A Phase III Study to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (HES)
- Conditions
- Hypereosinophilic Syndrome
- Interventions
- Biological: Placebo
- Registration Number
- NCT04191304
- Lead Sponsor
- AstraZeneca
- Brief 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). 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 117
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Benralizumab arm Benralizumab 1x Benralizumab SC injection Placebo arm Placebo 1x Benralizumab matching placebo SC injection
- Primary Outcome Measures
Name Time Method 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 an increase or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalisation
- Secondary Outcome Measures
Name Time Method Proportion of patients who experience 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 an increase or addition of new cytotoxic and/or immunosuppressive therapy, OR hospitalisation. For this endpoint patients who withdraw from the study without having flared are included in the analysis as a flare event.
number of HES worsenings/flares Up to 24 weeks Number of HES worsenings/flares (annualised rate/year) during the DB period
Time to first haematologic relapse Up to 24 weeks A haematologic relapse is defined as AEC ≥1000 cells/μL
Change from baseline in fatigue severity at week 24 Patient reported measure of fatigue severity (PROMIS fatigue short form 7a)
Proportion of patients who have haematologic relapse Up to 24 weeks Proportion of patients who have haematologic relapse during the DB treatment period. Haematologic relapse post-baseline: AEC ≥ 1000 cells/μL. Patients who withdraw without having had a hematologic relapse will be considered as a relapse event in this analysis
Proportion of patients who have AEC<500 cells/µL for 24 weeks Up to 24 weeks Proportion of patients who have AEC \< 500 cells/μL for 24 weeks.
Proportion of patients who require an increase in corticosteroid dose Up to 24 weeks Proportion of patients who require an increase in corticosteroid dose from baseline at any point in the double-blind treatment period
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 Serum Benralizumab concentrations.
Anti-drug antibodies (ADA) titers and neutralizing antibodies (nAb) as measure of immunogenicity Up to 24 weeks Anti-benralizumab antibodies and nAbs.
Adverse Events (AEs), vital signs and clinical laboratory assessments as an evaluation of safety and tolerability of benralizumab Up to 24 weeks AEs, vital signs and clinical laboratory assessments.
Trial Locations
- Locations (1)
Research Site
🇬🇧London, United Kingdom