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A Multicenter, Randomized, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Phase 3 Study to Evaluate the Efficacy 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 (RESOLUTE)

PHRR190918-002196

D3251C00014

2019-CT0507

A Multicenter, Randomized, Double-blind, Chronic-dosing, Parallel-group, Placebo-controlled Phase 3 Study to Evaluate the Efficacy 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

This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, Phase 3 study to evaluate the efficacy and safety of a benralizumab 100 mg dose administered by subcutaneous (SC) injection every 4 weeks for the first 3 doses and then every 8 weeks
thereafter (hereafter referred to as Q8W) in patients with moderate to very severe COPD with a history of frequent COPD exacerbations and elevated peripheral blood eosinophils (≥300/μL). Eligible patients must have a history of ≥2 moderate and/or severe COPD
exacerbations in the previous year despite receiving triple (ICS/LABA/LAMA) background therapy. Eligible patients must also have an elevated blood eosinophil count of ≥300/μL at screening supported by at least 1 historical result of ≥150/μL within the previous year.
Potentially eligible patients will enter the run-in period of 5 weeks. Patients who meet eligibility criteria will be randomized in a 1:1 ratio to receive either benralizumab 100 mg or placebo Q8W. The treatment period will be of variable duration and will continue until the last patient has the opportunity to complete a minimum of 56 weeks, at which point all patients will complete the study. The primary endpoint will be analyzed at Week 56.
At randomization, patients will be stratified by country and number of exacerbations in the previous year (2 or ≥3). Randomization to the stratum of 2 exacerbations in the previous year will be capped to ensure ≥70% of patients with ≥3 exacerbations in the previous year in the study population.
Patients will be maintained on triple (ICS/LABA/LAMA) background therapy, from enrollment throughout the run-in and treatment periods. Background inhaled medications may be provided/reimbursed by AstraZeneca, based on
local regulations on patient participation in research studies and medication access.

This study will be conducted at approximately 386 sites in 22 countries.

Regime Classification Priority
2017 - 2022 Global competitiveness and innovation in health Drug discovery and development
Start Date Duration in Months Target Completion Date Actual Completion Date
2019-10-01 48 2023-10-01 0000-00-00

Ongoing

Institution Classification Region LTO #
AstraZeneca Pharmaceuticals (Philippines) Inc. Private Business NCR LTO-3000002234602
Institution Classification Region LTO #
None None None
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Ariane Marmeto ariane.marmeto@astrazeneca.com AstraZeneca Pharmaceuticals Phils 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippines
Name E-Mail Institution and Institution Address
Ariane Marmeto ariane.marmeto@astrazeneca.com AstraZeneca Pharmaceuticals Phils 16th Floor, Inoza Tower, 40th Street, Bonifacio Global City, Taguig, 1634, Philippines
Name Expertise Affiliation
Charles Y. Yu, MD, MSc Pulmonology De La Salle Health Sciences Institute
Lawrence Raymond, MD Pulmonology Lung Center of the Philippines
Marie Grace Dawn T. Isidro, MD Pulmonology West Visayas State University
Ronnie Z. Samoro, MD Pulmonology HealthLink Iloilo Inc.
Project Location Institutional Ethics Review Board
De La Salle Health Sciences Institute De La Salle Health Sciences Institute Independent Ethics Committee
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
West Visayas State University West Visayas State University Unified Biomedical Research Ethics Review Committee
HealthLink Iloilo Inc. N/A

Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) with a History of Frequent COPD Exacerbations and Elevated Peripheral Blood Eosinophils

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; and/or
• Use of antibiotics; and/or
• An inpatient hospitalization or death due to COPD

  • Annualized rate of severe COPD exacerbationsa, where a severe COPD exacerbation is defined by symptomatic worsening of COPD requiring an inpatient hospitalization or results in death due to COPD
  • Annualized rate of COPD exacerbations that are associated with an emergency room/emergency department visit or a hospitalization due to COPD
  • Time to first COPD exacerbation
  • SGRQ totala and domain scores
  • CAT total score
  • E-RS:COPD total and domain scores
  • Change from baseline in pre-dose/pre-bronchodilator FEV1 a at the study site
  • Mortality rate
  • Annual rate of hospitalizations due to COPD; Length of hospital stay; ICU days; annual rate of hospitalizations and emergency department visits combined due to COPD; annual rate of unscheduled outpatient visits including unscheduled visits to study sites due to COPD; and annual rate of unscheduled healthcare encounters due to COPD
  • Serum benralizumab concentration
  • Anti-benralizumab antibodies
  • Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory, and ECG Assessments related to AEs cover
    • Occurrence/frequency
    • Relationship to IP as assessed by investigator
    • Intensity
    • Seriousness
    • Death
    • AEs leading to discontinuation of IP Other significant AEs
  • Annualized rate of COPD-related events, where an event is defined by symptomatic worsening and increase in rescue medication as recorded in the eDiary
  • EXACT-PRO
  • Clinically Important Deteriorations (CID)
  • Patient perception of effect item from the Onset of Effect Questionnaire (OEQ)
  • Reduction in dose and number of days on systemic corticosteroids
  • EQ-5D-5L
  • Peripheral blood eosinophil counts
  • Serum biomarkers
  • Exploratory transcriptomic biomarkers of peripheral
    blood: RNA Seq and RNA microarray profiling
  • A blood sample for DNA isolation will be collected from patients who have consented to participate in the exploratory genetic analyses component of the study

Recruiting

Clinical Trial

D3251C00014

20190711143830

2019-08-19

0000-00-00

14

Unspecified

Unspecified

2019-10-01

INCLUSION CRITERIA

Informed consent
1 Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses. The ICF process is described in Appendix A 3.
Age and Sex
2 Patient must be 40 to 85 years of age inclusive, at the time of signing the ICF.
3 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 = 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)

6 Documented history of 2 or more moderate and/or severe COPD exacerbations1 that required treatment with systemic corticosteroids (at least 3 days or a single depot formulation injection) and/or hospitalization within 52 weeks prior to enrollment.
(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 patient was on stable triple (ICS/LABA/LAMA) background therapy for COPD and not as a result of a step down in therapy, i.e. change from triple to dual therapy.
7 Documented use of triple (ICS/LABA/LAMA) background therapy for COPD throughout the year (52 weeks) prior to enrollment2.
(a) ICS dose should be equivalent to ≥500 mcg of fluticasone propionate daily.
(b) 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 triple (ICS/LABA/LAMA) background therapy must not exceed 2 months.
(c) 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 equivalent to ≥500 mcg of fluticasone propionate daily.)
8 Blood eosinophil count ≥300/μL at screening central laboratory testing, supported by at least 1 documented historical blood eosinophil count of ≥150/μL within 52 weeks of enrollment. In the absence of historical data, an additional blood eosinophil count may be
obtained by repeating the testing during the run-in period (at least 4 weeks apart).
9 CAT total score ≥15 at Visit 1.
Reproduction
10 Negative pregnancy test (serum) for female patients of childbearing potential at Visit 1 (enrollment).

11 Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control (confirmed by the investigator) from randomization throughout the study duration and within 16 weeks after last dose of IP. Highly effective forms of birth control include:
o Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation- oral, intravaginal, or transdermal
o Progestogen-only hormonal contraception associated with inhibition of ovulation- oral, injectable, or implantable
o Intrauterine device (IUD)
o Intrauterine hormone-releasing system (IUS)
o Bilateral tubal occlusion
o 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.)
o Vasectomized sexual partner (provided that partner is the sole sexual partner of the WOCBP study patient and that the vasectomized partner has received 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:
o Women treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range. Until FSH or luteinizing hormone (LH) is documented to be within menopausal range, treat the patient as WOCBP.
o Women ≥50 years old will be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment.
Additional eligibility criteria
12 Ability to read, write, and use electronic devices. 

Additional eligibility criteria to be confirmed prior to randomization:
13 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 -15 to -1).
14 At least 70% compliance with the patient’s triple (ICS/LABA/LAMA) background therapy (defined as taking all maintenance medication as scheduled for the day) during the entire run-in period based on the eDiary records.
15 Stable CAT total score during the run-in period, defined as a change in CAT score of ≤3 points compared to the run-in period baseline (i.e. Visit 1) assessment. If a patient demonstrates significant change (>3 points in either direction) in CAT score during the run-in period, the AZ study physician must be consulted to determine the patient's disposition and need for screening extension to further monitor CAT score variability; randomization may not occur without consultation and agreement with AZ study physician/delegate.
16 Stable FEV1 during the run-in period, defined as a change in FEV1 ≤400 mL and/or ≤25% compared to the run-in period baseline (i.e. Visit 1) assessment. If a patient demonstrates significant change (>400 mL and/or >25% in either direction) in FEV1 during the run-in period, the AZ study physician must be consulted to determine the patient's disposition and need for screening extension to further monitor for FEV1 variability; randomization may not occur without consultation and agreement with AZ study physician/delegate.

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).
2 Current diagnosis of asthma according to the Global Initiative for Asthma (GINA) or other accepted guidelines, prior history of asthma, or asthma-COPD overlap.
3 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 findings suggestive of acute infection.
4 Another diagnosed pulmonary or systemic disease that is associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangitis, hypereosinophilic syndrome).

5 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 theinvestigator and/or could:
 Affect the safety of the patient throughout the study
 Influence the findings of the study or their interpretation
 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.
7 Signs and/or symptoms of cor pulmonale and/or right ventricular failure.
8 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.
9 Use, or need for chronic use, of any non-invasive positive pressure ventilation device (NIPPV). Note: Patients using continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the study.
10 History of known immunodeficiency disorder including a positive test for human immunodeficiency virus, HIV-1 or HIV-2.
11 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.
12 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times the upper limit of normal (ULN), confirmed by repeated testing3 during the run-in period. Transient increase of AST/ALT level that resolves by the time of randomization is
acceptable if, in the investigator’s opinion, the patient does not have an active liver disease and meets other eligibility criteria.

13 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.
14 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.
15 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.
16 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.
17 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).
18 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).
19 Scheduled major surgical procedure during the course of the study. Minor elective procedures are allowed.
20 History of anaphylaxis to benralizumab or any other biologic therapy.


Prior/concomitant therapy
21 Receipt of blood products or immunoglobulins within 30 days prior to randomization.
22 Receipt of any marketed or investigational biologic product for any reason within 4 months or 5 half-lives prior to randomization, whichever is longer.
23 Receipt of live attenuated vaccines 30 days prior to randomization.

24 Chronic use of immunosuppressive medication (including but not limited to: methotrexate, troleandomycin, cyclosporine, azathioprine, rectal corticosteroids, and systemic corticosteroids) or expected need for chronic use during the study.
25 Chronic use of antibiotics4 if duration of treatment is Prior/concurrent clinical study experience
26 Receipt of any investigational non-biologic product within 30 days or 5 half-lives prior to enrollment.
27 Receipt of benralizumab within 12 months prior to enrollment.
28 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.
30 Pregnant, breastfeeding, or lactating women.
31 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
32 Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

Interventional

Benralizumab

Benralizumab is a humanized, afucosylated, monoclonal antibody that binds specifically to the human interleukin-5 (IL-5) receptor alpha subunit (IL-5Rα) on the target cell and directly depletes eosinophils through antibody-dependent cell-mediated cytotoxicity. The mechanism of action of benralizumab makes it a potential treatment option for the high unmet need in chronic obstructive pulmonary disease (COPD) patients with eosinophilic inflammation and at risk for exacerbations. Benralizumab is being developed as an add-on maintenance treatment and for prevention of exacerbations in patients with COPD.

Date Amendment Classification Reason
2020-02-10 Amendments related to the protocol Informed consent
2020-10-20 Amendments related to the protocol Informed consent
2021-05-03 Amendments related to the protocol Informed consent
2021-07-06 Changes to investigational medicinal product quality data concerning Changes to Quality IMPD
2021-08-18 Amendments related to the protocol Informed consent

Randomized

Double Blind

Unspecified

Parallel

To evaluate the effect of benralizumab 100 mg on COPD exacerbations in patients with moderate to very severe COPD

Phase III

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