Evaluation of Benralizumab on Structural and Lung Function Alterations in Severe Eosinophilic Asthma: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-506614-40-00
- Protocol
- D3250C00059
- Sponsor
- AstraZeneca AB
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **benralizumab** on submucosal eosinophils in endobronchial biopsies, as measured by major basic protein (MBP) staining. Additionally, the study aims to assess the impact of benralizumab on airway wall dimensions using quantitative computed tomography (QCT) imaging. These objectives are clinically relevant as they address the underlying inflammatory processes and structural changes in patients with severe eosinophilic asthma, potentially leading to improved management and therapeutic strategies for this condition.
Secondary objectives include evaluating the effect of benralizumab on various parameters: - Eosinophils in endobronchial biopsies via MBP staining - Small airway obstruction and computational fluid dynamics using QCT - Mucus plugging and large airway remodeling through histology and immunohistochemistry (IHC) - Small airway obstruction using airwave oscillometry (AO) - Changes in lung function via pre-bronchodilator (BD) and post-BD whole body plethysmography (WBP) - Airway function using spirometry - Basophil numbers in endobronchial biopsies via IHC - Short-term anti-inflammatory effects on primary and secondary endpoints measured by QCT, AO, WBP, and spirometry.
Participants
The clinical trial involves a total of **54 participants** diagnosed with **severe eosinophilic asthma**. The study population includes both male and female subjects, aged between 18 and 70 years. Participants were selected based on their ability to provide informed consent and their compliance with specific asthma treatment regimens, including the use of high-dose inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). The trial population is characterized by a history of physician-diagnosed asthma requiring continuous treatment, with a documented current treatment regimen. Participants are required to have an acceptable inhaler technique and a compliance rate of over 70% with inhaled asthma maintenance medication. Lifestyle considerations such as diet and physical activity are not specified, but participants must have fewer than 12 exacerbations in the six months prior to the study. The trial includes individuals with a blood eosinophil count meeting specific criteria and a weight of at least 40 kg. Both male and female participants are included, with specific criteria for women of childbearing potential to ensure safety and compliance with study protocols.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the effect of **benralizumab** on structural and lung function changes in patients with severe eosinophilic asthma. The trial will involve a parallel group design, with participants randomly assigned to receive either benralizumab or a placebo. The study aims to assess the impact of benralizumab on submucosal eosinophils in endobronchial biopsies and airway wall dimensions using quantitative computed tomography imaging. The trial is expected to commence recruitment on February 26, 2024, and conclude by September 9, 2026, with a maximum treatment period of 48 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, asthma history, and blood eosinophil count. Following successful screening, participants will be randomized and begin the treatment phase. Regular follow-up visits will be scheduled to monitor safety, efficacy, and compliance with the study protocol. These visits will include assessments of lung function, asthma control, and any adverse events. The end-of-study visit will occur after the treatment period, where final evaluations will be conducted to assess the primary and secondary endpoints.
The expected length of participant involvement in the study is approximately 48 weeks, with conditions for early termination including non-compliance with the study protocol, withdrawal of consent, or any adverse events that may compromise participant safety. The study will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their well-being is prioritized throughout the trial.
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 subcutaneously. The maximum daily dose is 30 mg, with a total maximum dose of 210 mg over the treatment period. The treatment duration is up to 48 weeks. Fasenra is manufactured by AstraZeneca AB and is authorized under the marketing authorization number EU/1/17/1252/001. The clinical packaging is manually assembled, packaged, and labeled.
The study also includes a **placebo** for benralizumab, which is a sterile liquid solution presented in an accessorized prefilled syringe for subcutaneous injection. The placebo is used as a comparator treatment in this double-blind, placebo-controlled study. The placebo is designed to match the appearance and administration route of Fasenra to maintain the study's blinding integrity.
Efficacy
The efficacy of benralizumab in the treatment of severe eosinophilic asthma will be assessed through a series of primary endpoints. These endpoints include the change, expressed as a percentage from baseline to the end of treatment (EOT), in eosinophil numbers, measured as number/mm² in the submucosa. Additionally, the change in airway wall area percentage (WA%) from baseline to EOT will be evaluated as the overall median for airway generations 3 and 4 combined. Supportive measures will include changes in airway lumen area (LA), airway wall area (WA), and airway wall thickness (WT), all expressed as percentages from baseline to EOT.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to understand and give written informed consent and has signed a written informed consent form (ICF) approved by the Investigator's Institutional Review Board (IRB)/Ethics Committee (EC), prior to conducting any study related procedures (including withholding of any asthma medications required for procedures)
- Male or female aged 18 through 70 years at the time of Visit 1
- History of physician-diagnosed asthma requiring continuous treatment with medium- or high-dose ICS (>250μg fluticasone propionate dry powder formulation equivalents total daily dose) plus LABA with or without additional controller medication for at least 12 months prior to Visit 1
- Documented current treatment with high-dose ICS plus LABA for at least 3 months prior to Visit 1 with or without additional asthma maintenance medication. If the participant is taking ICS plus LABA, the ICS and LABA can be parts of a combination product or given by separate inhalers. -For ICS plus LABA combination preparations, highest-strength maintenance doses approved in the given country will meet this criterion. -If the ICS and LABA are given by separate inhalers, then the participant must be on a high daily ICS dose during the last 3 months prior to Visit 1(see Appendix D for high daily ICS doses by formulation).
- Morning pre-BD FEV1 ≥ 50 to < 80% of PNV and ≥ 1 L at Visit 2, or morning pre-BD FEV1 ≥ 50 to < 90% of PNV, if documented historical pre-BD FEV1 value (within 12 months prior to screening visit) was < 80% of PNV. One retest is allowed
- A blood eosinophil count meeting any of 3 criteria below: - ≥ 300 cells/μL during screening at Visit 1 or Visit 2, OR - ≥ 220 to < 300 cells/μL during screening at Visit 1 or Visit 2 and documented eosinophil count of ≥ 300 cells/μL in the past 12 months, OR - ≥ 150 to < 300 cells/μL during screening at Visit 1 or Visit 2 PLUS one of the following: Presence of nasal polyps, or Pre-BD FVC < 65% predicted at Visit 2
- Weight of ≥40 kg
- Negative serum pregnancy test for female participants of childbearing potential at Visit 1
- Negative urine pregnancy test in female participants of childbearing potential prior to randomization and administration of IP
- Women are authorized to participate if they meet the following criteria: Female participants who cannot bear children as evidenced by: Women ""not of childbearing potential"" are defined as women who are either permanently sterilized (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 randomization without an alternative medical cause. The following age-specific requirements apply - Women <50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range. Until FSH is documented to be within menopausal range treat the participant as WOCBP - Women ≥50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. If criteria not met, participant should be regarded as having child bearing potential. Female participant capable of having children and both of the following conditions are met: - Have a negative urine pregnancy test prior to administration of the IP and - Must agree to use a highly effective method of birth control (confirmed by the investigator) from randomization throughout the study duration and within 12 weeks after last dose of IP. Highly effective methods ( those that can achieve a failure rate of less than 1% per year when used consistently and correctly) ) include: -Combined (estrogen 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 (IUD) -Intrauterine hormone-releasing system (IUS) -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 participant) -Vasectomized sexual partner provided that partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has received medical assessment of the surgical success
- Acceptable inhaler technique, as judged by the investigator.
- ACQ-6 >1.5
- Compliance with inhaled asthma maintenance medication >70% (calculated in the period from Visit 2 to Visit 3). The screening/run-in period may be extended to accommodate this criterion
- Fewer than 12 exacerbations within the 6 months prior to Visit 3
Exclusion Criteria
- Clinically important pulmonary disease other than asthma or participants who have ever been diagnosed with pulmonary or systemic disease, other than asthma, that are associated with elevated peripheral eosinophil counts.
- Life-threatening asthma, defined as episodes requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episodes within the 12 months prior to Visit 1.
- In participants undergoing bronchoscopy, a history of allergies or adverse drug reactions to medications used for pre-bronchoscopy procedures.
- Any disorders that is not stable in the opinion of the investigator and could affect the safety of the participant during the study, influence the findings of the studies or their interpretations, or impede the participant's ability to complete the entire duration of the study.
- Current smokers. Ex-smokers must not have smoked for a minimum of 12 months and should not have a smoking history >15 pack-years at Visit 1. Participants who use e-cigarettes or smoke marijuana will also be excluded from the study.
- Alcohol or drug abuse (past or present) or any conditions associated with poor compliance.
- Participants who are scheduled to be admitted to hospital or undergo inpatient surgery during the study.
- History of anaphylaxis to any biologic therapy.
- Known history of allergy or reaction to any component of the IP formulation
- History of cancer: - Participants who have had basal cell carcinoma, localized squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible provided that the participant curative therapy was completed at least 12 months prior to the date informed consent is obtained - Participants who have had other malignancies are eligible provided that the participant curative therapy was completed at least 5 years prior to the date informed consent is obtained
- A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy
- A history of known immunodeficiency disorder including a positive human immunodeficiency virus test.
- Current active liver disease, except for chronic stable hepatitis B and C, or other stable chronic liver disease are acceptable if participant otherwise meets eligibility criteria.
- In participants undergoing bronchoscopy, any medical condition that requires chronic treatment with chronic anti-coagulation, chronic aspirin, or anti-platelet therapy.
- In participants undergoing bronchoscopy, use of anticoagulants within 4 weeks prior to randomization into the study.
- In participants undergoing bronchoscopy, use of non-steroidal antiinflammatory drugs within 72 hours before or aspirin within 7 days of randomization
- Use of chronic (i.e. >4 weeks) immunosuppressive medication within 3 months prior to the date informed consent is obtained.
- Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
- Receipt of any marketed or investigational biologic for the treatment of asthma within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever is longer.
- Previously received benralizumab. Participants that participated in other studies with benralizumab but have been confirmed to have received placebo are eligible.
- Receipt of live attenuated vaccines 30 days prior to the date of randomization. Receipt of inactive/killed vaccinations is allowed provided they are not administered within 1 week before/after any IP administration.
- Change to allergen immunotherapy or new allergen immunotherapy within 30 days prior to the date of informed consent and anticipated changes in immunotherapy during the study.
- Receipt of bronchial thermoplasty in the last 24 months prior to Visit 1.
- Participation in an interventional clinical study during the past 3 months or participants previously randomized into this study. If it is documented that the participant was known to be on placebo treatment of a completed study, then a 3-month period is not required.
- Receipt of any investigational non-biologic within 30 days or 5 halflives prior to the date informed consent is obtained, whichever is longer.
- Any clinically significant abnormal findings, which in the opinion of the Investigator, may put the particpant at risk, or may influence the results of the study, or the participant's ability to complete the entire duration of the study.
- Alanine aminotransferase or aspartate aminotransferase level ≥3 times the upper limit of normal, confirmed by repeated testing during the screening period.
- Currently pregnant, breastfeeding or lactating women.
- Blood draws of 100 mL or more within 45 days prior to enrolment in the study.
- Radiological findings suggestive of a respiratory disease other than asthma that is contributing to the participant's respiratory symptoms.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 26 Feb 2024 | 19 |
 Sweden | Not Recruiting | 26 Feb 2024 | 8 |
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 |
|---|---|---|---|---|---|---|
Placebo for benralizumab for clinical trials is a sterile liquid solution presented in an accessorized prefilled syringe (apfs)
for subcutaneous injection. | Placebo | N/A | — | — | — | N/A |
Fasenra 30 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS | 30 | 48 | PRD5759002 |