Efficacy and Safety Evaluation of Benralizumab in Patients with Hypereosinophilic Syndrome: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial
- Trial ID
- 2023-510455-28-00
- Protocol
- D3254C00001
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **benralizumab** on the time to first worsening or flare of **Hypereosinophilic Syndrome (HES)**. This is clinically relevant as it aims to determine the efficacy of benralizumab in delaying disease exacerbations, which can significantly impact patient management and quality of life.
Secondary objectives include evaluating the effect of benralizumab on:
- The proportion of patients experiencing HES worsening or flares
- The number of HES worsenings/flares
- Time to first hematological relapse
- Patient-reported measure of fatigue
- The proportion of patients with hematologic relapse
- The number of patients maintaining an absolute eosinophil count (AEC) < 500 cells/μL for 24 weeks
- Corticosteroid use
- Health status/health-related quality of life (HRQoL) measures
Additionally, the study will assess the pharmacokinetics (PK), immunogenicity, safety, and tolerability of benralizumab in patients with HES. These secondary objectives are crucial for understanding the broader impact of benralizumab on disease management and patient outcomes.
Participants
The clinical trial investigating the effect of benralizumab on the time to first worsening or flare of **Hypereosinophilic Syndrome (HES)** includes a total of 53 participants. The study population comprises both male and female subjects aged 12 years and older. Participants were selected based on a documented diagnosis of HES, characterized by persistent eosinophilia and evidence of end organ manifestations attributable to the eosinophilia. The trial includes individuals with stable HES treatment regimens and those who have experienced signs or symptoms of HES worsening or flares. The study population is diverse, including both genders and a vulnerable population, ensuring a comprehensive evaluation of the treatment's efficacy across different demographic groups. Participants are required to have a corticosteroid responsiveness and meet specific health criteria, such as a negative test for the FIP1L1-PDGFRA fusion tyrosine kinase gene translocation. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **benralizumab** in patients with **Hypereosinophilic Syndrome (HES)**. The trial consists of a 24-week double-blind treatment period followed by an open-label extension. The primary objective is to assess the effect of benralizumab on the time to first HES worsening or flare. The study will involve a series of visits, starting with an inclusion (screening) visit to confirm eligibility based on specific criteria, including a documented diagnosis of HES and stable treatment regimens. Participants will be randomly assigned to receive either benralizumab or a placebo, administered via subcutaneous injection.
The trial will include multiple follow-up visits to monitor the participants' health status, treatment adherence, and any adverse events. These visits will also involve laboratory assessments to evaluate hematologic parameters and other relevant clinical markers. The end-of-study visit will conclude the trial, where final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety. The expected duration of participant involvement is approximately 24 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. The trial is estimated to end by March 2027, with recruitment having started in September 2020.
Treatment
The clinical trial involves the administration of **Fasenra**, a 30 mg solution for injection in a pre-filled syringe. The active substance in Fasenra is **benralizumab**, a protein of other origin. The pharmaceutical form is a solution for injection, and it is administered via the subcutaneous route. The dosing schedule involves a maximum daily dose of 30 mg, with a total maximum dose of 600 mg over the treatment period. The treatment period is set for 24 weeks. The product is sourced centrally by the sponsor from commercial unlabelled stock and is manually assembled, packaged, labeled, and released by AstraZeneca prior to use. Participant compliance with the dosing schedule will be monitored throughout the study.
The trial also includes a **placebo** group, which serves as a comparator treatment. The placebo is presented in a form that is not specified in the available data. It is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered in a manner consistent with the experimental treatment to ensure the integrity of the study design.
Additionally, a **Benralizumab Placebo** is utilized for clinical trials. This placebo is a sterile liquid solution presented in an accessorized prefilled syringe (APFS) for subcutaneous injection. The specific details regarding the pharmaceutical form and active substances are not provided. This placebo is used to further support the study's double-blind methodology, ensuring unbiased results in evaluating the efficacy and safety of benralizumab in patients with **Hypereosinophilic Syndrome (HES)**.
Efficacy
The efficacy of benralizumab in patients with **Hypereosinophilic Syndrome (HES)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the "Time to first HES worsening/flare," which will be evaluated using a hazard ratio. This endpoint considers HES clinical manifestations or laboratory abnormalities that necessitate an increase or burst of oral corticosteroids (OCS) of at least 10 mg/day for a minimum of two days, an increase or addition of new cytotoxic and/or immunosuppressive therapy, or hospitalization.
Secondary endpoints during the double-blind (DB) treatment period include the proportion of patients experiencing an HES worsening/flare, the annualized rate of HES worsenings/flares, time to first hematologic relapse (absolute eosinophil count [AEC] ≥ 1000 cells/μL), and fatigue severity measured by the PROMIS fatigue short form 7a at Week 24. Additional secondary endpoints during the open-label extension (OLE) treatment period include the proportion of patients experiencing an HES worsening/flare, the annualized rate of HES worsening/flare, fatigue assessment, and safety and tolerability evaluations through adverse events, vital signs, and clinical laboratory assessments. Serum benralizumab concentrations, anti-benralizumab antibodies, and neutralizing antibodies (nAbs) will also be measured, alongside assessments using the HES symptom questionnaire and health-related quality of life (HRQoL) via the SF-36v2.
Inclusion and Exclusion Criteria
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 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.
- 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.
- 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
- 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.
- 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
- 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: (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.
- 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.
- 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.
- 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.
- For women only: Currently pregnant, breastfeeding, or lactating women.
- Treatment with injectable (SC, IV, or IM) corticosteroids in the 4- week period prior to randomisation
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 07 Sept 2020 | 1 |
 Belgium | Not Recruiting | 07 Sept 2020 | 9 |
 Denmark | Not Recruiting | 07 Sept 2020 | 2 |
 France | Not Recruiting | 07 Sept 2020 | 27 |
 Germany | Not Recruiting | 07 Sept 2020 | 4 |
 Italy | Not Recruiting | 07 Sept 2020 | 5 |
 The Netherlands | Not Recruiting | 07 Sept 2020 | — |
 Poland | Not Recruiting | 07 Sept 2020 | 5 |
 Spain | Not Recruiting | 07 Sept 2020 | 2 |
| Netherlands | — | — | 5 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fasenra 30 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 30 | 24 | PRD5759004 |
Placebo | Placebo | N/A | — | — | — | N/A |
Benralizumab Placebo for clinical trials is a sterile liquid solution presented in an accessorized prefilled syringe (APFS) for subcutaneous injection. Please refer to the IMPD documentation enclosed. | Placebo | N/A | — | — | — | N/A |