CTRI/2023/11/059825 [Registered on: 14/11/2023] Trial Registered Prospectively
Last Modified On:
17/04/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group Trial
Public Title of Study
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
Scientific Title of Study
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)
Trial Acronym
RESOLUTE
Secondary IDs if Any
Secondary ID
Identifier
D3251C00014 VERSION 6.0 Date 06 Feb 2023
Protocol Number
NCT04053634
ClinicalTrials.gov
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Name
Designation
Affiliation
Address
Phone
Fax
Email
Details of Contact Person Scientific Query
Name
Tapankumar M Shah
Designation
Senior Director, Asia Area Cluster Head, Site Management & Monitoring
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road.
Bangalore KARNATAKA 560045 India
Phone
9535104975
Fax
Email
Tapankumar.shah@astrazeneca.com
Details of Contact Person Public Query
Name
Tapankumar M Shah
Designation
Senior Director, Asia Area Cluster Head, Site Management & Monitoring
Affiliation
AstraZeneca Pharma India Ltd.
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road.
KARNATAKA 560045 India
Phone
9535104975
Fax
Email
Tapankumar.shah@astrazeneca.com
Source of Monetary or Material Support
AstraZeneca AB, 151 85 Södertälje, Sweden
Primary Sponsor
Name
AstraZeneca Pharma India Ltd
Address
Block N1, 12th Floor, Manyata Embassy Business Park,
Rachenahalli, Outer Ring Road, Bangalore - 560045,
Karnataka, India
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
AstraZeneca AB
151 85 Södertälje, Sweden
Countries of Recruitment
Argentina Australia Austria Belgium Brazil Bulgaria Canada Chile China Colombia Czech Republic Denmark Germany Greece Hungary India Italy Japan Mexico Netherlands New Zealand Philippines Poland Republic of Korea Spain Sweden Turkey United Kingdom United States of America Viet Nam
Department of Pulmonary Medicine, Ring Road,
Gunadala, PIN - 520008 Krishna ANDHRA PRADESH
9985404458
vasireddyaruna@rediffmail.com
Dr Srikanth Krishnamurthy
Hindusthan Hospital
Department of Pulmonology, Room no. 133, 1st Floor,
522/3, 523/3 Nava India Road, Udaiyampalayam, Coimbatore. PIN 641028, Coimbatore TAMIL NADU
9894257706
drsrikanthcbe@gmail.com
Dr Santhosh Kumar
Institute of Chest Disease, Government Medical College
Department of Pulmonary Medicine, Chest Hospital Building Medical College, Medical College Entrance Road, PIN 673008 Kozhikode KERALA
9847105779
drpvsksanam@gmail.com
Dr Kavitha Chennupalli
Lalitha Super Specialty Hospital
Department of Pulmonology
Gowri Shankar Theater Road, Guntur, PIN-522001, India. Guntur ANDHRA PRADESH
9492039609
kavithachennupalli14@gmail.com
Dr Dhanasekar T
Sri Ramachandra Hospital
Department of TB and Chest Disease
Clinical Research Division,
Dental College Basement,
No.1 Ramachandra Nagar, Porur, PIN-600116
Chennai TAMIL NADU
8939133393
drdhanasekar@gmail.com
Dr Rohit Kumar
Vardhman Mahavir Medical College & Safdarjung Hospital
Room Number 614, Department of Pulmonary Critical Care & Sleep Medicine, Mahatma Gandhi Road, Safdarjung Campus, Ansari Nagar West, New Delhi, Delhi 110029, India. New Delhi DELHI
Benralizumab administered subcutaneously as a single injection via the APFS from W0 to W56
Comparator Agent
Placebo
Placebo administered subcutaneously as a single injection via the APFS from W0 to W56
Inclusion Criteria
Age From
40.00 Year(s)
Age To
85.00 Year(s)
Gender
Both
Details
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.
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 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.
6. 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.
7. 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. 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 must
be obtained by repeating the testing during the run-in period (at least 4 weeks apart).
9. 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).
11. 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.
Additional eligibility criteria to be confirmed prior to randomization (at the last run-in visit):
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 -14 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 run-in period based on the eDiary records.
15. 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.
ExclusionCriteria
Details
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 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.
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 results suggestive of acute infection.
4. Another diagnosed pulmonary or systemic disease associated with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis, 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 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.
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) 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 testing1 during the run-in period. Transient increase of AST/ALT level that resolves by the time of randomization is.
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 any biologic therapy or vaccine.
Prior/concomitant therapy
21. Receipt of blood products or immunoglobulins within 30 days prior to randomization.
22. 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.
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 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.
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
Method of Generating Random Sequence
Stratified randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
To evaluate the effect of benralizumab 100 mg on COPD exacerbations in patients
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
Outcome
TimePoints
To evaluate the effect of benralizumab 100 mg on
severe COPD exacerbations (leading to
hospitalization or death)
Annualized rate of severe COPD exacerbations will be accessed from Randomisation to Visit 17(week 56)
To evaluate the effect of benralizumab 100 mg on COPD exacerbations involving emergency room visits
and hospitalizations
Annualized rate of COPD exacerbations that are
associated with an emergency room/emergency
department visit or a hospitalization due to COPD will be accessed till week 56
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
Change from baseline in CAT total score
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
Mortality rate
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
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
Target Sample Size
Total Sample Size="642" Sample Size from India="20" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a randomized, double-blind,
placebo-controlled, parallel-group, multicenter, Phase 3 study to evaluate the
efficacy and safety of a benralizumab dose administered by subcutaneous
(SC) injection every 4 weeks for the first 3 doses and then every 8 weeks
thereafter (thereafter 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 stable triple (ICS/LABA/LAMA) background therapy for at least 3
months and ICS-based dual inhaled treatment for the remainder of the year.
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; see Section 4.1.3. The primary endpoint will
be analyzed at Week 56.
This Phase 3 study will evaluate the efficacy and
safety of benralizumab in patients with moderate to very severe COPD with
elevated peripheral blood eosinophils and a history of frequent COPD
exacerbations despite receiving triple (inhaled corticosteroid/long-acting β2
agonist/long-acting muscarinic antagonist [ICS/LABA/LAMA]) background therapy.
Approximately 2140 participants will be
screened/enrolled to achieve 642 participants globally.