This study has been transitioned to CTIS with ID 2022-503050-39-00 check the CTIS register for the current data. To evaluate the effect of benralizumab 100 mg on COPD exacerbations in patients with moderate to very severe COPD.
ID
Source
Brief title
Condition
- Lower respiratory tract disorders (excl obstruction and infection)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary objective: To evaluate the effect of benralizumab 100 mg on COPD
exacerbations in patients with moderate to very severe COPD.
Primary endpoint: 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
Secondary outcome
Secondary objectives:
- To evaluate the effect of benralizumab 100 mg on severe COPD exacerbations
(leading to hospitalization or death). Variable: Annualized rate of severe COPD
exacerbations a, where a severe COPD exacerbation is defined by symptomatic
worsening of COPD requiring an inpatient hospitalization or results in death
due to COPD.
- To evaluate the effect of benralizumab 100 mg on COPD exacerbations involving
emergency room visits and hospitalizations. Variable: Annualized rate of COPD
exacerbations that are associated with an emergency room/emergency department
visit or a hospitalization due to COPD.
- To evaluate the effect of benralizumab 100 mg on other parameters associated
with COPD exacerbations. Variable: Time to first COPD exacerbation.
- To evaluate the effect of benralizumab 100 mg on health status/health-related
quality of life. Variables: - Change from baseline in SGRQ total a and domain
scores. - Change from baseline in CAT total score.
- To evaluate the effect of benralizumab 100 mg on respiratory symptoms.
Variable: Change from baseline in E-RS:COPD total and domain scores.
- To evaluate the effect of benralizumab 100 mg on pulmonary function.
Variable: Change from baseline in pre-dose/pre-bronchodilator FEV1 at the study
site.
- To evaluate the effect of benralizumab 100 mg on all cause and
respiratory-related mortality. Variable: Mortality rate.
- To evaluate the effect of benralizumab 100 mg on health care resource
utilization due to COPD. Variable: 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.
- To evaluate the pharmacokinetics and immunogenicity of benralizumab in this
patient population. Variables: - Serum benralizumab concentration. -
Anti-benralizumab antibodies
Background summary
Chronic obstructive pulmonary disease (COPD) is a progressive disease and a
significant cause of morbidity and mortality
worldwide. In contrast to other chronic diseases, COPD is increasing in
prevalence and is projected to be the third leading cause of
death and disability worldwide by 2020.
Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the
economic burden of COPD. In addition to a
substantial economic burden, AECOPDs are also responsible for much of the
morbidity and mortality from COPD. Patients with
frequent AECOPD show associated increased airway inflammation and accelerated
decline in lung function compared with patients
with infrequent exacerbations.
Increasing evidence has accumulated in recent years to support the role of
eosinophilic inflammation in COPD. Airway and sputum eosinophilia have been
associated with exacerbations of COPD. Blood eosinophil levels are associated
with COPD exacerbations and likely predict corticosteroid therapy. These data
suggest blood and airway eosinophils may be used to help identify COPD patients
most likely to respond to corticosteroid therapy but also imply that therapies
specifically targeting eosinophils in COPD patients with elevated blood or
airway eosinophils may have beneficial effects.
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. The benralizumab COPD
clinical program consists of a Phase 2a study (identified as MI-CP196),
followed by two Phase 3 studies (identified as GALATHEA [D3251C00003] and
TERRANOVA [D3251C00004]) that evaluated benralizumab in patients with moderate
to very severe COPD with a history of exacerbations despite standard
maintenance therapy with inhaled corticosteroid/long-acting β2 agonist
(ICS/LABA), long acting muscarinic antagonist (LAMA)/LABA (double) or
ICS/LABA/LAMA (triple) across a range of baseline blood eosinophils.
Study objective
This study has been transitioned to CTIS with ID 2022-503050-39-00 check the CTIS register for the current data.
To evaluate the effect of benralizumab 100 mg on COPD exacerbations in patients
with moderate to very severe COPD.
Study design
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 (subject to extension, refer
to Section 4.1.1). 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 4.1.2. 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.
A total of 868 patients are expected to be randomized in the study at a 1:1
ratio to either benralizumab 100 mg SC or matching placebo treatment groups.
Intervention
Subjects will be randomized in a 1:1 ratio to either 100 mg Benralizumab or
placebo administered subcutaneous every four weeks for the first 3 doses and
then every 8 weeks thereafter.
Study burden and risks
Potential risks of benralizumab are as follows:
•Serious infections have been reported for benralizumab. A relationship between
eosinophil depletion and serious infection has not been established.
•Malignancies have been reported at a low incidence in the completed and
ongoing studies of benralizumab. Eosinophils have been found in association
with solid tumors, especially tumors of epithelial origin (breast and colon),
and may play an active role in tumor defense by modulating host defenses, or
may be a bystander effect. However, the cause and consequences (i.e.
pro-tumorigenic versus anti-tumorigenic) of eosinophil recruitment and
accumulation into tumors are unclear.
•Serious hypersensitivity reactions (including anaphylaxis) are an identified
risk of biologic therapy, including benralizumab. Anaphylaxis may be
life-threatening. Risk minimization includes a minimum of a 1 hour observation
period at the clinical site following IP administration for the appearance of
any acute drug reactions.
•Development of anti-drug antibodies (ADA) to benralizumab has been documented.
Theoretical risks of developing ADA may include decreased drug efficacy and
hypersensitivity reactions (e.g. anaphylaxis or immune complex disease). There
was no apparent impact of ADA on overall benralizumab safety or efficacy in the
previous Phase 3 studies in COPD patients.
•Eosinophils are a prominent feature of the inflammatory response to helminthic
parasitic infections, and the presence of infiltrating eosinophils has been
circumstantially associated with a positive prognosis in certain solid tumors.
Therefore, there is a theoretical risk that prolonged eosinophil depletion may
diminish the ability to defend against helminthic parasites or negatively
impact the natural history of certain malignant tumors. Risk minimization
measures include exclusion of patients with untreated parasitic infection and
active or recent malignancy, in conjunction with the performance of routine
pharmacovigilance activities.
Prinses Beatrixlaan 582
Den Haag 2595 BM
NL
Prinses Beatrixlaan 582
Den Haag 2595 BM
NL
Listed location countries
Age
Inclusion criteria
1. Provision of informed consent
2. Age 40 to 85 years
3. Male and/or female.
4. Current or former smoker with a tobacco history of >=10 packyears.
5. History of moderate to very severe COPD with a postbronchodilator
FEV1/FVC<0.70 and FEV1 <=65% of predicted normal value.
6. Documented history of 2 or more COPD exacerbations that required treatment
with systemic corticosteroids and/or hospitalization within 52 weeks prior to
enrollment.
(a) Exacerbations treated with antibiotics alone are excluded unless
accompanied by treatment with systemic corticosteroids and/or hospitalization.
(b) Hospitalization is defined as an inpatient admission >=24 hours
(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/LAMA3) 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) Total cumulative duration of not using inhaled double or being on triple
background therapy must not exceed 2 months.
(c) Stable therapy/doses for the last 3 months prior to randomization.
8. Blood eosinophil count >=300/µL at screening and documented historical
eosinophil count of >=150/µL within 52 weeks of enrollment (or repeated testing
during run-in).
9. CAT total score >=15 at Visit 1.
10. Negative pregnancy test for females of childbearing potential (WOCBP) at
Visit 1.
11. Women of childbearing potential (WOCBP) must agree to use a highly
effective method of birth control from randomization throughout the study and
12 weeks after last dose of IP. Women not of childbearing potential are defined
as women who are either permanently sterilized or postmenopausal (confirmed by
FSH test for women <50 years).
Exclusion criteria
1. Clinically important pulmonary disease other than COPD
2. Current diagnosis of asthma, prior history of asthma or asthma- COPD overlap
according to GINA/GOLD. Childhood history of asthma is allowed and defined as
asthma diagnosed and resolved before theage of 18.
3. Radiological findings of a respiratory disease other than COPD contributing
to respiratory symptoms. Solitary pulmonary nodules without appropriate follow
up or results of acute infection.
4. Another pulmonary or systemic disease associated with elevated peripheral
eosinophil counts.
5. Any unstable disorder that could affect patient safety, study findings or
the patient's ability to complete the study.
6. Any clinically significant abnormal findings in physical examination, vital
signs, ECG, laboratory tests could affect patient safety, study findings or the
patient's ability to complete the study.
7. Cor pulmonale and/or right ventricular failure.
8. Long-term treatment with oxygen >4.0 L/min and/or oxyhemoglobin saturation
<89% while breathing supplemental oxygen.
9. Use of any non-invasive positive pressure ventilation device m(NIPPV). Note:
use of CPAP for Sleep Apnea Syndrome is allowed.
10. Known immunodeficiency disorder, including positive HIV-1/2 testing.
11. Active liver disease. Chronic stable hepatitis B and C (including positive
HBsAg or hepatitis C antibody testing), or other stable chronic liver disease
are acceptable.
12. ALT or AST >=3 times the upper limit of normal, confirmed by repeated
testing during the run-in period.
13. Helminth parasitic infection within 24 weeks prior to enrollment, not
treated or failed to respond to standard of care therapy.
14. Alcohol or drug abuse within the past year, which may compromise the study
data.
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. Evidence of active tuberculosis, as judged by investigator. Patients with a
recent (within 2 years) first-time or newly positive PPD or Quantiferon test
need to complete an appropriate course of treatment before enrollment.
Evaluation will be according to the local standard of care.
17. Participation, or planned participation, in intensive COPD rehabilitation
program (maintenance phase of a rehabilitation is allowed).
18. History of surgical or endoscopic lung volume reduction within the 6 months
prior to enrollment. History of partial or total lung resection (single lobe or
segmentectomy is acceptable).
19. Scheduled major surgical procedure during the study. Minor elective
procedures are allowed.
20. History of anaphylaxis to any biologic therapy or vaccine.
21. Receipt of blood products or immunoglobulins within 30 days prior to
randomization.
22. Receipt of marketed or investigational biologic product within 4months 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.1
23. Receipt of live attenuated vaccines 30 days prior to randomization.
24. Chronic use of immunosuppressive medication or expected need for chronic
use during the study.
25. Chronic use of antibiotics if duration of treatment is <9 months prior to
randomization. Chronic macrolide or other antibiotic therapy is allowed
provided the patient has been on stable dose/regimen for >=9 months prior to
randomization and has had >=2 COPD exacerbations while on stable therapy.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2022-503050-39-00 |
| EudraCT | EUCTR2019-001800-39-NL |
| ClinicalTrials.gov | NCT04053634 |
| CCMO | NL72848.056.20 |