Efficacy and Safety of Benralizumab in Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) with a History of Frequent Exacerbations

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AstraZeneca AB

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

12 Nov 2019 → 28 Jul 2025

Decision date (initial)

2023-07-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2022-503050-39-00

EudraCT number

2019-001800-39

ClinicalTrials.gov

NCT04053634

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Efficacy, Pharmacodynamic, Pharmacogenomic, Safety

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

Secondary objectives 1

1. To evaluate the effect of benralizumab on severe COPD exacerbations (leading to hospitalization or death) - To evaluate the effect of benralizumab on COPD exacerbations involving emergency room visits and hospitalizations - To evaluate the effect of benralizumab on other parameters associated with COPD exacerbations - To evaluate the effect of benralizumab on health status/health-related quality of life - To evaluate the effect of benralizumab on respiratory symptoms - To evaluate the effect of benralizumab on pulmonary function - To evaluate the effect of benralizumab on all cause and respiratory-related mortality - To evaluate the effect of benralizumab on health care resource utilization due to COPD - To evaluate the pharmacokinetics and immunogenicity of benralizumab in this patient population

Conditions and MedDRA coding

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

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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 pack-years.
5. History of moderate to very severe COPD with a post-bronchodilator 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 on stable triple therapy for COPD. (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/LAMA) background therapy for COPD for ≥3 months immediately prior to enrollment. (a) Treatment with at least double inhaled therapy containing ICS 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 (c) Total cumulative duration of not being on double or triple background therapy must not exceed 2 months. (d) 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 enrollment throughout the study and within 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 28

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 findings 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 (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 vaccin
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 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 9

1. Annualized rate of severe COPD exacerbations, where a severe COPD exacerbation is defined by symptomatic worsening of COPD requiring an inpatient hospitalization or results in death due to COPD
2. Annualized rate of COPD exacerbations that are associated with an emergency room/emergency department visit or a hospitalization due to COPD
3. Time to first COPD exacerbation
4. - SGRQ total and domain scores - CAT total score
5. E-RS:COPD total and domain scores
6. Change from baseline in pre-dose/pre-bronchodilator FEV1 at the study site
7. Mortality rate
8. 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
9. - Serum benralizumab concentration - Anti-benralizumab antibodies

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AstraZeneca AB

Sponsor organisation

AstraZeneca AB

Address

Astraallen Gartuna, Karlebyhus Byggnad 674 Karlebyhus Byggnad 674

City

Sodertalje

Postcode

151 85

Country

Sweden

Scientific contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Public contact point

Organisation

AstraZeneca AB

Contact name

AstraZeneca Clinical Study Information Center

Locations

13 EU/EEA countries · 86 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 64 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

26 submissions — initial application plus substantial / non-substantial modifications