A Study to review the Effectiveness and Safety of Benralizumab 100 mg in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) with a History of Frequent COPD Exacerbations and Elevated Peripheral Blood Eosinophils

Phase 3

Active, not recruiting

• Conditions: Chronic obstructive pulmonary disease, unspecified,

• Registration Number: CTRI/2023/11/059825
• Lead Sponsor: AstraZeneca Pharma India Ltd

Brief Summary

This is a randomized, double-blind,placebo-controlled, parallel-group, multicenter, Phase 3 study to evaluate theefficacy and safety of a benralizumab dose administered by subcutaneous(SC) injection every 4 weeks for the first 3 doses and then every 8 weeksthereafter (thereafter referred to as Q8W) in patients with moderate to verysevere COPD with a history of frequent COPD exacerbations and elevatedperipheral blood eosinophils (≥300/μL). Eligible patients must have a historyof ≥2 moderate and/or severe COPD exacerbations in the previous year despitereceiving stable triple (ICS/LABA/LAMA) background therapy for at least 3months and ICS-based dual inhaled treatment for the remainder of the year.Eligible patients must also have an elevated blood eosinophil count of ≥300/μLat screening supported by at least 1 historical result of ≥150/μL within theprevious year.

 Potentially eligible patients will enter the run-inperiod of 5 weeks. Patients who meet eligibility criteria will be randomized ina 1:1 ratio to receive either benralizumab 100 mg or placebo Q8W. The treatmentperiod will be of variable duration and will continue until the last patienthas the opportunity to complete a minimum of 56 weeks, at which point allpatients will complete the study; see Section 4.1.3. The primary endpoint willbe analyzed at Week 56.

 This Phase 3 study will evaluate the efficacy andsafety of benralizumab in patients with moderate to very severe COPD withelevated peripheral blood eosinophils and a history of frequent COPDexacerbations despite receiving triple (inhaled corticosteroid/long-acting β2agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]) background therapy.

Approximately 2140 participants will bescreened/enrolled to achieve 642 participants globally.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-12-14
• Last Update Posted: 2024-04-17

Recruitment & Eligibility

• Status: Closed to Recruitment of Participants
• Sex: All
• Target Recruitment: 642

Inclusion Criteria

• Informed consent 1.
• Provision of signed and dated ICF prior to any mandatory study-specific procedures, sampling, and analyses.
• Age and Sex 2.
• Patient must be 40 to 85 years of age inclusive, at the time of signing the ICF.
• Male and/or female.
• Type of patient and disease characteristics 4.
• Current smoker or ex-smoker with a tobacco history of ≥10 pack-years (1 pack-year equal to 20 cigarettes smoked per day for 1 year).
• (Note: electronic cigarette [e-cigarette] use does not contribute to the pack-year count for eligibility.) 5.
• History of moderate to very severe COPD with a post-bronchodilator FEV1/forced vital capacity (FVC)<0.70 and a post-bronchodilator FEV1 ≤65% of predicted normal value at screening central spirometry assessment.
• Documented history of 2 or more moderate and/or severe COPD exacerbations12 that required treatment with systemic corticosteroids (at least 3 days or a single depot formulation injection) and/or hospitalization within 52 weeks prior to enrolment.
• (a) Exacerbations treated with antibiotics alone are not considered as meeting the criterion unless it is accompanied by treatment with systemic corticosteroids and/or hospitalization.
• (b) Hospitalization is defined as an inpatient admission ≥24 hours in the hospital, in an observation area, the emergency department, or other equivalent healthcare facility depending on the country and healthcare system.
• (c) Previous exacerbations should be confirmed to have occurred while the patient was on stable double or triple (ICS/LABA/LAMA) background therapy for COPD and not as a result of a gap or step down in the treatment.
• (d) At least one qualifying COPD exacerbation should occur while on stable uninterrupted triple therapy prior to enrolment.
• Documented use of triple (ICS/LABA/LAMA1) background therapy for COPD for ≥3 months immediately prior to enrollment.
• (a) Treatment with at least double inhaled therapy containing ICS (e.g. ICS/LABA or ICS/LAMA) for the remaining of 52 weeks prior to enrolment.
• Use of LABA/LAMA is allowed if ICS cannot be tolerated.
• (b) ICS in a dose approved for COPD or equivalent to ≥250 mcg of fluticasone propionate daily.2 (c) Patient could have switched therapies during the previous year and/or stepped down for short periods of time, although the total cumulative duration that the patient was not using inhaled double or triple background therapy must not exceed 2 months (d) Patient must be on stable therapy/doses for the last 3 months prior to randomization.
• (Individual component changes or switches between devices are allowed as long as the patient remains on ICS/LABA/LAMA with an acceptable ICS dose) 8.
• In the absence of historical data, an additional blood eosinophil count must be obtained by repeating the testing during the run-in period (at least 4 weeks apart).
• CAT total score ≥15 at Visit 1 (also see inclusion criterion 15).
• Reproduction 10.
• Negative pregnancy test (serum) for female patients of childbearing potential at Visit 1 (enrollment).
• Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control (confirmed by the investigator) from enrollment throughout the study duration and within 12 weeks after last dose of IP.
• Highly effective forms of birth control (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include: a)Combined (estrogen and progestogen containing) hormonal contraception b)associated with inhibition of ovulation- oral, intravaginal, or transdermal c)Progestogen-only hormonal contraception associated with inhibition of d)ovulation- oral, injectable, or implantable e)Intrauterine device (IUD) f)Intrauterine hormone releasing system g)Bilateral tubal occlusion h)Sexual abstinence, i.e. 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 patient.) i)Vasectomized sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomized partner has received j)medical assessment of the surgical success) 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 amenorrheic for ≥12 months prior to the planned date of randomization without an alternative medical cause.
• The following age-specific requirements apply: I.Women <50 years old will be considered postmenopausal if they have been a.amenorrheic 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 patient as WOCBP.
• II.Women ≥50 years old will be considered postmenopausal if they have been a.amenorrheic for 12 months or more following cessation of all exogenous b.hormonal treatment.
• Additional eligibility criteria 12.
• Ability to read, write, and use electronic devices.
• Compliance with eDiary completion during the run-in period, defined as at least 8 fully completed daily diary assessments in the 14-day period prior to randomization visit (i.e. Study Days -14 to -1).
• CAT score ≥15 at the last run-in visit prior to randomization and stable within ±3 points variance compared to previous visits.
• If a patient demonstrates significant change (>3 points in either direction) in CAT score during the run-in period, randomization must not occur without agreement with AZ study physician/delegate, and the run-in period must be extended for an additional 4 weeks.

Exclusion Criteria

• Medical conditions 1.
• Clinically important pulmonary disease other than COPD (e.g. active lung infection, clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia).
• Current diagnosis of asthma, according to the Global Initiative for Asthma (GINA) or other accepted guidelines, prior history of asthma, or asthma-COPD overlap according to GINA/GOLD2.
• Childhood history of asthma is allowed and defined as asthma diagnosed and resolved (i.e. not requiring the use of any maintenance or rescue medication) before the age of 18.
• Radiological findings suggestive of a respiratory disease other than COPD that is contributing to the patient s respiratory symptoms.
• Radiological findings of solitary pulmonary nodules without appropriate follow up and demonstration of stability as per standard of care or results suggestive of acute infection.
• Another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome).
• Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major physical impairment that is not stable in the opinion of the investigator and/or could: a.Affect the safety of the patient throughout the study b.Influence the findings of the study or their interpretation c.Impede the patient s ability to complete the entire duration of the study 6.
• Any clinically significant abnormal findings in physical examination, vital signs, ECG, hematology, clinical chemistry, or urinalysis during the run-in 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.
• Signs and/or symptoms of cor pulmonale and/or right ventricular failure.
• Patients receiving long-term treatment with oxygen >4.0 liters/minute (L/min).
• While breathing supplemental oxygen, patients should demonstrate an oxyhemoglobin saturation ≥89%.
• In order to be admitted to the study, patients on long-term oxygen therapy have to be ambulatory and be able to attend clinic visits.
• Use, or need for chronic use, of any non-invasive positive pressure ventilation device (NIPPV).
• Note: Patients using continuous positive airway pressure (CPAP) for Sleep Apnea Syndrome are allowed in the study.
• History of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2.
• Active liver disease.
• 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, esophageal or gastric varices, or persistent jaundice, or cirrhosis.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times the upper limit of normal (ULN), confirmed by repeated testing1 during the run-in period.
• Transient increase of AST/ALT level that resolves by the time of randomization is.
• 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.
• History of alcohol or drug abuse within the past year, which may compromise the study data interpretation as judged by investigator or AZ study physician.
• Malignancy, current or within the past 5 years, except for adequately treated non-invasive basal cell and squamous cell carcinoma of the skin and cervical carcinoma-in-situ treated with apparent success more than 1 year prior to Visit 1.
• Suspected malignancy or undefined neoplasms.
• Patients who, in the opinion of the investigator or qualified designee, have evidence of active TB.
• Patients with a recent (within 2 years) first-time or newly positive purified protein derivative (PPD) test or Quantiferon test need to complete an appropriate course of treatment before being considered for enrollment.
• Evaluation will be according to the local standard of care and may consist of history and physical examinations, chest X-ray, and/or TB test as determined by local guidelines.
• Patients participating in, or scheduled for, an intensive (active) COPD rehabilitation program (patients who are in the maintenance phase of a rehabilitation program are eligible to take part).
• Patients with a history of surgical or endoscopic (e.g. valves) lung volume reduction within the 6 months prior to enrollment.
• Patients with a history of partial or total lung resection (single lobe or segmentectomy is acceptable).
• Scheduled major surgical procedure during the course of the study.
• Minor elective procedures are allowed.
• History of anaphylaxis to any biologic therapy or vaccine.
• Prior/concomitant therapy 21.
• Receipt of blood products or immunoglobulins within 30 days prior to randomization.
• Receipt of marketed or investigational biologic product within 4 months or 5 half-lives prior to randomization, whichever is longer.
• Exception: Patients on stable therapy for 3 months before randomization who intend to stay on treatment throughout the study with marketed biologic products that are not likely to interfere with the safety assessment and/or efficacy of benralizumab, for example, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic diseases, can participate in the study.
• Receipt of live attenuated vaccines 30 days prior to randomization.
• Chronic use of antibiotics2 if the duration of treatment is <9 months prior to randomization (Week 0).
• Chronic macrolide or other antibiotic therapy is allowed provided the patient has been on a stable dose/regimen for ≥9 months prior to randomization and has had ≥2 COPD exacerbations while on stable therapy.
• If the patient was previously on chronic antibiotic but is no longer taking it, the patient cannot be randomized until 6 weeks after the last dose.
• Prior/concurrent clinical study experience 26.
• Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to enrollment, whichever is longer.
• Receipt of benralizumab within 12 months prior to enrollment.
• Known history of allergy or reaction to any component of the IP formulation.
• Other exclusions: 29.
• Donation of blood, plasma, or platelets within the past 90 days prior to enrollment.
• Pregnant, breastfeeding, or lactating women.
• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To evaluate the effect of benralizumab 100 mg on COPD exacerbations in patients	Annualized rate of moderate or severe COPD exacerbations, where a COPD exacerbation is defined by symptomatic worsening of COPD | Requiring - | Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids | Use of antibiotics and or | Inpatient hospitalization or death due to COPD
severe COPD	Annualized rate of moderate or severe COPD exacerbations, where a COPD exacerbation is defined by symptomatic worsening of COPD | Requiring - | Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids | Use of antibiotics and or | Inpatient hospitalization or death due to COPD

Secondary Outcome Measures

Name	Time	Method
To evaluate the effect of benralizumab 100 mg on	severe COPD exacerbations (leading to
To evaluate the effect of benralizumab 100 mg on COPD exacerbations involving emergency room visits	and hospitalizations
To evaluate the effect of benralizumab 100 mg on other parameters associated with COPD exacerbations	Time to first COPD exacerbation- From Randomisation to visit 17 (week 56)
To evaluate the effect of benralizumab 100 mg on health status/health-related quality of life	Change from baseline in SGRQ total & domain scores
To evaluate the effect of benralizumab 100 mg on respiratory symptoms	Change from baseline in E-RS COPD total and domain scores
To evaluate the effect of benralizumab 100 mg on pulmonary function	Change from baseline in pre-dose pre-bronchodilator FEV at the study site
To evaluate the effect of benralizumab 100 mg on all	cause and respiratory-related mortality
To evaluate the effect of benralizumab 100 mg on health care resource utilization due to COPD	Annual rate of hospitalizations due to COPD; Length of hospital stay; ICU days; annual rate of hospitalizations and emergency department visits

Trial Locations

Locations (10)

Aster Prime Hospitals; 🇮🇳 Hyderabad, TELANGANA, India

Asthma Bhawan; 🇮🇳 Jaipur, RAJASTHAN, India

Bhaktivedanta Hospital and Research Institute; 🇮🇳 Thane, MAHARASHTRA, India

Government Hospital for Chest and Communicable Disease (GHCCD); 🇮🇳 Visakhapatnam, ANDHRA PRADESH, India

Government Siddhartha Medical College; 🇮🇳 Krishna, ANDHRA PRADESH, India

Hindusthan Hospital; 🇮🇳 Coimbatore, TAMIL NADU, India

Institute of Chest Disease, Government Medical College; 🇮🇳 Kozhikode, KERALA, India

Lalitha Super Specialty Hospital; 🇮🇳 Guntur, ANDHRA PRADESH, India

Sri Ramachandra Hospital; 🇮🇳 Chennai, TAMIL NADU, India

Vardhman Mahavir Medical College & Safdarjung Hospital; 🇮🇳 Delhi, DELHI, India

Aster Prime Hospitals

🇮🇳Hyderabad, TELANGANA, India

Dr Boyilla Nagaraju

Principal investigator

9848883444

nagaraj.boyilla@gmail.com