment dose(s) and regimen for ≥4 weeks at the time of Visit 1.\n- 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.\n- AEC ≥1000 cells/μL at Visit 1 (assessed by local laboratory)\n- 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.\n- 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

• {"criterion_text":"- 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.\n- 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\n- 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.\n- A history of known immunodeficiency disorder other than that explained by the use of OCS or other therapy taken for HES. Positive HIV test.\n- 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.\n- For women only: Currently pregnant, breastfeeding, or lactating women.\n- Treatment with injectable (SC, IV, or IM) corticosteroids in the 4- week period prior to randomisation\n- Presence of FIP1L1-PDGFRA fusion tyrosine kinase gene translocation or other known imatinib-sensitive mutation.\n- Definitive diagnosis of eosinophilic granulomatosis with polyangiitis.\n- 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.\n- Hypereosinophilia of unknown significance\n- 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.\n- 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.\n- 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.\n- Diagnosis of systemic mastocytosis"}

Primary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"Time-to-event analysis on the Full Analysis Set (Population b) using a hazard ratio; intercurrent events handled with a treatment policy (include regardless of treatment discontinuation). HES worsening/flare is defined in the endpoint as clinical manifestations or laboratory abnormalities resulting in an increase/burst of oral corticosteroids (OCS) ≥10 mg/day for at least 2 days OR an increase/addition of cytotoxic and/or immunosuppressive therapy OR hospitalization."}

Secondary endpoints

• {"endpoint_text":"- \"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 [...]\"","definition_or_measurement_approach":"Multiple efficacy measures during the double-blind (DB) period including proportion with HES worsening/flares, annualised rate of HES worsenings/flares, time-to-first haematologic relapse (AEC ≥1000 cells/μL), PROMIS fatigue short form 7a at Week 24, proportions achieving/maintaining haematologic outcomes (e.g., AEC <500 cells/μL for 24 weeks), and measures of corticosteroid use, health status/HRQoL. Measurement methods cited in the endpoint text (e.g., PROMIS, AEC thresholds, event counts, time-to-event analyses)."}
• {"endpoint_text":"- \"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)\"","definition_or_measurement_approach":"During the open-label extension (OLE) period endpoints include proportion with HES worsening/flares, annualized rate, PROMIS fatigue, safety assessments (AEs, vitals, labs), PK and immunogenicity (serum benralizumab, anti-drug antibodies, neutralizing antibodies), HES symptom questionnaire and HRQoL (SF-36v2)."}

Italy

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

29-07-2024

Processing Time Days

35

Number Of Sites

2

Number Of Participants

5

Spain

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

18-07-2024

Processing Time Days

24

Number Of Sites

2

Number Of Participants

2

Austria

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

15-07-2024

Processing Time Days

21

Number Of Sites

1

Number Of Participants

1

Poland

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

06-08-2024

Processing Time Days

43

Number Of Sites

3

Number Of Participants

5

Netherlands

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

05-07-2024

Processing Time Days

11

Number Of Sites

1

Number Of Participants

5

France

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

10-07-2024

Processing Time Days

16

Number Of Sites

7

Number Of Participants

27

Denmark

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

10-07-2024

Processing Time Days

16

Number Of Sites

1

Number Of Participants

2

Belgium

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

11-07-2024

Processing Time Days

17

Number Of Sites

3

Number Of Participants

9

Germany

Earliest CTIS Part Ii Submission Date

24-06-2024

Latest Decision Or Authorization Date

12-07-2024

Processing Time Days

18

Number Of Sites

1

Number Of Participants

4

Primary sponsor

Full Name

AstraZeneca AB

Organisation Type

Pharmaceutical company

Country Of Registered Address

Sweden

Contract research organisations

Name

Fortrea Inc.

Responsibilities

IVRS30 – treatment randomisation; Vendor Management & Oversight; multiple operational trial management responsibilities (codes listed in record)

Name

PPD Development LP

Responsibilities

PK and ADA/nAb testing

Name

Labcorp Central Laboratory Services SARL

Responsibilities

Clinical chemistry; Clinical haematology; Serology/ endocrinology

Name

Fisher Clinical Services Inc.

Responsibilities

IP Distribution & Destruction

Name

Everest Clinical Research Corporation

Responsibilities

Service for Data Monitoring Committee (DMC) process and oversight of the committee

Third parties

• {"country":"Canada","full_name":"Cellcarta Biosciences Inc.","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"Sweden","full_name":"Olink Proteomics AB","duties_or_roles":"code:4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fisher Clinical Services Inc.","duties_or_roles":"IP Distribution & Destruction","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Everest Clinical Research Corporation","duties_or_roles":"Service for Data Monitoring Committee (DMC) process and oversight of the committee","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"IVRS30 – treatment randomisation; Vendor Management & Oversight (plus multiple operational roles coded)","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Clinical chemistry; Clinical haematology; Serology/ endocrinology","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"PK and ADA/nAb testing","organisation_type":"Pharmaceutical company"}